Ytterbium triflate promoted synthesis of benzimidazole derivatives

Article abstract of DOI:10.1055/s-2004-829555

Differently substituted benzimidazoles have been synthesised in very good yields in solvent-free conditions from o-phenylenediamine and aldehydes in the presence of Yb(OTf)₃ as catalyst. The method is applicable to aromatic, unsaturated and aliphatic aldehydes and to substituted o-phenylenediamines without significant differences.

Full text of DOI:10.1055/s-2004-829555

1
832
LETTER
Ytterbium Triflate Promoted Synthesis of Benzimidazole Derivatives
Y
M
tterbium Triflate Pro
a
moted Synt
s
hesis of
B
s
enzimidaz
i
ole De
m
r
ivatives o Curini,* Francesco Epifano, Francesca Montanari, Ornelio Rosati, Sara Taccone
Dipartimento di Chimica e Tecnologia del Farmaco – Sezione di Chimica Organica, Università di Perugia, Via del Liceo, 06123 Perugia,
Italy
Fax +39(075)5855116; E-mail: curmax@unipg.it
Received 24 March 2004
the utility of lanthanide triflates-catalyzed reactions in
Abstract: Differently substituted benzimidazoles have been syn-
solvent-free conditions, we have investigated the use of
thesised in very good yields in solvent-free conditions from o-phe-
Yb(OTf) as a catalyst for the preparation of substituted
catalyst. The method is applicable to aromatic, unsaturated and 2,4-dihydro-1H-1,5-benzodiazepines by condensation of
nylenediamine and aldehydes in the presence of Yb(OTf)3 as
3
aliphatic aldehydes and to substituted o-phenylenediamines without ketones with o-phenylenediamine; the corresponding cy-
1
2
significant differences.
clization products were obtained in very good yield. In
continuation of our work in studying heterocyclization re-
actions catalyzed by lanthanide triflates, we wish to report
in this paper the synthesis of benzimidazole derivatives
starting by condensation of aldehydes and o-phenylenedi-
Key words: aldehydes, benzimidazoles, catalysis, lanthanides
Benzimidazole structures are classified under several
1
amines promoted by Yb(OTf) under solvent-free condi-
classes of drugs, based on the possible substitution at dif-
3
tions (Scheme 1).
ferent positions of the benzimidazole nucleus. Introduc-
tion of a small substituent into the 2- and 5-positions is
characteristic for benzimidazole anti-helmintics; alterna-
tively, bulky 2-substituents characterize drugs used in the
treatment of peptic ulcer and are sometimes referred as
proton pump inhibitor; bulky 1- and 2-substituents are
found in H1-anti-histaminics. All these compounds con-
tain the benzimidazole skeleton and hence it has been as-
sumed that this skeleton is necessary for the therapeutic
effect.
Scheme 1
The reaction was carried out in neat at room temperature
for 30 minutes, using aldehyde (1.1 mmol) and o-phe-
Methods of benzimidazole synthesis include the conden-
nylenediamine (1 mmol) in the presence of Yb(OTf)
3
sation of o-aryldiamines and aldehyde in refluxing ni-
13
2
,3
(0.05 mmol). The results are summarized in Table 1.
trobenzene, the condensation of o-aryldiamines with
carboxylic acids or their derivatives in the presence of As shown in Table 1, aromatic, aliphatic and a,b-unsatur-
4
strong acids such as polyphosphoric acid or mineral ated aldehydes and substituted o-phenylenediamines react
5
acids and the thermal or acid promoted cyclization of N- without any significant difference to give the correspond-
N-arylbenzimidoyl)-1,4-benzoquinoneimines.6 Direct ing benzimidazole in good yield. Best results were ob-
(
condensation of o-aryldiamines and aldehydes is not a tained using 0.05 equivalents of Yb(OTf) , lower loading
3
good synthetic reaction, as it is well known to yield a com- resulted in lower yields, while upper loading did not in-
plex mixture, being 1,2-disubstituted benzimidazoles, the crease product yields significantly. The catalyst, recov-
bis anil and dihydrobenzimidazoles as the main side prod- ered by filtration from the reaction media can be reused
7
14
ucts. In this case, however, the addition of a transition several times without any loss of activity. It is interest-
8
9
metal, namely copper(II) acetate, mercury oxide or lead ing to note that other lanthanide triflates, used as catalysts
tetracetate allow a partial selective synthesis of benzim- in the same reaction conditions, yielded a complex mix-
idazoles. Unfortunately, many of these processes suffer ture of products. Referring to the reaction pathways de-
1
0
7
some limitations, such as drastic reaction conditions, low picted by Smith and Ho about the condensation between
yields, tedious work up procedures and co-occurrence of o-phenylenediamines and aldehydes, we can hypothesize
several side reactions.
that Yb(OTf) catalysis trigger the reaction towards the
3
selective formation of benzimidazole derivatives, proba-
bly by accelerating the air-oxidation of the dihydrobenz-
imidazole intermediate (Scheme 2).
During the last decade, rare earth metal triflates have been
found as unique Lewis acids. They are water tolerant, re-
usable catalysts and they can effectively promote several
carbon-carbon and carbon-heteroatom bond formation re- To this aim, we recorded the JMODXH NMR spectrum of
1
1
actions in good yield. As a part of our studies to explore a mixture containing 2-phenyl dihydrobenzimidazole
(
11), showing a diagnostic signal at d = 92.8 ppm of the
benzylic CH, before and after the addition of Yb(OTf) :
SYNLETT 2004, No. 10, pp 1832–1834
0
9
.0
8
.2
0
0
4
3
Advanced online publication: 15.07.2004
DOI: 10.1055/s-2004-829555; Art ID: G09204ST
after the addition of the catalyst we observed a progres-
sive disappearance of the signal at d = 92.8 ppm and an
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Ytterbium Triflate Promoted Synthesis of Benzimidazole Derivatives
1833
Table 1 Yb(OTf) -Catalyzed Formation of Benzimidazoles
3
Amine
Aldehyde
Product
Yield (%)a
93
Benzaldehyde
1
2
Hexanal
75
95
Cyclohexanecarboxaldehyde
3
4
5
Citronellal
81
81
71
Isobutyraldehyde
3
-Cyclohexene-1-carboxaldehyde
6
7
trans-Cinnamaldehyde
95
66
Benzaldehyde
8
9
Benzaldehyde
Benzaldehyde
82
73
1
0
a
Yield of pure isolated products, characterized by IR, GC-MS, H NMR and 13C NMR.
1
Synlett 2004, No. 10, 1832–1834 © Thieme Stuttgart · New York

1
834
M. Curini et al.
LETTER
4) Preston, P. N. Benzimidazoles and Congeneric Tricyclic
(
Compounds, In The Chemistry of Heterocyclic Compounds,
Part 1 Vol. 40; Weissberger, A.; Taylor, E. C., Eds.; Wiley:
New York, 1981, 6–60.
(
5) Grimmett, M. R. Imidazoles and their Benzo Derivatives, In
Comprehensive Heterocyclic Chemistry, Vol. 5; Katritzky,
A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984, 457–487.
6) Benincori, T.; Sannicolò, F. J. Heterocycl. Chem. 1988, 25,
(
Scheme 2
1029.
(
(
(
7) Smith, J. G.; Ho, I. Tetrahedron Lett. 1971, 38, 3541.
8) Weidenhagen, R. Ber. 1936, 69, 2263.
9) Jakobson, P.; Jannicke, M.; Meyer, F. Ber. 1896, 29, 2682.
increase of the signal at d = 156.3 ppm of the C=N in the
benzimidazole nucleus. Side-products were detected only
in some cases and were recovered in a yield <15%; a
similar effect was revealed when the same process was
(
10) Stevens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971.
(11) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L.
Chem. Rev. 2002, 6, 2227.
(12) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.
Tetrahedron Lett. 2001, 42, 3193.
1
5
catalyzed by Cu(OAc)2.
In summary, a simple work-up procedure, mild reaction
conditions and very good yields make our methodology a
valid contribution to the existing processes in the field of
benzimidazole derivatives synthesis.
(
13) Typical Procedure.
A mixture of o-phenylenediamine (1 mmol) and aldehyde
(1.1 mmol) was well stirred with Yb(OTf)
r.t. for 30 min. To this solution, CH Cl (2 mL) was added to
(0.05 mmol) at
3
2
2
get Yb(OTf) crystallized; the catalyst was removed by
3
filtration under reduced pressure and the residue was
Acknowledgment
purified by SiO
MeOH 99:1 as eluent. Compounds 1, 2, 3, 5, 6, 7, 8, 9 and
2
gel column chromatography using CH Cl –
2
2
Financial support from Università degli Studi di Perugia is grate-
fully acknowledged.
10 were identified by comparison with commercial samples.
2-(2,6-dimethylhept-5-enyl)-1H-benzimidazole (4).
1
White solid; mp 93–94 °C. H NMR (200 MHz, CDCl ): d =
3
1.01 (d, 6 H, J = 6.6 Hz), 1.27–2.27 (m, 5 H), 2.67–3.10 (m,
References
2
H), 5.01–5.21 (m, 1 H), 6.75 (s, 1 H), 7.15–7.65 (m, 4 H).
C NMR (50 MHz, CDCl ): d = 18.9, 19.5, 25.5, 25.6, 32.9,
1
3
(
1) Velik, J.; Baliharova, V.; Fink-Gremmels, J.; Bull, S.;
Lamka, J.; Skalova, L. Res. Vet. Sci. 2004, 76, 95.
3
36.9, 37.0, 116.7, 120.2, 122.1, 124.2, 136.3, 142.6, 146.6,
+
154.2. GC-MS: m/z = 242 [M ]. Anal. Calcd for C H N :
(
(
2) Yadagiri, B.; Lown, J. W. Synth. Commun. 1990, 20, 955.
3) Sun, Q.; Yan, B. Bioorg. Med. Chem. Lett. 1998, 8, 361.
16 22
2
C, 79.29; H, 9.15; N, 11.56. Found: C, 79.31; H, 9.16; N,
1.54.
1
(14) The reaction to yield compound 1 has been repeated three
times, through the catalyst washed with CH Cl and dried for
2
2
2
h at 70 °C with the following yields: 94%, 91%, and 91%.
15) Jerchel, D.; Fischer, H.; Kracht, M. Ann. Chem. 1952, 575,
62.
(
1
Synlett 2004, No. 10, 1832–1834 © Thieme Stuttgart · New York