Facile Synthesis of N -Substituted Benzimidazoles

Article abstract of DOI:10.1055/s-0035-1562436

A particularly mild and efficient one-pot synthesis of N-substituted benzimidazole derivatives was developed. 2-Fluoro-5-nitrophenylisocyanide reacts with a diverse set of primary amines to afford the respective products in moderate to very good yield (35-95%; 20 examples).

Full text of DOI:10.1055/s-0035-1562436

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
S. Kurhade et al.
Paper
Synthesis
Facile Synthesis of N-Substituted Benzimidazoles
O2N
NH2
Santosh Kurhade
Arianna Rossetti
Alexander Dömling
F
2 steps
60%
University of Groningen, Department of Drug Design,
A. Deusinglaan 1, 9713 AV Groningen,
The Netherlands
O2N
N
F
C
O2N
N
H2N-R
a.s.s.domling@rug.nl
r.t., 16 h
N
R
key isocyanide intermediate
R = alkyl, cycloalkyl,
aryl, heteroaryl
20 examples
35–95% yield
Received: 21.04.2016
Accepted after revision: 04.05.2016
Published online: 23.06.2016
are ligand-specific, require high temperature, show limited
functional group tolerance, and need to be handled very
carefully because they are highly air sensitive. Recently,
Boratyński et al. reported the synthesis of new chiral mono-
benzimidazoles from the reaction between enantiomeric
trans-1,2-diaminocyclohexane and 2-fluoronitrobenzene
in 3–4 steps.7
As our group works extensively on isocyanide-based
chemistry, we hypothesized that the issues described above
could be addressed by using o-fluorophenyl isocyanide in-
stead of o-bromophenyl isocyanide and by placing an elec-
tron-withdrawing functional group such as nitro or cyano
in the ring (especially para to fluoro) in o-fluorophenyliso-
cyanide, capable of undergoing aromatic nucleophilic sub-
stitution.
Thus, we developed a very simple, room-temperature,
one-pot operation to synthesize N-substituted benzimid-
azoles from the reaction between 2-fluoro-5-nitrophenyl-
isocyanide (1) and a diverse set of primary amines 2. The
proposed mechanism involves an aromatic nucleophilic
displacement of fluorine by the primary amine 2 followed
by an intramolecular cyclization.
To test this idea, we had to synthesize 1, which was ex-
pected to be capable of undergoing subsequent nucleophil-
ic aromatic substitution reactions. Thus, starting from 2-
fluoro-5-nitroaniline, we synthesized the corresponding
isocyanide according to Ugi in the classical sequence form-
ylation and dehydration in 60% overall yield (Scheme 1).
DOI: 10.1055/s-0035-1562436; Art ID: ss-2016-z0274-op
Abstract A particularly mild and efficient one-pot synthesis of N-sub-
stituted benzimidazole derivatives was developed. 2-Fluoro-5-nitro-
phenylisocyanide reacts with a diverse set of primary amines to afford
the respective products in moderate to very good yield (35–95%; 20 ex-
amples).
Key words isocyanides, nucleophilic aromatic substitution, benzimid-
azole
The benzimidazole core is of eminent importance par-
ticularly in the field of medicinal chemistry and, based on
its wide range of biological activities, has been classified as
a ‘privileged’ structure.1 Benzimidazole also occurs natural-
ly in N-ribosyl-dimethylbenzimidazole, which serves as an
axial ligand for cobalt in vitamin B12.2 Synthetic analogues
have been prescribed as anthelmintic, anti-inflammatory,
analgesic, anticancer, and vasodilator drugs.3 The classical
benzimidazole synthesis involves the condensation of an
ortho-phenylene diamine with a carboxylic acid or an acy-
lating agent, normally under rather drastic dehydrating
conditions.4 As a side product, 2-substituted benzimidaz-
oles are often formed under these conditions. N-Substitut-
ed benzimidazoles are synthesized either by base-mediated
direct alkylation of benzimidazoles with alkyl/aryl halides
or starting from N-substituted nitroanilines, which were re-
duced and cyclized with orthoformates.5
H
O
An isocyanide-based copper-catalyzed benzimidazole
synthesis has been reported by Lygin and de Meijere. Here
the primary amines add onto an isocyano group of o-bro-
moaryl isocyanide, followed by an intramolecular arylation
of the amidine intermediate to give N-substituted benzim-
idazoles.6 Often these kinds of copper-catalyzed reactions
O2N
N
F
C
O2N
NH2
F
O2N
NH
F
POCl3
Et3N
HCOOH
100 °C
2 h
1
60%
Scheme 1 Synthesis of 2-fluoro-5-nitrophenylisocyanide (1)8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
S. Kurhade et al.
Paper
Synthesis
Table 1 (continued)
O2N
N C
O2N
N
N
O2N
N
N
C
NH2R 2
Product 3
Yield (%)a
75
1
F
H
solvent
NH2
+
r.t., 16 h
NH2
O
S
S
O
3j
2j
O
intermediate
2a
3a
NH2
Scheme 2 Typical synthesis of 3a
78
80
80
N
N
3k
2k
Table 1 Synthesis of Benzimidazole Derivatives 3
NH2
2
2
2
O2N
N
F
C
O2N
N
N
H2N-R
N
N
H
H
r.t., 16 h
3l
2l
1
3
NH2
NH2R 2
Product 3
Yield (%)a
91
OH
3m
OMe
NH2
OH
2m
OMe
NH2
OMe
OMe
62
80
NH2
3a
3b
NH2
Br
2a
3n
2n
NH2
NH2·HBr
90
95
Br
2b
3o
2o
NH2
NH2
NH
NH
O
O
60
O
O
MeO
3c
OMe
MeO
2c
OMe
3p
2p
NH2
NH2
90
90
NHBoc
NHBoc
HO
HO
52c
60c
3d
2d
O
O
O
O
NH2
2q
3q
2
2
S
2NHBoc
OMe
S
2NHBoc
NH2
3e
HO
2e
HO
OMe
3r
2r
HCl·H2N
80
a Isolated yield.
b Reaction conducted with 4-fluroaniline (3.0 equiv) without solvent.
c General Procedure B was followed.
3f
2f
H2N
75
N
N
The reaction of 1 and 4-methoxybenzylamine (2a) in
the presence of triethylamine as base was chosen as a mod-
el system for the optimization of the reaction conditions.
The reaction worked well at room temperature in 14–18
hours in solvents such as CH2Cl2, tetrahydrofuran (THF),
and MeOH. However, the highest yield of 3a (91%) was
achieved with CH2Cl2 (Scheme 2). With the optimized con-
ditions for 3a in hand, a range of N-substituted benzimidaz-
oles 3b–r was synthesized from isocyanide 1 and a diverse
set of primary amines 2b–r (Table 1). In general, all amines
Bn
Bn
2g
3g
3h
3i
H2N
35
2h
H2N
65b
F
F
2i
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

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S. Kurhade et al.
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Synthesis
worked well except guanidine and N-Cbz-guanidine, which
failed to produce the desired product. Clearly, guanidine,
with its extensive delocalized charge and strong π-charac-
ter, is not expected to act like a classical amine.
NMR spectra were recorded with a Bruker Avance 500 spectrometer
[1H NMR (500 MHz), 13C NMR (126 MHz)]. Chemical shifts for 1H NMR
signals are reported as δ values and coupling constants are given in
hertz (Hz). The following abbreviations were used for spin multiplici-
ty: s = singlet, d = doublet, t = triplet, dd = double doublet, m = multi-
plet, br s = broad singlet. Chemical shifts for 13C NMR signals are re-
ported in ppm relative to the solvent peak. Thin-layer chromatogra-
phy was performed with Fluka precoated silica gel plates (0.20 mm
thick, particle size 25 μm). Flash chromatography was performed
with a Teledyne ISCO Combiflash Rf, using RediSep Rf Normal-phase
Silica Flash Columns (silica gel 60 Å, 230–400 mesh). Reagents were
available from commercial suppliers and used without any purifica-
tion unless otherwise noted. Other reagents were purchased from
Sigma Aldrich, ABCR, Acros and AK Scientific and were used without
further purification. Electrospray ionization mass spectra (ESI-MS)
were recorded with a Waters Investigator Semi-prep 15 SFC-MS in-
strument.
Electron-rich benzyl amine 2c, along with n-alkyl
amines 2b, 2d, and 2e, gave the highest yields of benzimid-
azole 3, exceeding those obtained with cycloalkyl amines 2f
and 2g. The lowest yield was observed with 3h (35%) using
adamantyl amine 2h, potentially because of the steric hin-
drance of the bulky adamantane group. Comparatively less
nucleophilic 4-fluoroaniline (2i) was also found to be suit-
able for this conversion, furnishing the corresponding benz-
imidazole 3i (65%) in slightly lower yield. Heterocyclic
amines such as 2-thiophene, 3-pyridine, and indole also
worked well to produce the corresponding benzimidazoles
in generally very good yields.
After very good results from first set of straightforward
amines 2a–l, we investigated the functional group toler-
ance of the reaction. Gratifyingly, the method works well
even in presence of alcohol-containing amines 2m, unpro-
tected diamines for example 1,3-diaminopropane (2n)
(previously we used mono-Boc-protected diamine 2d) as
well as highly reactive bromoalkylamine 2o, producing the
corresponding benzimidazole 3n and 3o, respectively, in
good yields. This methodology also worked well with pro-
tected amino acids such as methyl tryptophan 2p to pro-
duce potentially useful benzimidazole 3p in 60% yield.
Interestingly, when we subjected N- and C-unprotected
amino acids DL-phenylalanine 2q and DL-leucine 2r, the ex-
pected products were formed (Scheme 3). In these cases,
we switched to an aqueous solvent and KOH as a base to
render the zwitterionic amine of the amino acid more nuc-
leophilic. The products 3q (52%) and 3r (60%) were formed
in moderate yield along with methoxy substituted nitro-
phenylisocyanide 4 (20%).
General Procedure A
To a stirred solution of amine (0.66 mmol) in CH2Cl2 (1 mL) were add-
ed successively Et3N (0.66 mmol) and 2-fluoro-5-nitrophenylisocya-
nide (0.60 mmol). The resulting mixture was stirred at r.t. for 16 h.
The solvent was removed under reduced pressure and the residue
was purified by using flash chromatography to obtain the product.
Note: In the case of amine hydrochloride/hydrobromide salts, Et3N
(1.32 mmol) was used.
General Procedure B
To a suspension of amino acid (0.66 mmol) in MeOH (2 mL), KOH
(0.66 mmol) was added and the mixture was stirred at r.t. until com-
plete solubilization of the compound. Then 2-fluoro-5-nitrophenyl-
isocyanide (0.60 mmol) was added and the resulting mixture was
stirred at r.t. for 16 h. The solvent was removed under reduced pres-
sure and the residue was suspended in H2O (3 mL) and acidified to pH
~5 with 1 N aq HCl. The solid precipitate was collected by filtration
and dried under vacuo to obtain the product.
1-(4-Methoxybenzyl)-5-nitro-1H-benzo[d]imidazole (3a)
Obtained by using General Procedure A.
Yield: 0.155 g (91%); off-white solid; mp 137–138 °C.
O2N
N
N
O2N
N
F
C
1H NMR (500 MHz, CDCl3): δ = 8.73 (d, J = 2.0 Hz, 1 H), 8.19 (dd, J = 8.9,
2.1 Hz, 1 H), 8.09 (s, 1 H), 7.36 (d, J = 8.9 Hz, 1 H), 7.15 (d, J = 8.6 Hz,
2 H), 6.90 (d, J = 8.7 Hz, 2 H), 5.34 (s, 2 H), 3.80 (s, 3 H).
1. KOH, MeOH
r.t., 16 h
2. 1 N aq HCl
OH
1
O
13C NMR (126 MHz, CDCl3): δ = 160.02, 146.55, 143.86, 143.53,
+
3q
NH2
OH
138.07, 128.88, 126.22, 118.91, 117.26, 114.77, 110.26, 55.45, 49.13.
+
MS (ESI): m/z calcd for C15H13N3O3: 283.10 [M]+; found: 282.28 [M –
O2N
N
O
C
O
H]+.
2q
4
5-Nitro-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole (3b)
Obtained by using General Procedure A
Scheme 3 Synthesis of 3q from DL-phenylalanine
Yield: 0.109 g (90%); brown solid; mp 120–121 °C.
In conclusion, we have developed a very simple, mild,
and unprecedented one-pot benzimidazole synthesis that
proceeds in moderate to excellent yields. The methodology
offers excellent substrate generality and also demonstrates
tolerance towards a range of reactive functional groups.
Furthermore, the nitro group in the products 3 offers an ad-
ditional handle for further derivatization, for example
through reduction.
1H NMR (500 MHz, CDCl3): δ = 8.74 (d, J = 2.1 Hz, 1 H), 8.29 (dd, J = 8.9,
2.1 Hz, 1 H), 8.21 (s, 1 H), 7.58 (d, J = 8.9 Hz, 1 H), 5.01 (d, J = 2.6 Hz,
2 H), 2.58 (t, J = 2.6 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 145.78, 144.15, 143.46, 137.49,
119.19, 117.38, 110.05, 76.06, 75.06, 35.32.
MS (ESI): m/z calcd for C10H6N3O2: 201.05 [M]+; found: 202.15 [M +
H]+.
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D
S. Kurhade et al.
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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for [C10H7N3O2 + H]+: 202.0611; found:
HRMS (ESI): m/z [M + H]+ calcd for [C18H17N3O3 + H]+: 324.1342;
202.0611.
found: 324.1341.
1-(2,4-Dimethoxybenzyl)-5-nitro-1H-benzoimidazole (3c)
Obtained by using General Procedure A.
1-(1-Benzylpiperidin-4-yl)-5-nitro-1H-benzo[d]imidazole (3g)
Obtained by using General Procedure A.
Yield: 0.179 g (95%); white solid; mp 156–157 °C.
Yield: 0.151 g (75%); brown solid; mp 162–163 °C.
1H NMR (500 MHz, CDCl3): δ = 8.69 (d, J = 1.9 Hz, 1 H), 8.20 (dd, J = 8.9,
2.0 Hz, 1 H), 8.11 (s, 1 H), 7.49 (d, J = 9.0 Hz, 1 H), 7.13 (d, J = 9.0 Hz,
1 H), 6.50–6.42 (m, 2 H), 5.29 (s, 2 H), 3.80 (s, 6 H).
13C NMR (126 MHz, CDCl3): δ = 161.76, 158.58, 147.13, 143.56,
143.19, 138.18, 130.58, 118.59, 116.99, 115.08, 110.17, 104.51, 99.00,
55.52, 55.51, 44.79.
1H NMR (500 MHz, CDCl3): δ = 8.73 (d, J = 2.1 Hz, 1 H), 8.24 (dd, J = 9.0,
2.2 Hz, 1 H), 8.18 (s, 1 H), 7.51 (d, J = 9.0 Hz, 1 H), 7.37–7.34 (m, 4 H),
7.32–7.27 (m, 1 H), 4.26 (hept, J = 10.4, 5.1 Hz, 1 H), 3.61 (s, 2 H),
3.14–3.10 (m, 2 H), 2.29–2.19 (m, 3 H), 2.19–2.13 (m, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 145.89, 142.68, 142.48, 138.21,
137.75, 128.85, 128.14, 126.93, 117.73, 115.68, 111.38, 61.81, 53.37,
51.93, 31.63.
MS (ESI): m/z calcd for C16H15N3O4: 313.11 [M]+; found: 336.17 [M +
Na]+.
MS (ESI): m/z calcd for C19H20N4O2: 336.16 [M]+; found: 337.24 [M +
H]+, 335.03 [M – H]+.
tert-Butyl [3-(5-Nitro-1H-benzo[d]imidazol-1-yl)propyl] Carba-
mate (3d)
1-(Adamantan-1-yl)-5-nitro-1H-1,3-benzodiazole (3h)
Obtained by using General Procedure A.
Obtained by using General Procedure A.
Yield: 0.173 g (90%); brown solid; mp 131–132 °C.
Yield: 0.062 g (35%); brown solid; mp 198 °C (decomp.).
1H NMR (500 MHz, CDCl3): δ = 8.68 (d, J = 2.1 Hz, 1 H), 8.24–8.14 (m,
2 H), 7.45 (d, J = 8.9 Hz, 1 H), 4.86 (br s, 1 H), 4.30 (t, J = 7.0 Hz, 2 H),
3.19 (q, J = 6.5 Hz, 2 H), 2.10 (hept, J = 6.5 Hz, 2 H), 1.43 (s, 9 H).
1H NMR (500 MHz, CDCl3): δ = 8.71 (d, J = 2.3 Hz, 1 H), 8.22 (s, 1 H),
8.17 (dd, J = 9.1, 2.3 Hz, 1 H), 7.77 (d, J = 9.1 Hz, 1 H), 2.40–2.36 (m, J =
2.7 Hz, 9 H), 1.91–1.83 (m, 6 H).
13C NMR (126 MHz, CDCl3): δ = 156.33, 146.74, 143.78, 143.33,
13C NMR (126 MHz, CDCl3): δ = 144.68, 143.67, 143.22, 136.85,
137.93, 118.84, 117.28, 109.69, 43.05, 37.75, 30.69, 28.45.
117.70, 117.36, 113.47, 58.36, 42.23, 36.07, 29.61.
MS (ESI): m/z calcd for C15H20N4O4: 320.14 [M]+; found: 321.24 [M +
MS (ESI): m/z calcd for C17H19N3O2: 297.15 [M]+; found: 298.11 [M +
H]+, 343.29 [M + Na]+.
H]+.
tert-Butyl (2-{[2-(5-Nitro-1H-benzo[d]imidazol-1-yl)eth-
1-(4-Fluorophenyl)-5-nitro-1H-benzo[d]imidazole (3i)
yl]thio}ethyl) Carbamate (3e)
Obtained from 1 (0.6 mmol), Et3N (0.66 mmol), and 4-fluroaniline
Obtained by using General Procedure A.
(3.0 mmol) without solvent.
Yield: 0.198 g (90%); brown solid; mp 120–122 °C.
Yield: 0.100 g (65%); white solid; mp 228–229 °C.
1H NMR (500 MHz, CDCl3): δ = 8.74 (d, J = 2.2 Hz, 1 H), 8.27 (dd, J = 8.9,
2.2 Hz, 1 H), 8.18 (s, 1 H), 7.56 (d, J = 9.0 Hz, 1 H), 4.81 (s, 1 H), 4.47 (t,
J = 6.8 Hz, 2 H), 3.27 (q, J = 6.3 Hz, 2 H), 3.02 (t, J = 6.8 Hz, 2 H), 2.59 (t,
J = 6.9 Hz, 2 H), 1.44 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 155.96, 146.69, 143.91, 143.25,
137.77, 119.02, 117.35, 109.76, 45.42, 40.05, 32.36, 31.65, 28.50,
28.47.
1H NMR (500 MHz, CDCl3): δ = 8.81 (d, J = 2.2 Hz, 1 H), 8.28 (dd, J = 9.0,
2.1 Hz, 1 H), 8.24 (s, 1 H), 7.56–7.47 (m, 3 H), 7.37–7.30 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 161.67 (d, J = 246.4 Hz), 147.57,
143.08 (d, J = 45.4 Hz), 137.71, 131.40 (d, J = 2.7 Hz), 126.82 (d, J =
7.4 Hz), 119.03, 117.01 (d, J = 23.0 Hz), 116.91, 116.07, 111.37 (d, J =
4.8 Hz).
MS (ESI): m/z calcd for C13H8FN3O2: 257.06 [M]+; found: 258.04 [M +
MS (ESI): m/z calcd for C16H22N4O4S: 366.13 [M]+; found: 311.03 [M –
t-Bu]+, 367.29 [M + H]+.
H]+.
5-Nitro-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole (3j)
Obtained by using General Procedure A.
(S)-1-(8-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-nitro-1H-
benzo[d]imidazole (3f)
Yield: 0.117 g (75%); white solid; mp 120–121 °C.
Obtained by using General Procedure A.
1H NMR (500 MHz, CDCl3): δ = 8.73 (d, J = 2.2 Hz, 1 H), 8.24 (dd, J = 8.9,
2.1 Hz, 1 H), 8.14 (s, 1 H), 7.47 (d, J = 9.0 Hz, 1 H), 7.33 (dd, J = 5.1,
1.2 Hz, 1 H), 7.07 (dd, J = 3.6, 1.1 Hz, 1 H), 7.01 (dd, J = 5.1, 3.5 Hz,
1 H), 5.59 (d, J = 0.8 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 146.12, 143.92, 143.41, 137.70,
136.51, 127.55, 127.52, 126.91, 119.03, 117.29, 110.06, 44.27.
Yield: 0.155 g (80%); brown solid; mp 175–176 °C.
1H NMR (500 MHz, CDCl3): δ = 8.75 (d, J = 2.2 Hz, 1 H), 8.26 (dd, J = 9.0,
2.2 Hz, 1 H), 8.12 (s, 1 H), 7.53 (d, J = 8.9 Hz, 1 H), 7.21 (t, J = 7.9 Hz,
1 H), 6.80 (d, J = 7.8 Hz, 1 H), 6.75 (d, J = 8.2 Hz, 1 H), 4.86–4.73 (m,
1 H), 3.82 (s, 3 H), 3.46 (dd, J = 17.4, 5.7 Hz, 1 H), 3.05 (ddd, J = 16.9,
13.8, 8.1 Hz, 2 H), 2.93 (dt, J = 17.2, 5.1 Hz, 1 H), 2.38 (td, J = 7.8,
5.1 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 157.23, 144.32, 143.75, 143.32,
137.67, 135.96, 127.47, 121.74, 121.07, 118.66, 117.30, 110.15,
107.60, 55.38, 52.80, 29.99, 28.63, 27.99.
MS (ESI): m/z calcd for C12H9N3O2S: 259.04 [M]+; found: 260.18 [M +
H]+.
5-Nitro-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazole (3k)
Obtained by using General Procedure A.
MS (ESI): m/z calcd for C18H17N3O3: 323.12 [M]+; found: 324.20 [M +
Yield: 0.119 g (78%); brown solid; mp 146–147 °C.
H]+.
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E
S. Kurhade et al.
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Synthesis
1H NMR (500 MHz, CDCl3): δ = 8.74 (d, J = 2.2 Hz, 1 H), 8.64–8.60 (m,
2 H), 8.21 (dd, J = 8.9, 2.1 Hz, 1 H), 8.15 (s, 1 H), 7.44 (dt, J = 8.0, 2.1 Hz,
1 H), 7.35 (d, J = 8.9 Hz, 1 H), 7.31 (dd, J = 7.9, 4.8 Hz, 1 H), 5.46 (s,
2 H).
MS (ESI): m/z calcd for C10H10BrN3O2: 283.0 [M(79Br) + H]+, 285.0
[M(81Br) + H]+; found: 284.06 [M(79Br) + H]+, 286.01 [M(81Br) + H]+.
Methyl 3-(1H-Indol-3-yl)-2-(5-nitro-1H-benzo[d]imidazol-1-
yl)propanoate (3p)
13C NMR (126 MHz, CDCl3): δ = 150.46, 148.68, 146.37, 144.09,
143.50, 137.74, 134.77, 130.26, 124.18, 119.28, 117.48, 109.99, 47.01.
Obtained by using General Procedure A.
MS (ESI): m/z calcd for C13H10N4O2: 254.08 [M]+; found: 255.20 [M +
Yield: 0.130 g (60%); brown solid; mp 179–180 °C.
H]+, 253.00 [M – H]+.
1H NMR (500 MHz, DMSO-d6): δ = 10.75 (br s, 1 H), 8.60 (s, 1 H), 8.46
(d, J = 2.2 Hz, 1 H), 8.09 (dd, J = 9.0, 2.2 Hz, 1 H), 7.78 (d, J = 9.0 Hz,
1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.23 (d, J = 8.1 Hz, 1 H), 7.03–6.99 (m,
1 H), 6.95–6.91 (m, 1 H), 6.89 (d, J = 2.4 Hz, 1 H), 5.99 (dd, J = 10.4,
5.4 Hz, 1 H), 3.82–3.71 (m, 5 H).
13C NMR (126 MHz, DMSO-d6): δ = 169.74, 147.59, 142.79, 142.14,
138.30, 135.89, 126.65, 123.82, 121.13, 118.59, 118.07, 117.93,
115.67, 115.64, 111.45, 108.17, 58.43, 52.97, 26.78.
1-[2-(1H-Indol-3-yl)ethyl)-5-nitro-1H-benzo[d]imidazole (3l)
Obtained by using General Procedure A.
Yield: 0.147 g (80%); brown solid; mp 241–242 °C.
1H NMR (500 MHz, DMSO-d6): δ = 10.84 (s, 1 H), 8.52 (d, J = 2.2 Hz,
1 H), 8.41 (s, 1 H), 8.14 (dd, J = 9.0, 2.2 Hz, 1 H), 7.79 (d, J = 9.0 Hz,
1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.07 (ddd, J = 8.0,
6.9, 1.2 Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 6.97 (td, J = 7.4, 6.9, 1.0 Hz,
1 H), 4.63 (t, J = 7.2 Hz, 2 H), 3.27 (t, J = 7.1 Hz, 2 H).
MS (ESI): m/z calcd for C19H16N4O4: 364.12 [M]+; found: 365.15 [M +
H]+, 363.26 [M – H]+.
13C NMR (126 MHz, DMSO-d6): δ = 148.18 (d), 142.57, 142.44, 138.30,
136.13, 126.87, 123.35, 121.07, 118.42, 118.12, 117.74, 115.62 (d),
111.42, 111.08, 110.06, 45.41, 25.48.
2-(5-Nitro-1H-benzo[d]imidazol-1-yl)-3-phenylpropanoic Acid
(3q)
MS (ESI): m/z calcd for C17H14N4O2: 306.11 [M]+; found: 307.12 [M +
Obtained by using General Procedure B.
H]+, 305.04 [M – H]+.
Yield: 0.097 g (52%); brown solid; mp 213–214 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.60 (s, 1 H), 8.46 (d, J = 2.3 Hz,
1 H), 8.11 (dd, J = 9.0, 2.2 Hz, 1 H), 7.80 (d, J = 9.1 Hz, 1 H), 7.17–7.04
(m, 5 H), 5.88 (dd, J = 11.1, 5.1 Hz, 1 H), 3.68–3.55 (m, 2 H).
3-(5-Nitro-1H-benzo[d]imidazol-1-yl)-3-phenylpropan-1-ol (3m)
Obtained by using General Procedure A.
Yield: 0.143 g (80%); brown solid; mp 133–135 °C.
13C NMR (126 MHz, DMSO-d6): δ = 170.92, 148.14, 143.17, 142.53,
138.82, 136.80, 129.07, 128.76, 127.19, 118.48, 116.04, 111.87, 59.38,
36.68.
HRMS (ESI): m/z [M + H]+ calcd for [C16H13N3O4 + H]+: 312.0978;
found: 312.0978.
1H NMR (500 MHz, DMSO-d6): δ = 8.96 (s, 1 H), 8.54 (d, J = 2.2 Hz,
1 H), 8.12 (dd, J = 9.0, 2.2 Hz, 1 H), 7.82 (d, J = 9.0 Hz, 1 H), 7.50–7.44
(m, 2 H), 7.39–7.32 (m, 2 H), 7.32–7.25 (m, 1 H), 5.93 (dd, J = 9.0,
6.6 Hz, 1 H), 4.77 (t, J = 4.8 Hz, 1 H), 3.46–3.37 (m, 1 H), 3.35–3.26 (m,
2 H), 2.69 (ddt, J = 14.3, 9.0, 5.5 Hz, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 146.52, 142.86, 142.62, 139.73,
137.95, 128.85, 128.09, 126.77, 118.02, 115.75, 111.56, 57.07, 56.28,
36.50.
4-Methyl-2-(5-nitrobenzoimidazol-1-yl)pentanoic Acid (3r)
Obtained by using General Procedure B.
Yield: 0.100 g (60%); brown solid; mp 182–184 °C.
MS (ESI): m/z calcd for C16H15N3O3: 297.11 [M]+; found: 298.17 [M +
1H NMR (500 MHz, CDCl3): δ = 8.71 (d, J = 2.0 Hz, 1 H), 8.53 (s, 1 H),
8.29 (dd, J = 9.0, 2.0 Hz, 1 H), 7.59 (d, J = 9.1 Hz, 1 H), 5.17 (dd, J = 10.2,
5.5 Hz, 1 H), 2.33–2.24 (m, 1 H), 2.22–2.12 (m, 1 H), 1.53–1.38 (m,
1 H), 0.98 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.6 Hz, 3 H).
H]+, 295.84 [M – H]+.
3-(5-Nitro-1H-benzo[d]imidazol-1-yl)propan-1-amine (3n)
Obtained by using General Procedure A.
13C NMR (126 MHz, CDCl3): δ = 171.92, 145.86, 144.48, 140.00,
Yield: 0.116 g (62%); yellow solid; mp 90 °C (decomp.).
137.35, 119.75, 116.08, 110.95, 57.87, 40.85, 25.04, 22.75, 21.55.
1H NMR (500 MHz, MeOD): δ = 8.54 (d, J = 2.1 Hz, 1 H), 8.47 (s, 1 H),
8.24 (dd, J = 9.0, 2.2 Hz, 1 H), 7.80 (d, J = 9.0 Hz, 1 H), 4.46 (t, J = 7.3 Hz,
2 H), 2.81 (t, J = 7.4 Hz, 2 H), 2.15 (quint, J = 7.3 Hz, 2 H).
MS (ESI): m/z calcd for C13H15N3O4: 277.11 [M]+; found: 278.07 [M +
H]+, 276.12 [M – H]+.
13C NMR (126 MHz, DMSO-d6 + MeOD): δ = 148.60, 143.16, 142.94,
138.65, 118.29, 116.05, 111.44, 42.66, 37.94, 31.85.
Acknowledgment
HRMS (ESI): m/z [M + H]+ calcd for [C10H12N4O2 + H]+: 221.1033;
found: 221.1033.
The work was financially supported by the Innovative Medicines Ini-
tiative Joint Undertaking under Grant Agreement No. 115489, the re-
sources of which are composed of financial contributions from the
European Union’s Seventh Framework Programme (FP7/2007-2013)
and EFPIA companies’ in-kind contribution.
1-(3-Bromopropyl)-5-nitro-1H-benzo[d]imidazole (3o)
Obtained by using General Procedure A.
Yield: 0.136 g (80%); pale-yellow solid; mp 106–107 °C.
1H NMR (500 MHz, CDCl3): δ = 8.74 (d, J = 2.2 Hz, 1 H), 8.27 (dd, J = 8.9,
2.2 Hz, 1 H), 8.14 (s, 1 H), 7.53 (d, J = 8.9 Hz, 1 H), 4.49 (t, J = 6.6 Hz,
2 H), 3.35 (t, J = 5.8 Hz, 2 H), 2.43 (dt, J = 6.6, 5.6 Hz, 2 H).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562436.
13C NMR (126 MHz, CDCl3): δ = 146.54, 143.94, 143.31, 137.83,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

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S. Kurhade et al.
Paper
Synthesis
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