Phosphite-mediated synthesis of benzimidazoles: A one-pot four-component approach from nitrophenols

Article abstract of DOI:10.1002/ejoc.201100939

Benzimidazoles may be formed in high yield through the phosphite-triggered reductive cyclization of o-nitroaniline derivatives. This reaction was used for the one-pot synthesis of benzimidazoles from o-nitrophenols and isocyanides. The mechanism is discus

Full text of DOI:10.1002/ejoc.201100939

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100939
Phosphite-Mediated Synthesis of Benzimidazoles: A One-Pot Four-Component
Approach from Nitrophenols
Laurent El Kaïm,*[a] Laurence Grimaud,*[a] and Srinivas Reddy Purumandla[a]
Keywords: Cyclization / Nitrogen heterocycles / Fused-ring systems / Multicomponent reactions
Benzimidazoles may be formed in high yield through the
phosphite-triggered reductive cyclization of o-nitroaniline
derivatives. This reaction was used for the one-pot synthesis
of benzimidazoles from o-nitrophenols and isocyanides. The
mechanism is discussed in relation with nitroso intermedi-
ates.
served. We could not find any benzimidazole synthesis
starting from N-alkyl-substituted o-nitroanilines under Ca-
dogan conditions.[10]
Introduction
In the last 20 years the renewed interest for isocyanide
chemistry and isocyanide-based multicomponent reactions
(IMCR)[1] is certainly due to their ability to deliver libraries
of medicinally privileged structures[2] by using fast and ef-
ficient synthetic pathways. Benzimidazoles have been exten-
sively used in medicinal chemistry, displaying antiarrhyth-
mic, antiulcer, anticancer, fungicidal, and antiviral activi-
ties.[3] Following our interest in the multicomponent synthe-
sis of heterocycles, we wished to develop fast, multicompo-
nent access towards these scaffolds from simple nitroarene
derivatives. Benzimidazoles are usually prepared from o-
phenylenediamine derivatives,[4] which may be obtained
from reduction of nitroaniline intermediates. Two direct
paths are reported for the cyclization of N,N-dialkyl-o-ni-
troanilines (Scheme 1). Their thermal dehydration gives ac-
cess to benzimidazole oxides that must be reduced in a fur-
ther step.[5] Metal-catalyzed reductive coupling under CO
pressure[6] is more straightforward, but hampered by high
prices and safety issues. Thinking about a more convenient
Scheme 1. Benzimidazole formation from nitroanilines.
Results and Discussion
To test these hypotheses on a functionalized starting ma-
cyclodehydration towards benzimidazoles, we surmised that terial, Ugi–Smiles adduct 1a was prepared from the corre-
heating the product under reductive conditions with phos- sponding benzylamine, isocyanide, and o-nitrophenol.[11]
phites could lead to benzimidazoles in one step through ni- Compound 1a was then heated under neat conditions with
troso intermediates. Nitroarenes, under treatment with triethyl phosphite at 160 °C for 2 h (Scheme 2). We were
phosphites, are known to form nitroso and nitrene deriva- delighted to observe the formation of benzimidazole 2a in
tives that might insert into various C–H bonds in an intra- a 48% isolated yield. After testing different solvents (aceto-
molecular manner (Cadogan reaction).[7] The Cadogan re- nitrile, toluene, DMF) and temperatures, 1a was isolated in
action usually involves C–H aryl bond insertion, but inter- 69% yield by heating the reaction to reflux in toluene (1 m)
esting couplings with allyl residues (nitroso–ene reaction)[8] by using 12 equiv. of triethyl phosphite. This could be fur-
and N–N or N–P bond formation[9] have also been ob- ther optimized under microwave conditions: heating in
DMF (2 m) at 165 °C for 25 min with P(OEt)3 (8 equiv.)
gave 2a in 80% isolated yield. Both steps, Ugi–Smiles and
phosphite reductive cyclization, could be performed in the
same pot just replacing MeOH by DMF in the second step
with a similar yield (Table 1, Entry 1). This new benzimid-
azole synthesis was tested on several Ugi–Smiles adducts,
as displayed in Table 1, with yields given directly from the
starting o-nitrophenols.
[a] DCSO-UMR 7652: CNRS-ENSTA-Ecole Polytechnique,
Laboratoire Chimie et Procédés,
Ecole Nationale Supérieure de Techniques Avancées,
32 Bd Victor, 75739 Paris Cedex 15, France
Fax: +33-1-45528322
E-mail: laurent.elkaim@ensta-paristech.fr
grimaud@dcso.polytechnique.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100939.
Eur. J. Org. Chem. 2011, 6177–6180
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. El Kaïm, L. Grimaud S. R. Purumandla
SHORT COMMUNICATION
Table 1.One-pot four-component synthesis of benzimidazoles.
Entry
R1
R2
R3
R4
2[a] (Yield)
1
2
3
4
5
6
7
8
Cy
Cy
Cy
4-ClC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
Ph
4-MeOC6H4
4-MeC6H4
2-ClC6H4
2-MeOC6H4
2-furyl
iBu
iBu
Et
Et
H
H
2a (80%)
2b (72%)
2c (83%)
2d (61%)
2e (64%)
2f (72%)
2g (74%)
2h (73%)
2i (60%)
2j (23%)
–
MeO
MeO
MeO
MeO
Me
MeO
MeO
Me
4-ClC6H4CH2
4-MeOC6H4CH2
3,4-(MeO)2C6H3CH2
4-MeOC6H4CH2
CH3(CH2)5
iBu
iBu
Et
Et
iBu
Et
Cy
9
tBu
tBu
Cy
10
11
12
Me(CH2)2
CH2=CH
Cl
H
Cy
iBu
–
[a] Using P(OEt)3 (8 equiv.) in 2 m DMF in the second step.
Scheme 3. Possible mechanism.
formation)[5b] as well as heated under microwave conditions
at 160 °C for 1 h. The recovery of unreacted 1a seems to
indicate that the nitroso path is more likely followed.
All examples given in Table 1 involve aliphatic aldehydes.
When aromatic aldehydes and benzylic amines react to-
gether in the Ugi–Smiles coupling, the presence of two dif-
ferent benzylic positions in the adduct may be associated
with selectivity issues. This was confirmed by the formation
of a mixture of benzimidazoles 2k and 3k when using p-
Scheme 2. Benzimidazole formation from Ugi–Smiles adduct 1a.
The reaction is only efficient with benzylic amino deriva-
tives, as shown by the lack of reactivity of allyl and butyl
adducts (Table 1, Entries 11 & 12). The lower yield obtained
with furfurylamine is due to the formation of important
side products in the second step.
Two mechanistic hypotheses may be advanced for this
phosphite-induced reaction. A thermal dehydration to
benzimidazole oxides followed by reduction by the phos-
phite as pictured in Scheme 1 or a prior reduction to nitroso
derivatives followed by a 1,5-sigmatropic process, cycliza-
tion, and dehydration (Scheme 3).[12]
To give some clues about the mechanism, a solution of
Ugi intermediate 1a in acetic acid was heated at reflux for
several days (conditions reported for benzimidazole oxide Scheme 4. Fate of aromatic aldehydes.
6178 Eur. J. Org. Chem. 2011, 6177–6180
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Phosphite-Mediated Synthesis of Benzimidazoles
chlorobenzaldehyde and a benzylic amine as starting part-
ners (Scheme 4). Product 3k probably results from an inter-
mediate cyclization followed by a final aromatization
through isocyanate release. When the amine component
cannot be involved in the cyclization process, this pathway
is the only one observed, as shown by the exclusive forma-
tion of 3l when starting with butylamine and p-chlorobenz-
aldehyde (Scheme 4).
Acknowledgments
We thank the Centre National de la Recherche Scientifique
(CNRS) and École Nationale Supérieure de Techniques Avancées
(ENSTA) for financial support; S. R. P. thanks the L’Agence Na-
tionale de la Recherche (ANR) (CP2D2008-Muse) for a fellowship.
[1] For some reviews see: a) J. Zhu, H. Bienaymé (Eds.), Multicom-
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Conclusions
As a conclusion, we have disclosed a new phosphite-me-
diated reductive cyclization of o-nitroaniline derivatives
through the activation of the C–H aminobenzylic position.
Combined with a first Ugi–Smiles step, these conditions al-
lowed us to achieve one of the shortest IMCR routes for
access to benzimidazole derivatives from simple commer-
cially available starting materials.[13] We are further studying
the interest of phosphite-triggered reactions in IMCRs.
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Experimental Section
General Procedure for the Synthesis of Benzimidazoles: To a 3 m
solution of carbonyl derivative (1 mmol) in methanol was added
successively benzylamine (1 mmol), isocyanide (1 mmol, 1.0 equiv.),
and o-nitrophenol (1 mmol). The reaction mixture was stirred at
60 °C until completion of the Ugi–Smiles coupling and then cooled
to room temperature. After removing the excess amount of meth-
anol, the crude Ugi–Smiles adduct was used in the next step. To a
2 m solution of Ugi–Smiles adduct (1 mmol) in DMF was added
triethyl phosphite (8 mmol), and the tube was sealed. The mixture
was heated under microwave irradiation (165 °C, 200 W) for
25 min. After completion of the reaction, the excess amount of tri-
ethyl phosphite was removed in vacuo, and the residue was purified
by flash chromatography on silica gel.
2a: The typical procedure was followed employing the isovaleral-
dehyde (107 μL, 1.0 mmol), p-chlorobenzylamine (122 μL,
1.0 mmol), cyclohexylisocyanide (124 μL, 1.0 mmol), o-nitrophenol
(139 mg, 1.0 mmol), and triethyl phosphite (1.37 mL, 8.0 mmol) to
afford compound 2a (338 mg, 80%) as a white solid by flash
chromatography on silica gel. Rf = 0.8 (petroleum ether/diethyl
1
ether, 50:50). M.p. 177–178 °C. H NMR (400 MHz, CDCl3): δ =
7.85 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 8.3 Hz, 2 H), 7.51 (d, J =
8.3 Hz, 2 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.37–7.28 (m, 2 H), 5.84
(br. d, J = 8.3 Hz, 1 H), 5.04 (dd, J = 4.0, 11.1 Hz, 1 H), 3.94–3.83
(m, 1 H), 2.25–2.16 (m, 1 H), 2.12–2.04 (m, 1 H), 1.92–1.82 (m, 2
H), 1.69–1.53 (m, 3 H), 1.40–1.26 (m, 2 H), 1.09–1.00 (m, 2 H),
0.75–0.65 (m, 1 H), 0.89–0.81 (m, 1 H), 0.59 (d, J = 6.3 Hz, 3 H),
0.43 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 168.1, 154.1, 143.6, 136.6, 133.3, 130.5, 129.4, 128.1, 123.6, 123.4,
120.7, 112.3, 59.2, 48.8, 37.9, 33.0, 32.8, 25.2, 24.8, 24.7, 24.4, 22.9,
[9] For a selection: N–N: a) J. I. G. Cadogan, M. Cameron-Wood,
R. K. Mackie, R. J. G. Searle, J. Chem. Soc. 1965, 4831–4837;
b) C. Nyffenegger, E. Pasquinet, F. Suzenet, D. Poullain, C.
Jarry, J.-M. Leger, G. Guillaumet, Tetrahedron 2008, 64, 9567–
9573; N–P: c) R. Haggam, J. Conrad, U. Beifuss, Tetrahedron
Lett. 2009, 50, 6627–6630; d) R. J. Sundberg, J. Am. Chem.
Soc. 1966, 88, 3781–3789.
20.5 ppm. IR (thin film): ν = 3310, 2933, 2857, 1644, 1522, 1477,
˜
1453, 1408, 1369, 1272, 1261, 1091, 1017 cm–1. HRMS: calcd. for
C25H30ClN3O 423.2077; found 423.2074.
[10]
The synthesis of benzimidazoles by heating phosphites with
imines formed between aromatic aldehydes and o-nitroaniline
has been reported: J. I. G. Cadogan, R. Marshall, M. D. M.
Smith, M. J. Todd, J. Chem. Soc. C 1970, 2441–2443.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for all new
compounds.
Eur. J. Org. Chem. 2011, 6177–6180
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. El Kaïm, L. Grimaud S. R. Purumandla
SHORT COMMUNICATION
[11]
ture, we find it convenient to explain the activation of a poorly
acidic CH2 position.
a) L. El Kaïm, L. Grimaud, J. Oble, Angew. Chem. 2005, 117,
8175; Angew. Chem. Int. Ed. 2005, 44, 7961–7164; b) L.
El Kaïm, M. Gizolme, L. Grimaud, J. Oble, J. Org. Chem.
2007, 72, 4169–4180; c) A. Barthelon, L. El Kaim, M. Gizolme,
Eur. J. Org. Chem. 2008, 5974–5987.
[13] For benzimidazole formations using Ugi adducts see ref.[4e–4h]
The closest report of benzimidazole preparation from nitro-
phenol (4g) involves a four-step sequence compared to the pres-
ent two-step synthesis.
[12] Even though such a sigmatropic process of nitroso derivatives
has, to the best of our knowledge, no precedent in the litera-
Received: June 29, 2011
Published Online: September 21, 2011
6180
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Eur. J. Org. Chem. 2011, 6177–6180