A protocol to 2-aminobenzimidazoles via copper-catalyzed cascade addition and cyclization of o-haloanilines and carbodiimides

Article abstract of DOI:10.1021/jo200014v

An efficient strategy for the synthesis of a variety of 2-animobenzimidazole derivatives has been developed. The reaction proceeded from o-haloanilines and carbodiimides via copper(I)-catalyzed domino reaction in the presence of tert-butoxide to afford the corresponding 2-animobenzimidazole derivatives in good to excellent yields. o-Haloanilines could be o-iodoaniline, o-bromoaniline, and o-chloroaniline derivatives. Carbodiimides could be symmetrical and unsymmetrical substrates with aryl or alkyl substituents. The reaction exhibited a good regioselectivity when unsymmetrical carbodiimides were employed.

Full text of DOI:10.1021/jo200014v

ARTICLE
pubs.acs.org/joc
A Protocol to 2-Aminobenzimidazoles via Copper-Catalyzed Cascade
Addition and Cyclization of o-Haloanilines and Carbodiimides
Fei Wang, Shangjun Cai, Qian Liao, and Chanjuan Xi*
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing 100084, China
S Supporting Information
b
ABSTRACT: An efficient strategy for the synthesis of a variety of
2-animobenzimidazole derivatives has been developed. The reaction
proceeded from o-haloanilines and carbodiimides via copper(I)-catalyzed
domino reaction in the presence of tert-butoxide to afford the correspond-
ing 2-animobenzimidazole derivatives in good to excellent yields. o-
Haloanilines could be o-iodoaniline, o-bromoaniline, and o-chloroaniline
derivatives. Carbodiimides could be symmetrical and unsymmetrical
substrates with aryl or alkyl substituents. The reaction exhibited a good regioselectivity when unsymmetrical carbodiimides were
employed.
’ INTRODUCTION
2-aminobenzimidazoles via copper-catalyzed cascade addition/cycli-
zation of o-haloanilines with various carbodiimides.
2-Aminobenzimidazoles as an important subclass of benzimida-
zoles have attracted much attention due to their varied biological
activities toward numerous diseases (Figure1).1 For example, 2-ami-
nobenzimidazole core structures can be found in commercial drugs
such as astemizole,2 mizolastine,3 and CID-2858522.4 More recently,
2-aminobenzimidazole derivatives were once more reported as factor
Xa (FXa) inhibitors,5 poly(ADP-ribose)polymerase (PARP)
inhibitors,6 and as human cytomegalovirus (HCMV) inhibitors.7
Development of an effective method to construct functionalized
benzimidazole scaffold is thus highly relevant to drug discovery.
Many methods for syntheses of 2-aminobenzimidazole derivatives
have been developed thus far.8 Conventionally, protocols for their
preparation of 2-aminobenzimidazole included the nucleophilic
aromatic substitution (SNAr) reaction of an amino nucleophile with
a 2-halobenzimidazole, which often need high temperature or high
pressure.9 This method was greatly improved subsequently owing to
the development of palladium- and nickel-catalyzed amination.10
Another way to prepare 2-aminobenzimidazoles involved reaction of
benzene-1,2-diamine with thiocyanate11,12 or thiourea.13 Although
these protocols provided access to 2-aminobenzimidazoles, they
suffered limitations in scope and generality. Furthermore, some
protocols proceeded in harsh reaction conditions or low yields.
Recently, one-pot strategies for the synthesis of various useful
heterocyclic compounds based on the copper-catalyzed CꢀX
(X = N, O, and S) bond formation have been studied.14ꢀ16 For
example, benzimidazoles could be efficiently formed via aryl amina-
tion/condensative cyclization processes.14aꢀc More recently, copper-
catalyzed methods enabled the coupling of o-haloanilines with
carbodiimides, which provided a straightforward method to 2-ami-
nobenzimidazoles, although protocol only worked for N,N0-
diphenylcarbodiimide.17 The development of general, cheap
methodology to create 2-aminobenzimidazoles is still desirable.
Herein we would like to report a general and practical route to
’ RESULTS AND DISCUSSION
Initially, we used the o-iodoaniline 1a and N,N0-dicyclohexylcar-
bodiimide (DCC) 2a as the starting materials and CuI as precatalyst,
N,N0-dimethylethane-1,2-diamine (DMEDA) as the ligand, and
Cs2CO3 as base in toluene at 90 °C. Encouragingly, the product
3a was obtained in 23% yield monitored by GC (Table 1, entry 1).
Then different solvents such as 1,4-dioxane, CH3CN, dimethylfor-
mamide (DMF), and dimethyl sulfoxide (DMSO) were screened.
To our delight, the yield greatly increased to 64% when N-methyl-2-
pyrrolidone (NMP) was employed as solvent (entries 2ꢀ6). Next,
the bases were evaluated in the reaction. Clearly, the basicity had a
t
great effect on the reaction. BuONa was superior to Cs2CO3,
K3PO4, DBU, and DABCO (entries 7ꢀ10). Among the ligands
examined in the reaction, N,N,N0,N0-tetramethylethane-1,2-diamine
(TMEDA), 1,10-phenanthroline, L-proline, and 2,20-bipyridine
(entries 11ꢀ14) as ligands showed analogous results. These results
suggested that the ligands might not participate in the reaction at all,
which is a dramatically different effect of a ligand in usually coupling
reactions. Indeed, we were pleased to find that, in the absence of a
ligand, the desired product formed in an excellent yield (entry 15).
The reaction showed a dependence on the temperature. When the
reaction was treated at 70 °C, almost no product formed (entry 16).
On the other hand, without use of CuI, the reaction proceeded to less
than 12% yield (entry 17).
To confirm the structure of the product, colorless single
crystals of 3a suitable for X-ray diffraction analysis were obtained
by recrystallization in dichloromethane/n-hexane (1/1) at room
temperature. The structure of 3a18 clearly shows the formation of
Received: January 5, 2011
Published: March 17, 2011
r
2011 American Chemical Society
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ARTICLE
and 3). Then o-bromoaniline and its derivatives were applied under
the optimized conditions. To our delight, the reaction with o-
bromoanilines could proceed smoothly (entries 4ꢀ5 and 7ꢀ16).
For example, when 2-bromoaniline 1d was treated with DCC 2a
under the optimized conditions, the desired product was obtained in
85% yield at 110 °C (entry 4). Although the desired product was
also afforded at 90 °C for 24 h with 60% yield, some amount of 1d
still remained. The reaction of monosubstituted 2-bromoanilines
with 2a proceeded always in excellent yields regardless of electron-
donating or electron-withdrawing groups linked on the benzene
ring (entries 5, 7ꢀ9, and 15ꢀ16) except for the methoxyl group and
the nitrile group (entries 6 and 17, respectively). When the
substrates with multisubstitution on the benzene ring were used,
the reaction could also proceed well (entries 10ꢀ14). Generally,
substrate 1 tolerated electron-withdrawing groups were a little
favorable in the reaction. When 2-bromopyridin-3-amine was tested
under the reaction condition, the target molecule was not detected
and the starting material remained (entry 18). Subsequently,
2-chloroanilines were tested under the optimized conditions. In
this case, the desired products were obtained in lower yields (entries
19 and 20) even raised the reaction temperature to 120 °C and
prolonged the reaction time to 48 h. When 4-nitro-2-chloroaniline
was treated with 2a, product 1-(2-chloro-4-nitrophenyl)-2,3-dicy-
clohexylguanidine 4 was obtained without ring-closure (entry 21).19
Next, other carbodiimides (Figure 2) were used in the reaction. The
reaction of N,N0-diisopropylcarbodiimide (DIC) 2b could be
performed smoothly and the desired products formed in excellent
yields (entries 22ꢀ26). When N,N0-diphenylcarbodiimide 2c was
used as the substrate, the desired products were obtained with
moderate yields (entries 27ꢀ29). Carbodiimides possessing a
combination of aliphatic and aromatic substituents such as N-cyclo-
hexyl-N0-phenylcarbodiimide 2d, N-butyl-N0-phenylcarbodiimide
2e, N-cyclohexyl-N0-p-tolylcarbodiimide 2f, and N-cyclohexyl-N0-
p-chlorophenyl-carbodiimide 2g were employed, only N-alkyl-1-
aryl-2-aminobenzimidazoles 3uꢀzwere afforded in satisfying yields,
indicating a high regioselectivity for the reaction (entries 30ꢀ35).
With regard to the above presented results, we propose the
following approach for this reaction, which is summarized in
Scheme 1. In the presence of a proper base and copper(I)
catalyst, amine 1 attacks the carbon atom of NCN on carbodii-
mide 2.19 Intermediate 5 could be formed, which undergoes ring-
closure to yield product 3 with elimination of copper halide.20
Preferential cyclization of guanidine occurs from an NH-aryl
rather than an NH-alkyl group.
Figure 1. Examples of some biologically active compounds.
Table 1. Optimization between o-Iodoaniline and N,N0-
Dicyclohexylcarbodiimidea
entry
base
ligand
solvent temp (°C) yield {%)b
1
2
3
4
5
6
7
8
9
Cs2CO3 DMEDA
Cs2CO3 DMEDA
Cs2CO3 DMEDA
Cs2CO3 DMEDA
Cs2CO3 DMEDA
Cs2CO3 DMEDA
toluene
dioxane
CH3CN
DMF
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
70
90
23
21
10
50
27
64
42
15
23
71
76
72
78
86
92
2
DMSO
NMP
K3PO4
DBU
DMEDA
DMEDA
NMP
NMP
DABCO DMEDA
NMP
10 tBuONa DMEDA
11 tBuONa 1,10-phenanthroline NMP
NMP
12 tBuONa L-proline
13 tBuONa 2,20-bipyridine
14 tBuONa TMEDA
15 tBuONa no ligand
16 tBuONa no ligand
17c tBuONa no ligand
NMP
NMP
NMP
NMP
NMP
NMP
’ CONCLUSION
12
a Unless otherwise noted the reactions were performed in a sealed tube
with 1a (0.5 mmol), 2a (0.5 mmol), base (1.0 mmol), CuI (10 mol %),
and ligand (20 mol %) in solvent (1 mL) for 24 h. b The yields were
evaluated by GC with n-dodecane as internal standard. CuI was not
added in the reaction.
We have developed a concise and efficient one-pot method to
synthesize N,1-disubstituted-1H-2-aminobenzimidazoles using CuI
as catalyst under ligand-free conditions. Various N,1-disubstituted-
1H-2-aminobenzimidazoles were conveniently synthesized in good
to excellent yields. The present protocol showed a high regioselec-
tivity when unsymmetrical substrates were employed.
c
the N,1-disubstituted-1H-2-aminobenzimidazoles skeleton, in
which the CdN double bond is within the five-membered ring.
On the basis of these results, the optimal condition involved the
following parameters: CuI as a precatalyst, tBuONa as a base, NMP
as a solvent, and reaction temperature at 90 °C with ligand free.
Under these optimized conditions, a study on the substrate scope
was carried out, and the results are summarized in Table 2. First, we
used o-iodoaniline derivatives 1 to react with 2a. Both methyl group
and fluoro atom on phenyl showed good performance (entries 2
’ EXPERIMENTAL SECTION
General Information. All the reactions were carried out in predried a
screwcapped test tube with a Teflon-lined septum under N2 atmosphere.
Unless otherwise indicated, all materials were obtained from commercial
sources and used as received. DMF, toluene, 1,4-dioxane, NMP, and DMSO
were fresh distilled. Column chromatography was performed on silica gel
(particle size 10ꢀ40 μm). 1HNMRand 13C NMR spectra were recorded on
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Table 2. CuI-Catalyzed One-Pot Reactions of 2-Haloanilines 1 with Carbodiimides 2a
a Unless otherwise noted the reactions were performed in a sealed tube with 1 (0.5 mmol), 2 (0.5 mmol), tBuONa (1.0 mmol), CuI (10 mol %) in NMP
(1 mL) for 24 h. b Isolated yield. c The reaction was monitored by GC-MS but the product was not isolated. d 1-(2-Chloro-4-nitrophenyl)-2,3-
dicyclohexylguanidine 4 was obtained under the reaction conditions.
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31.0, 34.1, 52.0, 54.9, 109.5, 116.5, 118.9, 120.7, 133.4, 142.9, 153.1; GC-MS
(EI, m/z) 297 (Mþ), 214, 133; HRMS calcd for C19H27N3 298.2278 (M þ
H)þ, found 298.2281.
N,1-Dicyclohexyl-6-methyl-1H-2-aminobenzimidazole (3b):
light brown solid, 136 mg (87% yield), mp 209ꢀ211 °C; 1H NMR (300
MHz, CDCl3) δ 1.24ꢀ1.31 (m, 4 H), 1.36ꢀ1.49 (m, 4 H), 1.63ꢀ1.81 (m,
4 H), 1.87ꢀ1.98 (m, 4 H), 2.09ꢀ2.17 (m, 4 H), 2.42 (s, 3 H), 3.77ꢀ3.81
(m, 1 H), 3.92 (br, 2 H, NH, NCH), 6.88 (d, JHꢀH =7.2 Hz, 1 H), 7.04 (s, 1
H), 7.35 (d, JHꢀH = 7.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 21.9,
25.1, 25.5, 25.9, 26.3, 31.0, 34.1, 52.0, 54.8, 110.0, 116.1, 121.7, 128.5, 133.5,
140.6, 153.0; GC-MS (EI, m/z) 311 (Mþ), 228, 147; HRMS calcd for
C20H29N3 312.2434 (M þ H)þ, found 312.2431.
N,1-Dicyclohexyl-6-fluoro-1H-2-aminobenzimidazole (3c):
light brown solid, 145 mg (92% yield), mp 229ꢀ231 °C; 1H NMR (300
MHz, CDCl3) δ 1.21ꢀ1.34 (m, 4 H), 1.40ꢀ1.53 (m, 4 H), 1.64ꢀ1.77 (m,
4 H), 1.87ꢀ1.99 (m, 4 H), 2.03ꢀ2.18 (m, 4 H), 3.74ꢀ3.78 (m, 1 H), 3.92
(br, 1H, NCH), 4.00 (br, 1 H, NH), 6.79(t,JFꢀH =17.8 Hz, JHꢀH =9.3 Hz,
1 H), 6.96 (d, JFꢀH = 8.9 Hz, 1H), 7.33ꢀ7.37 (m, 1H); 13C NMR (75
Figure 2. Varieties of carbodiimides.
Scheme 1. Proposed Reaction Pathway
MHz, CDCl3) δ 25.1, 25.4, 25.9, 26.2, 30.9, 34.0, 52.1, 55.1, 97.2 (d, JFꢀC
=
28.0 Hz), 107.7 (d, JFꢀC = 23.7 Hz), 116.3 (d, JFꢀC = 10.0 Hz), 133.3 (d,
JFꢀC = 12.2 Hz), 139.0, 153.6, 157.5 (d, JFꢀC = 232.3 Hz); GC-MS (EI, m/
z) 315 (Mþ), 232, 151; HRMS calcd for C19H26FN3 316.2184 (M þ H)þ,
found 316.2176.
N,1-Dicyclohexyl-6-bromo-1H-2-aminobenzimidazole (3d):
light brown solid, 154 mg (82% yield), mp 232ꢀ233 °C; 1H NMR (300
MHz, CDCl3) δ 1.19ꢀ1.31 (m, 4 H), 1.35ꢀ1.53 (m, 4 H), 1.64ꢀ1.81 (m,
4 H), 1.87ꢀ1.98 (m, 4 H), 2.02ꢀ2.18 (m, 4 H), 3.74ꢀ3.82 (m, 1 H),
3.91ꢀ3.94 (m, 1 H), 4.06 (s, 1 H, NH), 7.15 (d, JHꢀH = 8.6 Hz, 1 H),
7.27ꢀ7.34 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 25.0, 25.3, 25.8, 26.2,
31.0, 34.0, 52.1, 55.0, 111.4, 112.4, 117.5, 123.7, 134.6, 142.0, 153.5; GC-MS
(EI, m/z) 375 (Mþ), 294, 211; HRMS calcd for C19H26BrN3 376.1383 (M
þ H)þ, found 376.1370.
N,1-Dicyclohexyl-4-bromo-1H-2-aminobenzimidazole (3e):
1
light brown solid, 160 mg (85% yield), mp 89ꢀ90 °C; H NMR (300
MHz, CDCl3) δ 1.24ꢀ1.29 (m, 4 H), 1.41ꢀ1.53 (m, 4 H), 1.62ꢀ1.81 (m,
4 H), 1.87ꢀ2.00 (m, 4 H), 2.05ꢀ2.18 (m, 4 H), 3.80ꢀ3.84 (m, 1 H),
3.95ꢀ4.04 (m, 2H, NH, NCH), 6.82 (t, JHꢀH = 15.8 Hz, JHꢀH = 7.9 Hz, 1
H), 7.17 (d, JHꢀH = 7.9 Hz, 1 H), 7.23 (d, JHꢀH = 7.9 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ 25.0, 25.4, 25.9, 26.2, 31.0, 33.9, 52.0, 55.2, 108.6,
109.8, 119.7, 123.8, 134.0, 141.6, 153.4; GC-MS (EI, m/z) 375 (Mþ), 294,
211; HRMS calcd for C19H26BrN3 376.1383 (M þ H)þ, found 376.1370.
N,1-Dicyclohexyl-4,6-dibromo-1H-2-aminobenzimidazole(3f):
light brown solid, 203 mg (89% yield), mp 182ꢀ183 °C; 1H NMR (300 MHz,
CDCl3) δ 0.83ꢀ0.87 (m, 1 H), 1.18ꢀ1.30 (m, 4 H), 1.40ꢀ1.53 (m, 4 H),
1.64ꢀ1.77 (m, 4 H), 1.86ꢀ2.03 (m, 5 H), 2.13ꢀ2.17 (m, 2 H), 3.73ꢀ3.74
(m, 1 H), 4.02 (br, 2 H, NH, NCH), 7.27 (s, 1 H), 7.36 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 24.9, 25.3, 25.8, 26.1, 30.9, 33.8, 52.0, 55.4, 109.9, 111.0,
111.5, 126.1, 134.7, 141.0, 153.7; GC-MS (EI, m/z) 455 (Mþ), 372, 291;
HRMS calcd for C19H25Br2N3 454.0488 (M þ H)þ, found 454.0482.
N,1-Dicyclohexyl-4-bromo-6-methyl-1H-2-aminobenzi-
midazole (3g): light brown solid, 164 mg (84% yield), mp
a 300 MHz NMR spectrometer at ambient temperature with CDCl3 as the
solvent and TMS as internal standard. Chemical shifts (δ) were given in ppm,
referenced to the residual proton resonance of TMS, to the carbon resonance
of CDCl3 (77.16). Coupling constants (J) were given in hertz (Hz). The
terms m, d, s refer to multiplet, doublet, and singlet. The melting points were
measured on a digital melting point apparatus and were uncorrected. GC-MS
spectra were recorded on GC-MS system and the reaction progress was
monitored by GC. GC yields, using n-dodecane as internal standard, were
obtained in proportion to the integral area of the n-dodecane signal.
General Procedure for the Synthesis of N,1-Disubstituted-1H-
2-aminobenzimidazoles 3. A sealed tube was charged with the mixture
of o-haloaniline 1 (0.5 mmol), tBuONa (1.0 mmol, 0.096 g), CuI (10 mol %,
10 mg), and carbodiimide21 2 (0.5 mmol) then stirred in NMP (1 mL) at
room temperature under nitrogen atmosphere. Half an hour later, the tube
was sealed and the mixture was allowed to stir at 90ꢀ110 °C for 16ꢀ48 h.
After completion of the reaction, the mixture was cooled to room tempera-
ture, then H2O (5 mL) was added and the mixture was extracted with EtOAc
(3 ꢁ 5 mL) and dried by anhydrous Na2SO4. Evaporation of the solvent
followed by purification on silica gel (petroleum ether/ethyl acetate = 3/1 or
dichloromethane/methanol = 100:1 or petroleum ether/ethyl acetate/
triethyamine = 16/4/1) provided the corresponding product 3.
1
175ꢀ177 °C; H NMR (300 MHz, CDCl3) δ 1.18ꢀ1.30 (m, 4 H),
1.35ꢀ1.53 (m, 4 H), 1.63ꢀ1.77 (m, 4 H), 1.86ꢀ1.99 (m, 4 H),
2.04ꢀ2.17 (m, 4 H), 2.39 (s, 3 H), 3.78 (m, 1 H), 3.87ꢀ3.90 (br, 1
H, NH), 4.00 (m, 1 H), 6.96 (s, 1 H), 7.07 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 21.5, 25.0, 25.4, 25.9, 26.2, 31.0, 33.9, 52.0, 55.2, 109.1, 109.3,
124.6, 129.7, 134.1, 139.5, 153.2; GC-MS (EI, m/z) 389 (Mþ), 308, 225;
HRMS calcd for C20H28BrN3 390.1539 (M þ H)þ, found 390.1531.
N,1-Dicyclohexyl-4-bromo-6-chloro-1H-2-aminobenzimida-
zole (3h): light brown solid, 178 mg (87% yield), mp 188ꢀ190 °C; 1H
NMR (300 MHz, CDCl3) δ 1.21ꢀ1.30 (m, 4 H), 1.34ꢀ1.53 (m, 4 H),
1.64ꢀ1.82 (m, 4 H), 1.86ꢀ1.99 (m, 4 H), 2.03ꢀ2.17 (m, 4 H), 3.71ꢀ3.79
(m, 1 H), 4.01 (br, 2 H, NH, NCH), 7.14 (s, 1 H), 7.23 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 24.9, 25.3, 25.8, 26.1, 30.9, 33.8, 52.0, 55.4, 108.8,
N,1-Dicyclohexyl-1H-2-aminobenzimidazole (3a): light brown
solid, 127 mg (88% yield), mp 237ꢀ239 °C; 1H NMR (300 MHz, CDCl3)
δ 1.20ꢀ1.31 (m, 4 H), 1.35ꢀ1.50 (m, 4 H), 1.64ꢀ1.82 (m, 4 H),
1.89ꢀ1.98 (m, 4 H), 2.05ꢀ2.19 (m, 4 H), 3.79ꢀ3.87 (m, 1 H), 3.97
(br, 2 H, NH, NCH), 6.97 (t, JHꢀH = 14.1 Hz, JHꢀH = 7.6 Hz, 1 H), 7.06 (t,
JHꢀH = 14.1 Hz, JHꢀH = 1.9 Hz, 1 H), 7.24 (d, JHꢀH = 8.6 Hz, 1H), 7.48 (d,
JHꢀH = 7.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 25.1, 25.5, 25.9, 26.3,
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109.4, 123.5, 124.2, 134.1, 140.6, 153.9; GC-MS (EI, m/z) 411 (Mþ), 328,
247; HRMS calcd for C19H25BrClN3 410.0993 (M þ H)þ, found
410.0991.
N,1-Dicyclohexyl-6-chloro-4-fluoro-1H-2-aminobenzimidazole
(3i): light brown solid, 154 mg (88% yield), mp 206ꢀ207 °C; 1H NMR
(300 MHz, CDCl3) δ 1.17ꢀ1.30 (m, 4 H), 1.34ꢀ1.50 (m, 4 H),
1.62ꢀ1.81 (m, 4 H), 1.87ꢀ1.97 (m, 4 H), 2.00ꢀ2.16 (m, 4 H),
J
HꢀH = 5.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 20.9, 23.5, 45.5, 46.4,
97.0 (d, JFꢀC = 28.7 Hz), 107.8 (d, JFꢀC = 23.7 Hz), 116.4 (d, JFꢀC = 10.0
Hz), 132.9 (d, JFꢀC = 12.9 Hz), 139.0, 153.6, 157.5 (d, JFꢀC = 231.6 Hz);
GC-MS (EI, m/z) 235 (Mþ), 192, 151; HRMS calcd for C13H18FN3
236.1558 (M þ H)þ, found 236.1562.
N,1-Diisopropyl-4,6-dibromo-1H-2-aminobenzimidazole (3p):
light brown solid, 162 mg (87% yield), mp 155ꢀ156 °C; 1H NMR (300
MHz, CDCl3) δ 1.31 (d, JHꢀH = 6.5 Hz, 6 H), 1.54 (d, JHꢀH = 6.9 Hz, 6 H),
3.97 (s, 1 H, NH),4.27(m,1H),4.33(m,1H),7.26(d,JHꢀH =1.7Hz, 1H),
7.38 (d, JHꢀH =1.7Hz, 1H);13CNMR(75MHz, CDCl3) δ20.9, 23.5, 45.5,
46.8, 110.0, 111.2, 111.3, 126.1, 134.3, 141.1, 153.7; GC-MS (EI, m/z) 375
(Mþ), 333, 291; HRMS calcd for C13H17Br2N3 373.9862 (M þ H)þ, found
373.9867.
3.76ꢀ3.84 (m, 1 H), 4.00 (m, 1 H), 4.13 (s, 1 H, NH), 6.82 (d, JHꢀH
=
10.0 Hz, 1 H), 7.02 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 25.0, 25.3,
25.8, 26.1, 30.8, 33.9, 52.0, 55.2, 106.1, 108.1 (d, JFꢀC = 21.5 Hz), 123.5 (d,
JFꢀC = 10.0 Hz), 129.9 (d, JFꢀC = 15.8 Hz), 136.5 (d, JFꢀC = 11.5 Hz),
151.4 (d, JFꢀC = 248.1 Hz), 153.5; GC-MS (EI, m/z) 349 (Mþ), 266, 185;
HRMS calcd for C19H26ClFN3 350.1794 (M þ H)þ, found 350.1798.
N,1-Dicyclohexyl-4,6-difluoro-1H-2-aminobenzimidazole (3j):
light brown solid, 151 mg (91% yield), mp 196ꢀ197 °C; 1H NMR (300
MHz, CDCl3) δ1.18ꢀ1.29 (m, 4 H), 1.33ꢀ1.51(m, 4H), 1.63ꢀ1.81 (m, 4
H), 1.88ꢀ1.97 (m, 4 H), 2.01ꢀ2.17 (m, 4 H), 3.76ꢀ3.84 (m, 1 H), 3.99 (m,
1 H), 4.05 (s, 1 H, NH), 6.60 (t, JFꢀH = 20.9 Hz, JFꢀH = 10.6 Hz, 1 H), 6.80
(d, JFꢀH =8.9Hz, 1H);13CNMR(75MHz,CDCl3) δ25.0, 25.3, 25.8, 26.1,
30.8, 33.9, 51.9, 55.2, 93.5 (d, JFꢀC =28.7Hz),96.0(dd,JFꢀC =28.0 Hz, JFꢀC
= 22.2 Hz), 127.2 (d, JFꢀC = 15.8 Hz), 135.4 (t, JFꢀC = 25.8 Hz, JFꢀC = 14.3
N,1-Diisopropyl-4,6-difluoro-1H-2-aminobenzimidazole (3q):
light brown solid, 112 mg (89% yield), mp 195ꢀ196 °C; 1H NMR (300
MHz, CDCl3) δ 1.30 (d, JHꢀH = 6.2 Hz, 6 H), 1.55 (d, JHꢀH = 6.3 Hz, 6 H),
4.05 (s, 1 H, NH), 4.28ꢀ4.36 (m, 2 H), 6.61 (t, JFꢀH = 20.6 Hz, JFꢀH = 10.6
Hz, 1 H), 6.78 (d, JHꢀH =8.9Hz, 1H);13CNMR(75MHz, CDCl3) δ20.8,
23.4, 45.4, 46.7, 93.2 (dd, JFꢀC = 28.0 Hz, JFꢀC = 3.6 Hz), 96.1 (dd, JFꢀC
=
28.0 Hz, JFꢀC = 22.2 Hz), 127.2 (d, JFꢀC = 15.8 Hz), 135.1 (dd, JFꢀC = 15.1
Hz, JFꢀC = 12.2 Hz), 151.1 (dd, JFꢀC = 246.7 Hz, JFꢀC = 14.3 Hz), 153.3,
156.6 (dd, JFꢀC = 244.5 Hz, JFꢀC = 10.8 Hz); GC-MS (EI, m/z) 253 (Mþ),
210, 169; HRMS calcd for C13H17F2N3 254.1463 (M þ H)þ, found
254.1460.
Hz), 151.1 (dd, JFꢀC = 247.4 Hz, JFꢀC = 15.1 Hz), 153.4, 156.5 (dd, JFꢀC
=
233.0 Hz, JFꢀC = 10.8 Hz); GC-MS (EI, m/z) 333 (Mþ), 250, 169; HRMS
calcd for C19H25F2N3 334.2089 (M þ H)þ, found 334.2086.
N,1-Dicyclohexyl-6-nitro-1H-2-aminobenzimidazole (3k):
light yellow solid, 106 mg (62% yield), mp 249ꢀ250 °C; 1H NMR (300
MHz, CDCl3) δ 1.22ꢀ1.37 (m, 4 H), 1.43ꢀ1.55 (m, 4 H), 1.67ꢀ1.87
(m, 4 H), 1.94ꢀ2.05 (m, 4 H), 2.07ꢀ2.19 (m, 4 H), 3.85 (m, 1 H,
NCH), 4.02 (m, 1 H, NCH), 4.31 (br, 1 H, NH), 7.39 (d, JHꢀH = 8.9 Hz,
1 H), 8.07 (d, JHꢀH = 8.9 Hz, 1 H), 8.13 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 25.0, 25.3, 25.7, 26.2, 31.1, 33.9, 52.3, 55.5, 105.6, 115.2,
118.4, 132.9, 140.3, 149.2, 156.4; GC-MS (EI, m/z) 342 (Mþ), 259, 178;
HRMS calcd for C19H26N4O2 343.2129 (M þ H)þ, found 343.2125.
N,1-Dicyclohexyl-6-(methoxycarbonyl)-1H-2-aminobenzimida-
zole (3l): white solid, 146 mg (82% yield), mp 218ꢀ219 °C; 1H NMR (300
MHz, CDCl3) δ 1.19ꢀ1.30 (m, 4 H), 1.36ꢀ1.50 (m, 4 H), 1.64ꢀ1.76 (m, 4
H), 1.89ꢀ1.97 (m, 4 H), 2.04ꢀ2.19 (m, 4 H), 3.86ꢀ4.01 (m, 5 H, CH3,
NCH), 4.37 (br, 1 H, NH), 7.43 (d, JHꢀH = 8.2 Hz, 1 H), 7.82 (d, JHꢀH = 8.3
Hz, 1 H), 7.93 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 25.0, 25.2, 25.7, 26.1,
31.0, 33.9, 51.9, 52.1, 54.9, 110.9, 115.4, 120.4, 123.3, 133.2, 147.4, 155.1, 168.2;
GC-MS (EI, m/z) 355 (Mþ), 272, 191; HRMS calcd for C21H29N3O2
356.2333 (M þ H)þ, found 356.2338.
N,1-Diphenyl-1H-2-aminobenzimidazole (3r):17. light brown
solid, 92 mg (65% yield), mp 176ꢀ177 °C; 1H NMR (300 MHz, CDCl3) δ
6.30 (s, 1H, NH), 6.99ꢀ7.09 (m, 3H), 7.17ꢀ7.21 (m, 1 H), 7.30ꢀ7.31(m,
2 H), 7.46ꢀ7.48 (m, 2 H), 7.52ꢀ7.62 (m, 6 H); 13C NMR (75 MHz,
CDCl3) δ 108.4, 117.6, 118.3, 121.0, 122.3, 122.5, 127.5, 129.3, 129.4, 130.8,
134.5, 134.6, 139.3, 142.3, 149.0; GC-MS (EI, m/z) 285 (Mþ), 269, 208.
N,1-Diphenyl-6-methyl-1H-2-aminobenzimidazole (3s):17.
light brown solid, 90 mg (60% yield), mp 196ꢀ198 °C; 1H NMR (300
MHz, CDCl3) δ 2.39 (s, 3 H, CH3), 6.22 (s, 1 H, NH), 6.81 (s, 1 H),
6.98ꢀ7.03 (m, 2 H), 7.25ꢀ7.35 (m, 3 H), 7.48ꢀ7.51 (m, 2 H), 7.61ꢀ7.65
(m, 5 H); 13C NMR (75 MHz, CDCl3) δ 21.7, 108.7, 117.2, 118.1, 118.3,
122.4, 123.4, 127.6, 129.3, 129.5, 130.8, 134.7, 134.7, 139.4, 140.24, 148.7;
GC-MS (EI, m/z) 299 (Mþ), 283, 220.
N,1-Diphenyl-6-fluoro-1H-2-aminobenzimidazole (3t): light
1
brown solid, 109 mg (72% yield), mp 185ꢀ186 °C; H NMR (300
MHz, CDCl3) δ 6.26 (s, 1 H, NH), 6.69ꢀ6.72 (m, 1 H), 6.91 (m, 1 H),
6.99ꢀ7.04 (m, 1 H), 7.25ꢀ7.35 (m, 2 H), 7.46ꢀ7.51 (m, 2 H), 7.54ꢀ7.65
(m, 6 H); 13C NMR (75 MHz, CDCl3) δ 96.0 (d, JFꢀC = 28.0 Hz), 109.5
(d, JFꢀC = 24.4 Hz), 117.8 (d, JFꢀC = 9.3 Hz), 118.2, 122.6, 127.3, 129.3,
129.7, 131.0, 134.1, 134.7 (d, JFꢀC = 12.9 Hz), 138.5, 139.1, 149.5, 158.8 (d,
JFꢀC = 235.2 Hz); GC-MS (EI, m/z) 303 (Mþ), 287, 226; HRMS calcd for
C19H14FN3 304.1245 (M þ H)þ, found 304.1252.
N,1-Diisopropyl-1H-2-aminobenzimidazole (3m): light brown
solid, 94 mg (86% yield), mp 171ꢀ173 °C; 1H NMR (300 MHz, CDCl3) δ
1.31 (d, JHꢀH = 6.5 Hz, 6 H), 1.56 (d, JHꢀH = 6.9 Hz, 6 H), 4.00 (br, 1 H,
NH), 4.27 (m, 1 H), 4.36 (m, 1 H), 6.99 (t, JHꢀH = 15.1 Hz, JHꢀH = 7.6 Hz,
1 H), 7.08 (t, JHꢀH = 15.1 Hz, JHꢀH = 7.2 Hz, 1 H), 7.23 (d, JHꢀH = 7.5 Hz,
1 H), 7.49 (d, JHꢀH = 7.9 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 21.0,
23.6, 45.3, 46.2, 109.3, 116.5, 119.1, 120.8, 133.0, 142.9, 153.0; GC-MS (EI,
m/z) 217 (Mþ), 174, 133; HRMS calcd for C13H19N3 218.1652 (M þ
H)þ, found 218.1657.
N-Cyclohexyl-1-phenyl-1H-2-aminobenzimidazole (3u):
1
light brown solid, 93 mg (64% yield), mp 52ꢀ53 °C; H NMR (300
MHz, CDCl3) δ 1.03ꢀ1.21 (m, 3 H), 1.39ꢀ1.47 (m, 2 H), 1.60ꢀ1.72
(m, 3 H), 2.11ꢀ2.14 (m, 2 H), 3.94ꢀ3.98 (m, 1 H, NCH), 4.05 (s, NH),
6.91ꢀ6.99 (m, 2 H), 7.12 (t, JHꢀH = 6.9 Hz, 1 H), 7.42 (d, JHꢀH = 7.2
Hz, 2 H), 7.47ꢀ7.62 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 25.0,
25.7, 33.8, 51.6, 107.8, 116.3, 119.7, 121.8, 127.0, 128.8, 130.6, 135.0,
135.2, 142.9, 153.0; GC-MS (EI, m/z) 291 (Mþ), 209; HRMS calcd for
C19H21N3 292.1808 (M þ H)þ, found 292.1811.
N,1-Diisopropyl-6-methyl-1H-2-aminobenzimidazole (3n):
light brown solid, 95 mg (83% yield), mp 209ꢀ210 °C; 1H NMR (300
MHz, CDCl3) δ1.30 (d, JHꢀH =6.2 Hz, 6 H), 1.56 (d, JHꢀH =7.2Hz, 6H),
2.42 (s, 3 H), 3.88 (s, 1 H, NH), 4.22(m, 1H),4.34(m, 1H),6.89(d,JHꢀH
=
8.2 Hz, 1 H), 7.03 (s, 1 H), 7.36 (d, JHꢀH = 7.9 Hz, 1 H); 13C NMR (75
MHz, CDCl3) δ 21.0, 21.9, 23.6, 45.3, 46.1, 109.8, 116.1, 121.8, 128.6,
133.2, 140.7, 152.8; GC-MS (EI, m/z) 231 (Mþ), 189, 174, 147; HRMS
calcd for C14H21N3 232.1808 (M þ H)þ, found 232.1802.
N-Cyclohexyl-6-methyl-1-phenyl-1H-2-aminobenzimidazole
(3v): light brown solid, 87 mg (57% yield), mp 75ꢀ76 °C; 1H NMR (300
MHz, CDCl3) δ 1.09ꢀ1.26 (m, 3 H), 1.38ꢀ1.50 (m, 2 H), 1.60ꢀ1.71 (m,
3 H), 2.10ꢀ2.13 (m, 2 H), 2.35 (s, 3 H, CH3), 3.91ꢀ4.01 (m, 2 H, NH,
NCH), 6.72 (s, 1 H), 6.93 (d, JHꢀH = 7.9 Hz, 1 H), 7.39ꢀ7.42 (m, 3 H),
7.51 (d, JHꢀH = 7.2 Hz, 1 H), 7.57ꢀ7.62 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ21.6, 25.0, 25.8, 33.9, 51.7, 108.3, 115.9, 122.8, 127.2, 128.7, 129.5,
130.6, 135.2, 135.4, 140.7, 152.8; GC-MS (EI, m/z) 305 (Mþ), 223; HRMS
calcd for C20H23N3 306.1965 (M þ H)þ, found 306.1971.
N,1-Diisopropyl-6-fluoro-1H-2-aminobenzimidazole (3o):
light brown solid, 105 mg (90% yield), mp 221ꢀ222 °C; 1H NMR (300
MHz, CDCl3) δ1.31(d, JHꢀH = 6.5 Hz, 6 H), 1.55 (d, JHꢀH =6.9 Hz, 6 H),
3.96 (s, 1 H, NH), 4.21 (m, 1 H), 4.31 (m, 1 H), 6.81 (t, JFꢀH = 18.5 Hz,
JHꢀH =10.0 Hz, 1 H), 6.94 (d, JHꢀH =9.3 Hz, 1 H), 7.36 (dd, JFꢀH =8.6 Hz,
3178
dx.doi.org/10.1021/jo200014v |J. Org. Chem. 2011, 76, 3174–3180

The Journal of Organic Chemistry
ARTICLE
N-Cyclohexyl-6-fluoro-1-phenyl-1H-2-aminobenzimidazole
(3w): light brown solid, 87 mg (57% yield), mp 93ꢀ94 °C; 1H NMR (300
MHz, CDCl3) δ 1.09ꢀ1.26 (m, 3 H), 1.38ꢀ1.50 (m, 2 H), 1.60ꢀ1.72 (m,
3 H), 2.10ꢀ2.13 (m, 2 H), 3.90ꢀ3.96 (m, 1 H, NCH), 4.04 (s, 1 H, NH),
6.63 (dd, JFꢀH = 8.6 Hz, JHꢀH = 2.4 Hz, 1 H), 6.80ꢀ6.86 (m, 1 H),
7.38ꢀ7.41 (m, 3 H), 7.48ꢀ7.53 (m, 1 H), 7.57ꢀ7.62 (m, 2 H); 13C NMR
(75 MHz, CDCl3) δ 24.9, 25.7, 33.7, 51.7, 95.6 (d, JFꢀC = 28.7 Hz), 108.7
(d, JFꢀC = 23.7 Hz), 116.3 (d, JFꢀC = 10.0 Hz), 126.9, 129.1, 130.7, 134.6,
135.3 (d, JFꢀC = 12.9 Hz), 138.9, 153.4, 158.1 (d, JFꢀC = 233.8 Hz); GC-
MS (EI, m/z) 309 (Mþ), 227; HRMS calcd for C19H20FN3 310.1714
(M þ H)þ, found 310.1719.
’ REFERENCES
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18, 1918.
N-Butyl-1-phenyl-1H-2-aminobenzimidazole (3x): light brown
oil, 104 mg (79% yield); 1H NMR (300 MHz, CDCl3) δ0.92 (t, JHꢀH =7.2
Hz, 3 H), 1.34ꢀ1.44 (m, 2 H), 1.56ꢀ1.68 (m, 2 H), 3.49ꢀ3.56 (m, 2 H),
4.20 (br, 1 H, NH), 6.90ꢀ7.00 (m, 2 H), 7.12 (m, 1 H), 7.41 (d, JHꢀH = 7.9
Hz, 2 H), 7.48ꢀ7.60 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 13.9, 20.1,
32.0, 43.1, 107.8, 116.4, 119.8, 122.8, 127.0, 128.8, 130.5, 134.9, 135.3,
142.8, 153.7; GC-MS (EI, m/z) 265 (Mþ), 222, 208; HRMS calcd for
C17H19N3 266.1652 (M þ H)þ, found 266.1654.
N-Cyclohexyl-1-p-tolyl-1H-2-aminobenzimidazole (3y):
1
light brown solid, 94 mg (62% yield), mp 48ꢀ50 °C; H NMR (300
MHz, CDCl3) δ 1.12ꢀ1.26 (m, 3 H), 1.43ꢀ1.47 (m, 2 H), 1.60ꢀ1.72
(m, 3 H), 2.09ꢀ2.13 (m, 2 H), 2.46 (s, 3 H, CH3), 3.96 (m, 1 H, NCH),
4.03 (br, 1 H, NH), 6.88ꢀ6.98 (m, 2 H), 7.08ꢀ7.13 (m, 1 H), 7.28 (d,
JHꢀH = 8.2 Hz, 2 H), 7.38 (d, JHꢀH = 8.3 Hz, 2 H), 7.51 (d, JHꢀH = 7.8
Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 21.4, 25.0, 25.8, 33.8, 51.6,
107.8, 116.3, 119.6, 121.7, 126.9, 131.2, 132.2, 135.4, 138.9, 142.9, 153.2;
GC-MS (EI, m/z) 305 (Mþ), 223; HRMS calcd for C20H23N3:
306.1965 (M þ H)þ, found 306.1961.
(5) Zhao, Z. S.; Arnaiz, D. O.; Griedel, B.; Sakata, S.; Dallas, J. L.;
Whitlow, M.; Trinh, L.; Post, J.; Liang, A.; Morrissey, M. M.; Shaw, K. J.
Bioorg. Med. Chem. Lett. 2000, 10, 963.
(6) White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.; Griffin,
R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.; Srinivasan, S.; Golding,
B. T. J. Med. Chem. 2000, 43, 4084.
N-Cyclohexyl-1-(4-chlorophenyl)-1H-2-aminobenzimidazole
(3z): light brown solid, 90 mg (55% yield), mp 65ꢀ66 °C; 1H NMR (300
MHz, CDCl3) δ 1.05ꢀ1.21 (m, 3 H), 1.42ꢀ1.47 (m, 2 H), 1.61ꢀ1.73 (m,
3 H), 2.10ꢀ2.14 (m, 2 H), 3.98 (br, 2 H, NCH, NH), 6.89 (d, JHꢀH = 7.8
Hz, 1 H), 6.98 (m, 1 H), 7.13 (m, 1 H), 7.37 (d, JHꢀH = 8.7 Hz, 2 H), 7.51
(d, JHꢀH = 7.8 Hz, 1 H), 7.57 (d, JHꢀH = 8.7 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 25.0, 25.7, 33.8, 51.7, 107.7, 116.5, 119.9, 122.1, 128.5, 130.9,
133.5, 134.7, 135.0, 142.9, 152.8; GC-MS (EI, m/z) 325 (Mþ), 243; HRMS
calcd for C19H20ClN3 326.1419 (M þ H)þ, found 326.1415.
(7) Zhu, Z.; Lippa, B.; Drach, J. C.; Townsend, L. B. J. Med. Chem.
2000, 43, 2430.
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Matsuo, M. Chem. Pharm. Bull. 1993, 41, 301. (b) Brain, C. T.; Brunton,
S. A. Tetrahedron Lett. 2002, 43, 1893. (c) Senanayake, C. H.; Hong, Y.;
Xiang, T.; Wilkinson, H. S.; Bakale, R. P.; Jurgens, A. R.; Pippert, M. F.;
Butler, H. T.; Wald, S. A. Tetrahedron Lett. 1999, 40, 6875. (d) Hong, Y.;
Senanayake, C. H.; Xiang, T.; Vandenbossche, C. P.; Tanoury, G. J.;
Bakale, R. P.; Wald, S. A. Tetrahedron Lett. 1998, 39, 3121. (e) He, H.-F.;
Wang, Z.-J.; Bao, W. Adv. Synth. Catal. 2010, 352, 2905. (f) Wang, Q.;
Schreiber, S. L. Org. Lett. 2009, 11, 5178. (g) Evindar, G.; Batey, R. A.
Org. Lett. 2003, 5, 133.
2-(2-Chloro-4-nitrophenyl)-1,3-dicyclohexylguanidine (4):
light brown solid, 57 mg (32% yield), mp 163ꢀ164 °C; 1H NMR (300
MHz, CDCl3) δ 1.10ꢀ1.20 (m, 6 H), 1.29ꢀ1.41 (m, 4 H), 1.60ꢀ1.74 (m,
6 H), 2.00ꢀ2.05 (m, 4 H), 3.43 (m, 1 H, NCH), 3.75 (s, 1 H, NH), 6.96 (d,
JHꢀH = 8.6 Hz, 1 H), 8.00 (d, JHꢀH = 8.9 Hz, 1 H), 8.26 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 24.9, 25.6, 33.8, 50.7, 123.5, 123.6, 126.1, 128.3, 141.1,
150.0, 155.0; GC-MS (EI, m/z) 378 (Mþ), 343, 261; HRMS calcd for
C19H27ClN4O2 379.1895 (M þ H)þ, found 379.1893.
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(b) Kawasaki, I.; Taguchi, N.; Yoneda, Y.; Yamashita, M.; Ohta, S.
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’ ASSOCIATED CONTENT
S
Supporting Information. Copies of spectra and the
b
crystallographic data of product 3a. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(12) (a) Snow, R. J.; Butz, T.; Hammach, A.; Kapadia, S.; Morwick,
T. M.; Prokopowicz, A. S.; Takahashi, H.; Tan, J. D.; Tschantz, M. A.;
Wang, X. Tetrahedron Lett. 2002, 43, 7553. (b) Wu, C.-Y.; Sun, C.-M.
Tetrahedron Lett. 2002, 43, 1529.
Corresponding Author
*E-mail: cjxi@tsinghua.edu.cn.
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’ ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (20872076, 20972085, and 21032004) and
by Specialized Research Fund for the Doctoral Program of
Higher Education (200800030072)
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