A one-pot three-component reaction to access 1-alkyl-2-aryl-5- nitrobenzimidazoles under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2010.06.094

A novel and expeditious method to access 1-alkyl-2-aryl-5- nitrobenzimidazoles has been developed. Enlisting solvent-free conditions, 2-fluoro-5-nitroaniline, a primary amine, and substituted aldehyde were melted together in one-pot to generate a variety of 1-alkyl-2-aryl-5- nitrobenzimidazoles.

Full text of DOI:10.1016/j.tetlet.2010.06.094

Tetrahedron Letters 51 (2010) 4459–4461
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Tetrahedron Letters
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A one-pot three-component reaction to access
1-alkyl-2-aryl-5-nitrobenzimidazoles under solvent-free conditions
*
F. Anthony Romero , Remond Moningka
Department of Discovery & Preclinical Sciences, Merck & Co., PO Box 2000, Rahway, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and expeditious method to access 1-alkyl-2-aryl-5-nitrobenzimidazoles has been developed.
Enlisting solvent-free conditions, 2-fluoro-5-nitroaniline, a primary amine, and substituted aldehyde
were melted together in one-pot to generate a variety of 1-alkyl-2-aryl-5-nitrobenzimidazoles.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 24 May 2010
Revised 16 June 2010
Accepted 17 June 2010
Available online 22 June 2010
R1
R1
Benzimidazoles are a widely used motif in drug discovery. In
particular, 1-alkyl-2-aryl-substituted benzimidazoles appear in
numerous patents and publications for a variety of targets. Some
recent examples are inhibitors of HIV replication,1a hedgehog path-
way,1b and histone deacetylases.1c One method to access 1-alkyl-2-
aryl-substituted benzimidazoles is via a multistep process (Scheme
1).1c,2 First, a substituted nitrobenzene undergoes a SNAr (nucleo-
philic aromatic substitution) reaction with a primary amine to af-
ford the substituted nitroaniline. Reduction of the nitro group
followed by benzimidazole formation with the requisite aldehyde
provides the 1-alkyl-2-aryl-benzimidazole.
NO2
LG
NO2
reduction
SNAr
NH2
R2
+
R2
N
H
R3
H
R1
R1
R3
NH2
N
N
O
R2
oxidant
N
H
R2
Scheme 1.
Inconnectionwithadrugdiscoveryprogramwerequiredameth-
od to quickly access a variety of 5-substituted-1-alkyl-2-aryl benz-
imidazoles in a parallel approach. Most of our requisite analogs
could be accessed through a 1-alkyl-2-aryl-5-nitrobenzimidazole.
We chose to start our investigation with 2-fluoro-5-nitroaniline
from which we could potentially derive our requisite compounds.
We initially explored a multistep process as described in Scheme
1, but soon realized that the primary amine addition to 2-fluoro-
5-nitroaniline (1) in the SNAr reaction was not general with some
leading to very little conversion and others taking several days to
complete. In the literature there are not very many examples of SNAr
with compound 1. Examples that are in the literature generally take
at least 48 h to complete and the product is obtained in low yield.1c,3
The poor reactivity of 1 is most likely due to the electron-donating
amino group. One option we did consider was starting with 1,5-dini-
tro-2-fluorobenzene and performing a selective nitro reduction to
the requisite diamino compound after the SNAr with the amine
(Scheme 1, where R1 = 5-nitro and LG = F). As expected the SNAr
reactions proceeded smoothly with a variety of amines, but access
to our final benzimidazoles was tedious since this method required
a selective reduction of the 1-nitro group to the amine followed by
Table 1
Various conditions attempted for the one-pot 1,2-disubstituted benzimidazole
formation
H
O2N
NH2
O2N
N
N
O
F
H3CO
NH2
1
3
OCH3
Entry Solvent Temperature
Time
(h)
Result
1
2
3
4
5
EtOH
DMF
DMSO
NMP
NMP
Reflux
Reflux
160 °C
200 °C
16
16
16
16
2
No reaction
No reaction
No reaction
Partial conversion, 2%
Partial conversion, 5%
100–200 °C
(microwave)
100 °C
6
7
None
None
8
8
Partial conversion,
22%
Complete, 65%
140 °C
* Corresponding author. Tel.: +1 732 594 6040.
E-mail address: anthony_romero@merck.com (F.A. Romero).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.094

4460
F. A. Romero, R. Moningka / Tetrahedron Letters 51 (2010) 4459–4461
Table 3
thebenzimidazole formation. Althoughthismethodwas productive,
we felt that it was not practical for a parallel synthesis method.
We then turned our attention back to our initial investigation
with 2-fluoro-5-nitroaniline (1) because this would ultimately pro-
vide the most straightforward route. We attempted to explore a
one-pot procedure to access the requisite benzimidazoles that
would be highly amenable to a parallel approach. We explored var-
ious conditions by combining 2-fluoro-5-nitroaniline (1), 2-
methoxyethyl amine and benzaldehyde in one-pot using air as
the oxidant.4 Some of the conditions are highlighted in Table 1.
The solvent, temperature, and time were all investigated, but most
conditions gave the unreacted starting material (Table 1, entries 1–
3) or very little product (Table 1, entries 4 and 5: 2% and 5% iso-
lated yield, respectively). Only the starting material and product
were observed in the reaction mixture for entries 4–6. In one of
our last attempts to probe this reaction we combined the above re-
agents neat and heated them to 100 °C for 8 h and partial conver-
sion was observed with an isolated yield of 22%. When the
temperature was raised to 140 °C for 8 h we gratifyingly observed
excellent conversion and an isolated yield of 65%.5
Exploration of various primary amines
H
O
O2N
NH2
F
O2N
N
N
+
R NH2
R
Aldehyde
Entry
Yield (%)
H2N
1
2
3
54
77
57
H2N
H2N
N
H2N
H2N
H2N
4
5
6
60
65
49
OH
OCH3
CN
O
H2N
H2N
7
8
9
65
33
52
N
Table 2
H2N
H2N
Exploration of substituted benzaldehydes
10
74
H
OCH3
O2N
NH2
F
O2N
N
N
H2N
O
11 ortho
12 para
24
57
H2N
H2N
+
OCH3
R
R
13
0
OCH3
Aldehyde
Entry
Yield (%)
H
1 ortho
2 meta
3 para
36
71
40
O
OH
Encouraged by this result, we set out to explore the generality
of this one-pot three-component reaction. The results are summa-
rized in Tables 2 and 3.
H
O
4 ortho
5 meta
6 para
71
63
79
We first explored the scope of the reaction of substituted aryl
aldehydes with 2-fluoro-5-nitroaniline and 2-methoxyethyl amine
(Table 2). It should be noted that while a few substrates (in Tables
2 and 3) required less time and/or lower temperature for comple-
tion, we identified 8 h at 140 °C as the optimal conditions as a gen-
eral parallel synthesis protocol for this reaction. The yield proved
relatively independent of whether the substituent on the benzalde-
hyde was an electron-donating or electron-withdrawing group
that might significantly alter the reactivity (Table 2, entries
1–17). In addition, the placement of this substituent on the benz-
aldehyde (ortho, meta, para) also appeared to not have a significant
effect on the yield of the reaction. Heteroaryl aldehydes worked
equally well (entries 18 and 19). However, alkyl aldehydes (Table
2, entries 20 and 21) do not appear to work under these conditions.
Only the starting material was observed for entries 20 and 21
(Table 2).
Next we turned our attention to investigating various amines
with 2-fluoro-5-nitroaniline and benzaldehyde (Table 3). Both al-
kyl and heteroalkyl amines (entries 1–7) proved successful under
these conditions. Steric bulk close to the amine such as in entry
1 of Table 3 appeared to not have a significant impact on the yield
as compared to the others in the table. While benzyl and heterob-
enzyl amine derivatives (entries 8–12) provided good conversion,
aniline (entry 13) did not and only the unreacted starting material
was observed.
OCH3
NH2
Ph
H
O
7 ortho
8 para
67
77
H
O
9 ortho
10 meta
11 para
72
82
76
H
O
12 ortho
13 meta
14 para
80
89
92
CN
H
O
15 ortho
16 meta
17 para
60
59
70
CF3
H
O
18
72
S
H
O
19
85
N
H
O
20
21
0
0
H
We postulate that the reaction proceeds first through the
SNAr reaction followed by the cyclization with the aldehyde and
O

F. A. Romero, R. Moningka / Tetrahedron Letters 51 (2010) 4459–4461
4461
subsequent air oxidation to the benzimidazole.6 Under inert reac-
tion conditions the reaction does not proceed and only the inter-
mediate SNAr product is isolated. Also, when we run this reaction
under the same conditions without any aldehyde we obtain an
excellent conversion to the substitution product suggesting that
this step occurs first. Currently, we have no explanation as to why
the substitution proceeds readily with 1 without a solvent as com-
pared to with a solvent (even in high concentration; up to 1 M).
In summary, we developed a highly efficient and novel method
to access a wide variety of 1-alkyl-2-aryl-5-nitrobenzimidazoles by
enlisting a solvent-free melt procedure using air as the oxidant.
The reaction is quite versatile and robust with a variety of
functional groups on the amine and the aryl moieties. This method
allowed for an expeditious route to a large library of 1-alkyl-2-aryl-
5-nitrobenzimidazoles without the need of the multistep method
that has been used by others to assemble these types of molecules.
Without the need for solvent or added oxidant, this reaction condi-
tion eliminates solvent waste and is both green and cost-efficient.
Dina, M. S.; Goldsmith, R.; Gould, S. E.; Guichert, O.; Gunzner, J. L.; Halladay, J.;
Jia, W.; Khojasteh, C.; Koehler, M. F. T.; Kotkow, K.; La, H.; LaLonde, R. L.; Lau, K.;
Lee, L.; Marshall, D.; Marsters, J. C.; Murray, L. J.; Qian, C.; Rubin, L. L.; Salphati,
L.; Stanley, M. S.; Stibbard, J. H. A.; Sutherlin, D. P.; Ubhayaker, S.; Wang, S.;
Wong, S.; Xie, M. Bioorg. Med. Chem. Lett. 2009, 19, 5576; (c) Yoakim, C.; Deroy,
P.; Duplessis, M.; Gagnon, A.; Goulet, S.; Hucke, O.; Lemke, C.; Surprenant, S. WO
2008067644, 2008.
2. (a) Goker, H.; Alp, M.; Ates-Alagoz, Z.; Yildiz, S. J. Heterocycl. Chem. 2009, 46, 936;
(b) Portilla, J.; Quiroga, J.; Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo, J.; Mata, E.
G. Synthesis 2008, 387.
3. Barvian, K. K.; Carpenter, A. J.; Cooper, J. P.; Feldman, P. L.; Guo, Y. C.; Handlon, A.
L.; Hertzog, D. L.; Hyman, C. E.; Peat, A. J.; Peckham, G. E.; Speake, J. D.; Swain, W.
R.; Tavares, F. X.; Zhou, H. WO 2004092181, 2004.
4. Example of benzimidazole formation from a phenylenediamine and aldehyde
using air as the oxidant: (a) Li, Y.; Zhao, N.; Wang, Y.-L.; Wang, J.-Y. Henan Shifan
Daxue Xuebao Bianjibu 2008, 36, 92; (b) Abonia, R.; Castillo, J.; Cuervo, P.;
Insuasty, B.; Quiroga, J.; Ortíz, A.; Nogueras, M.; Cobo, J. Eur. J. Org. Chem. 2010,
317.
5. Representative experimental procedure: 2-Fluoro-5-nitroaniline
1 (100 mg,
0.64 mmol), 2-ethanolamine (78.3 mg, 1.28 mmol) and benzaldehyde (136 mg,
1.28 mmol) were all added to a 1 dram vial with a stir bar. The vial was capped
and heated to 140 °C for 8 h. The residue was purified by flash chromatography
(EtOAc/hexanes;
a gradient of 0–100% EtOAc) to yield entry 4 in Table 3
(110 mg, 60%): 1H (CDCl3, 400 MHz) d 8.41 (d, J = 2.0 Hz, 1H), 8.18 (dd, J = 9.0,
2.0 Hz, 1H), 7.81 (m, 2H), 7.58 (d, J = 9.0 Hz, 1H), 7.53 (m, 1H), 7.45 (m, 2H), 4.40
(t, J = 5.1 Hz, 2H), 4.13 (t, J = 5.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) d 158.2,
143.6, 142.4, 141.2, 130.9, 130.4, 130.2, 129.4, 118.4, 115.7, 112.7, 59.9, 48.0.
6. The reaction is run under a sealed vial to prevent the loss of the volatile primary
amine. Although a sealed vial is used, no care is used to exclude air from the
reaction vessel.
References and notes
1. (a) Thaler, F.; Varasi, M.; Gaglidrdi, S.; Colombo, A.; Minucci, S.; Mercurio, C. WO
2009150129, 2009.; (b) Robarge, K. D.; Brunton, S. A.; Castanedo, G. M.; Cui, Y.;