A highly efficient synthesis route for the rapid generation of 1,2,5,6-tetrasubstituted benzimidazoles

Article abstract of DOI:10.1055/s-2008-1077791

Herein we describe the facile generation of novel benzimidazoles starting from 5-chloro-4-iodo-2-nitroaniline. A synthesis protocol was established which allows the parallel synthesis of compound arrays as well as the rapid generation of single representa

Full text of DOI:10.1055/s-2008-1077791

LETTER
1467
A Highly Efficient Synthesis Route for the Rapid Generation of
1,2,5,6-Tetrasubstituted Benzimidazoles
Efficient
S
ö
ynthesis of
1
r
,2,5,6-T
g
etrasubstituted Be
n
J
zimidazol
.
es Duschmalé, Thomas J. Woltering, Konrad H. Bleicher*
F. Hoffmann-La Roche AG, Pharma Research, 4070 Basel, Switzerland
Fax +41(61)6886965; E-mail: konrad.bleicher@roche.com
Received 7 March 2008
Ar
N
N
I
NO2
Abstract: Herein we describe the facile generation of novel benz-
imidazoles starting from 5-chloro-4-iodo-2-nitroaniline. A synthe-
sis protocol was established which allows the parallel synthesis of
compound arrays as well as the rapid generation of single represen-
tatives thereof.
R'''
R'R"N
Cl
NHBoc
R
2
1
Scheme 1 General synthesis route for 1,2,5,6-functionalized benz-
imidazoles 2 starting from Boc-protected 5-chloro-4-iodo-2-nitroani-
line (1).
Key words: benzimidazoles, parallel synthesis, medicinal chemis-
try, palladium coupling, nucleophilic aromatic substitution
NO2
NH2
I
NO2
NH2
(ii), (iii)
Hit discovery and lead generation are key strategies in
modern pharmaceutical research. The identification of
chemical starting points and the subsequent optimization
of those are fundamental activities within medicinal
chemistry.1,2 Besides drug likeness and novelty of a com-
pound class, the chemical tractability is mandatory for
rapid success, particularly in the early stage of a drug dis-
covery program. Benzimidazoles are well-known ele-
ments in nature and thus appear quite frequently in
pharmaceutical products such as astemizole, omeprazole,
or candesartan to name but a few. The chemical synthesis
of the benzimidazole core is well established and has been
reviewed in a number of journals and books.3 We were
looking for a synthesis strategy to generate 1,2,5,6-tetra-
substituted benzimidazoles of type 2 (Scheme 1), based
upon diverse sets of readily available building blocks and
the ability to generate compound arrays using parallel
synthesis technologies. To obtain maximum flexibility for
the array design, the introduction of the different residues
should be possible at any stage of the reaction protocol.
Our contribution herein describes a chemical synthesis
route where an orthogonally functionalized benzene ring
can be regarded as a core structure for the generation of
highly diverse 1,2-phenylenediamines and the resulting
benzimidazole derivatives thereof. Building blocks that
were used for decorating the core scaffold consisted of
alkyl and benzyl halides, primary and secondary amines,
boronic acids, and carboxylic acids.
(i)
1
Cl
Cl
3
4
Scheme 2 Synthesis route for Boc-protected 5-chloro-4-iodo-2-ni-
troaniline (1). Reagents and conditions: (i) ICl, NaOAc, AcOH,
60 °C, 2 h, 99%; (ii) (Boc)2O (2 equiv), DMAP, THF, r.t., 16 h,
quant.; (iii) TFA (2 equiv), CH2Cl2, 0 °C, 3 h, 99%.
when treated with TFA at 0 °C to generate the desired
core structure 1 in high yield and purity.5
Instead of synthesizing full combinatorial arrays, we were
rather looking for reaction protocols that are highly flexi-
ble and allow the rapid follow-up synthesis of singletons.
Therefore we investigated broadly applicable reaction
conditions for the introduction of R, R¢R¢¢N and Ar, al-
ways starting from compound 1.
For the introduction of R an N-alkylation of the Boc-pro-
tected anilide nitrogen was envisaged using alkyl and ben-
zyl halides as building blocks. Due to the high acidity of
this nitrogen, mild bases such as sodium hydride or cesi-
um carbonate can be used for deprotonation. Addition of
the corresponding alkyl or benzyl halides in DMF at room
temperature leads in most cases to full conversions
(Scheme 3). A catalytic amount of KI was added when us-
ing alkyl or benzyl chlorides as starting material.6
I
NO2
Starting from commercially available 5-chloro-2-nitro-
aniline (3) a further point of diversification can be easily
introduced by ICl treatment to generate 5-chloro-4-iodo-
2-nitroaniline (4, Scheme 2).4 Treatment of compound 4
with Boc anhydride leads to the bis-Boc-protected com-
pound which undergoes selective single Boc cleavage
(i)
1
Cl
NBoc
R
5
Scheme 3 Synthesis route for N-alkylation of 1. Reagents and con-
ditions: (i) alkyl or benzyl halide (1 equiv), Cs2CO3 (1 equiv), DMF,
r.t., 16 h.
SYNLETT 2008, No. 10, pp 1467–1470
x
x
.x
x
.2
0
0
8
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1077791; Art ID: G07208ST
© Georg Thieme Verlag Stuttgart · New York

1468
J. J. Duschmalé et al.
LETTER
MeO
Table 1 Yields for Representative Compounds after N-Alkylation
of 1
I
NO2
NO2
(i)
Compound
R
Yield (%)
86
Cl
NHBoc
Cl
NHBoc
*
5a
7
1
O
Scheme 5 Synthesis route for Suzuki coupling of (1). Reagents and
conditions: (i) 4-methoxyphenylboronic acid (1.1 equiv), Pd(PPh3)4
(0.02 equiv), aq Na2CO3 soln, DMF, 80 °C, 16 h.
5b
5c
98
95
*
Cl
DMF under elevated temperature using tetrakis(triphen-
ylphosphine)palladium as a catalyst.8 Complete conver-
sion to compound 7 was observed by LC-MS.
*
Three representative compounds 5a–c are depicted in
Table 1. The yields reported correspond to products iso-
lated via silica gel chromatography.
Full conversion and satisfactory yields are also observed
with the chlorine being substituted with sterically more
demanding residues as exemplified in Table 3
(Scheme 6). Here the Suzuki coupling was performed af-
ter the introduction of R¢R¢¢N. For library production a
proper purification is not really necessary. The represen-
tative compounds shown in Table 4 were purified though
via crystallization to report the corresponding yields.
For the introduction of N-nucleophiles at position 5 of
compound 1 a rapid and high-yielding conversion to inter-
mediate 6 (Scheme 4) is observed when treating com-
pound 1 with an excess of the corresponding amine
R¢R¢¢NH in DMSO at elevated temperature (80 °C). The
conversions observed are usually quantitative. Addition
of water results in the precipitation of the products. No
further purification is necessary although we crystallized
the resulting material from MeOH to be able to report
proper yields.7
Ar
NO2
(i), (ii)
1
R'R"N
NHBoc
8
Scheme 6 Synthesis route for 4,5-bis-substituted-2-nitroanilines.
Reagents and conditions: (i) R¢R¢¢H (5 equiv), DMSO, 80 °C 2 h; (ii)
ArB(OH)2 (1.1 equiv), Pd(PPh3)4 (0.02 equiv), aq Na2CO3 soln,
DMF, 80 °C, 16 h.
I
NO2
I
NO2
(i)
R'R"N
NBoc
Cl
NBoc
1
6
Table 3 Yields for Representative Compounds after Suzuki Cou-
plings and Crystallization from MeOH or MeCN
Scheme 4 Synthesis route for nucleophilic displacement of chlorine
in 1. Reagents and conditions: (i) primary or secondary amine (5
equiv), DMSO, 80 °C, 3 h.
Compound
R¢R¢¢N
Ar
Yield (%)
78a
Cl
Table 2 summarizes three representative compounds 6a–
c generated via SNAr displacement reactions.
8a
O
N
*
*
Table 2 Yields for Representative Compounds after SNAr Reaction
of 1
8b
8c
65a
78b
N
*
*
Compound
RN
Yield (%)
87
H
N
O
*
*
6a
O
N
*
a Crystallization from MeOH.
b Crystallization from MeOH.
6b
6c
98
96
N
*
Various procedures have been established for the reduc-
tion of nitrobenzenes. For our purposes we felt that the
Zn-powder method was most appropriate since it is a high
yielding reaction, which tolerates many functional groups
and can be handled reasonably well in a parallel synthesis
set-up.9
H
N
*
Although the chlorine atom is highly activated due to the
para-nitro group present in the benzene ring system, bo-
ronic acid couplings can be achieved selectively when us-
ing mildly basic conditions (aq Na2CO3 soln). This is
exemplified in Scheme 5 were the corresponding Suzuki
product was generated successfully in an 88% yield after
silica gel chromatography. The reaction was performed in
Concerning the acylation step we investigated various
coupling reagents where HATU was identified to deliver
the best results. Besides the rapid reaction kinetics, it can
also easily be removed by an additional extraction step.10
Synlett 2008, No. 10, 1467–1470 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of 1,2,5,6-Tetrasubstituted Benzimidazoles
1469
MeO
Boc cleavage with neat TFA leads to clean monoacylated
1,2-phenylenediamines which partially cyclize to the cor-
responding benzimidazoles. Complete conversion is ob-
tained after TFA evaporation, dissolution in acetic acid
and heating to 80 °C for two hours (for library production
we extended the reaction time to 16 h).11
N
N
(i)–(vii)
Cl
1
N
10
Based on the findings mentioned above various synthesis
routes can be envisaged to create the corresponding com-
pound arrays. We generated a sublibrary with R being H
since the H-bonding capability of the benzimidazole moi-
ety was required based on the pharmacophore hypothesis
available. Therefore a reaction sequence was chosen start-
ing from 1 with SNAr reactions, followed by Suzuki cou-
plings to generate intermediates of type 8. Reduction,
acylation, and cyclization lead to the corresponding benz-
imidazoles as shown in Scheme 7.
Scheme 8 Synthesis route for 1,2,5,6-tetrasubstituted-benzimidazo-
les. Reagents and conditions: (i) ethyl iodide (1 equiv), Cs2CO3 (1
equiv), DMF, r.t., 16 h; (ii) pyrrolidine (5 equiv), DMSO, 80 °C, 2 h;
(iii) 4-methoxyphenylboronic acid (1.1 equiv), Pd(PPh3)4 (0.02
equiv), aq Na2CO3 soln, DMF, 80 °C, 16 h; (iv) Zn powder, sat.
NH4Cl, MeOH, r.t., 16 h; (v) 4-chlorobenzoic acid (1.1 equiv), HATU
(1.1 equiv), DIPEA (1.1 equiv), DMF, r.t. 1 h; (vi) TFA, r.t., 2 h; (vii)
AcOH, 80 °C, 16 h.
action mixtures. Starting from 1 mmol of 1 we were able
to isolate 32% of product 10 after silica gel chromatogra-
phy (average 85% yield per step).
Cl
Using the reaction protocols described above, we were not
only able to generate highly diverse subsets of compound
arrays, but rather respond very quickly to the biological
and physicochemical data obtained from the first libraries.
Additionally, further benzoannelated heterocycles such as
benzimidazolones, 1,4-dihydroquinoxaline-2,3-diones,
and 1,3-dihydrobenzodiazepin-2-ones were successfully
N
(i)–(iv)
R"'
8a
N
N
H
O
9
Scheme 7 Synthesis route for 2,5,6-trisubstituted-benzimidazoles.
Reagents and conditions: (i) Zn powder, sat. NH4Cl, MeOH, r.t., 16
h; (ii) RCOOH (1.1 equiv), HATU (1.1 equiv), DIPEA (1.1 equiv), prepared from the corresponding 1,2-phenylenediamines
DMF, r.t. 1 h; (iii) TFA, 2 h; (iv) AcOH, 80 °C, 16 h.
obtained from 8. Their detailed chemical syntheses and
the corresponding biological activities will be reported in
due course.
Table 4 summarizes three representative compounds 9a–
c generated from the corresponding nitroaniline 8a via ni-
troreduction, N-acylation, Boc cleavage, and cyclization
reactions to their corresponding benzimidazoles. The re-
coveries mentioned below summarize the last four reac-
tion steps after purification via preparative HPLC. The
yields for the single reaction steps are not reported sepa-
rately since these chemical transformations usually pro-
ceed very smoothly under full conversion to the
corresponding products.
References and Notes
(1) Bleicher, K. H.; Nettekoven, M.; Peters, J.-U.; Wyler, R.
Chimia 2004, 58, 588.
(2) Bleicher, K. H.; Boehm, H.-J.; Mueller, K.; Alanine, A.
Nature Rev. Drug Discov. 2003, 2, 396.
(3) Imidazole and Benzimidazole Synthesis; Ross Grimmett, M.,
Ed.; Academic Press: London, 1997.
(4) Wilson, J. G.; Hunt, F. C. Austr. J. Chem. 1983, 36, 2317.
(5) (a) Adam, G.; Alanine, A.; Goetschi, E.; Mutel, V.;
Woltering, T. J. WO 2001029011, 2001; Chem. Abstr. 2001,
134, 311234. (b) Adam, G.; Goetschi, E.; Mutel, V.;
Wichmann, J.; Woltering, T. J. WO 2002083652, 2002;
Chem. Abstr. 2002, 137, 325447.
Table 4 Yields for Representative Compounds after Preparative
HPLC
Compound
R¢¢¢
Yield (mg/%) Yield (%)
(6) General Procedure for N-Alkylation Reactions
(5-Chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl
ester (1, 1 mmol) was dissolved in DMF (10 mL) and
alkylating agent (1 equiv) and Cs2CO3 was added. In case of
benzyl chlorides, a catalytic amount of KI was added. The
reaction mixture was stirred at r.t. overnight. After
evaporation of the solvent, the crude was taken up in EtOAc
and extracted with a sat. NaHCO3 solution. The residue
could be purified by column chromatography using SiO2 or
used directly in the following step.
9a
30
52
47
62
*
N
N
N
9b
9c
*
67
76
*
(7) General Procedure for Nucleophilic Displacement
To exemplify the feasibility for rapid singleton synthesis
of such tetrasubstituted benzimidazoles we generated
compound 10 in seven steps starting from compound 1
where only the product was isolated properly (Scheme 8).
All crude intermediates were recovered from simple fil-
tration after ice-water treatment of the corresponding re-
Reactions
(5-Chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl
ester (1, 10 mmol) was dissolved in DMSO and amine (5
equiv) added. The reaction mixture was stirred at 80 °C for
3 h. After addition of H2O, the product precipitated from the
solution and was filtered off, washed twice with H2O and
dried under vacuum. The residue could be purified by
Synlett 2008, No. 10, 1467–1470 © Thieme Stuttgart · New York

1470
J. J. Duschmalé et al.
LETTER
purified by column chromatography using SiO2 or used
crystallization from MeOH or used directly in the following
step.
directly in the following step.
(8) General Procedure for Suzuki Coupling Reactions
(5-Chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl
ester (1, 2 mmol) was dissolved in DMF. Then, arylboronic
acid (1.1 equiv), tetrakis(triphenylphosphine)-palladium
(0.02 equiv), and sat. Na2CO3 solution (1.5 mL) were added.
The reaction mixture was heated to 80 °C overnight. The
crude product was extracted from EtOAc–H2O. The residue
could be purified by crystallization from MeOH or MeCN or
used directly in the following step.
(10) General Procedure for Acylation Reactions
The corresponding anilines were dissolved in DMF and
added to a mixture of carboxylate (1 equiv), HATU, and
DIPEA. The reaction mixture was stirred at r.t. for 2 h. The
solvent was evaporated and the resulting residue taken up in
EtOAc and extracted with aq NaHCO3. The crude product
was not further purified.
(11) General Procedure for Cyclization Reactions
The crude products from the previous step were treated with
neat TFA and stirred at r.t. for 2 h. Depending on the residues
introduced, partial cyclization to the corresponding
benzimidazole was observed. Full conversion was obtained
after evaporation of the TFA, dissolution of the mixture in
AcOH and heating to 80 °C overnight. All final library
products were isolated by preparative HPLC and
characterized via LC-MS.
(9) General Procedure for Nitro Reductions
The corresponding nitroanilines were suspended in a
mixture of MeOH and sat. aq NH4Cl (2:1). An excess of zinc
powder was added and the reaction mixture stirred at r.t.
overnight. The remaining solid was filtered off. After
evaporation of the organic solvent, EtOAc was added and
the crude product extracted with H2O. The residue could be
Synlett 2008, No. 10, 1467–1470 © Thieme Stuttgart · New York

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