Preparation of 2-substituted benzimidazoles and related heterocycles directly from activated alcohols using TOP methodology

Article abstract of DOI:10.1055/s-2004-829060

A one-pot procedure for preparing 2-substituted benzimidazoles directly from activated alcohols in good to excellent yields using a new Tandem Oxidation Process (TOP) is reported. The use of this methodology to prepare 2-substituted benzoxazoles and 2-substituted benzothiazoles is also described.

Full text of DOI:10.1055/s-2004-829060

1628
LETTER
Preparation of 2-Substituted Benzimidazoles and Related Heterocycles
Directly from Activated Alcohols Using TOP Methodology
P
reparationof 2-S
e
ubstitute
d
c
Benzimida
i
zoles
a
l
i
tedHe
a
terocycles D. Wilfred, Richard J. K. Taylor*
University of York, Heslington, York, UK, YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 3 March 2004
ably proceed by way of the corresponding aldehyde gen-
erated in situ.6 Again, very high temperatures (200 °C)
and autoclave conditions were required.
Abstract: A one-pot procedure for preparing 2-substituted benzim-
idazoles directly from activated alcohols in good to excellent yields
using a new Tandem Oxidation Process (TOP) is reported. The use
of this methodology to prepare 2-substituted benzoxazoles and 2-
substituted benzothiazoles is also described.
We have recently designed a range of transformations
based on manganese dioxide-mediated tandem oxidation
processes (TOPs) of primary alcohols.7,8 The resulting al-
dehydes have been trapped in situ with a range of Wittig
reagents and amines.7 Recently, this methodology has
been extended to enable quinoxalines and related hetero-
cycles to be prepared directly from a-hydroxy ketones and
1,2-diamines.8 We therefore decided to investigate the
one-pot preparation 2-substituted benzimidazoles using a
TOP method. Thus, the aim was to commence with an al-
cohol and carry out in situ the oxidation–double conden-
sation–aromatisation as shown in Scheme 1. The use of
manganese dioxide to convert dihydrobenzimidazoles
into benzimidazoles has been previously reported.2,9
Key words: 2-substituted benzimidazoles, 2-substituted benzox-
azoles, 2-substituted benzothiazoles, tandem oxidation procedure,
one-pot
2-Substituted benzimidazoles and their derivatives have
been shown to exhibit fungicide, antitumour, immuno-
suppressant and anti-convulsant properties,1 and have re-
cently been prepared as ligands for asymmetric catalysis.2
There are many methods available for the synthesis of
these heterocycles,1 although reaction of 1,2-phenylene-
diamines with carbonyl reagents is one of the most impor-
tant.1–5 For example, condensation of 1,2-phenyl-
enediamines with carboxylic acids or derivatives in the
presence of polyphosphoric acid at 170–180 °C gives a
range of 2-arylbenzimidazoles.3 More recently, polymer-
bound esters have been treated with 1,2-phenylenedi-
amines and a Lewis acid in refluxing toluene in a solid-
supported route to benzimidazoles.4 As is evident from
these examples, such transformations often require harsh
conditions. An alternative approach utilises aldehydes, or
derivatives, as the condensation partner with 1,2-phe-
nylenediamines, followed by aromatisation of the inter-
mediate dihydrobenzimidazole.2,5 In addition, there is one
report of the direct preparation of 2-substituted benzimi-
dazoles from alcohols; Watanabe et al. prepared 2-substi-
tuted benzimidazoles by the ruthenium-catalysed reaction
of 1,2-phenylenediamines with alcohols which presum-
Initial studies were carried out using benzyl alcohol and 4
equivalents of N-methyl 1,2-phenylenediamine in the
presence of 15 equivalents of activated manganese diox-
ide in dichloromethane at reflux for 18 hours. We were
delighted to obtain the desired 1-methyl-2-phenylbenzim-
idazole (1a) in 35% yield. Carrying out the reaction in
benzene improved the yield to 54% and changing to tolu-
ene resulted a further increase in yield to 78%. We then
added various amounts of 2 M HCl in diethyl ether to as-
sist the condensation and found that addition of 15 mol%
HCl with 2.5 equivalents of N-methyl 1,2-phenylenedi-
amine in toluene at reflux gave 1-methyl-2-phenylbenz-
imidazole (1a) in an excellent yield (90%).10 The
methodology is simple and the spent oxidant is easily
removed by filtration.
Me
N
MnO2, sieves
∆, 18 h
Me
N
MnO2
OH
Ph
O
Ph
Ph
Ph
MeHN
N
N
H
1a
H2N
CH2Cl2, ∆, 35%
PhH, ∆, 54%
PhMe, ∆, 78%
PhMe,HCl, ∆, 90%
Scheme 1
SYNLETT 2004, No. 9, pp 1628–1630
2
2.
0
7.
2
0
0
4
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829060; Art ID: D06104ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of 2-Substituted Benzimidazoles and Related Heterocycles
1629
Having completed this optimisation study, we proceeded ix).Thus, the same conditions gave reasonable yields (56–
to investigate the TOP sequence on a range of alcohols us- 65%) of the 2-substituted benzimidazoles (1b–d) derived
ing N-methyl 1,2-phenylenediamine (Table 1, entries i– from p-methoxy, p-bromo and p-nitro-benzyl alcohols
Table 1 Conversion of Alcohols into Benzimidazole Derivativesa
Entry
i
Alcohol
Diamine
Product
Isolated yield (%)b
90
1a
1b
ii
65
65
56
iii
iv
1c
1d
v
1e
71
vi
1f
55
28
vii
1g
viii
ix
1h
1i
25
c
–
x
1j
76
a With manganese dioxide (15 equiv), N-methyl or N-phenyl 1,2-phenylenediamine (2.5 equiv), 15 mol% HCl (w.r.t diamine) and 4 Å mol
sieves, in toluene at 105 °C for 18 h.
b All products are known and gave data consistent with literature values.
c No product was obtained after 18 h reflux as above.
Synlett 2004, No. 9, 1628–1630 © Thieme Stuttgart · New York

1630
C. D. Wilfred, R. J. K. Taylor
LETTER
MnO2, sieves
MnO2, sieves
PhMe, ∆, 18 h
PhMe, ∆, 18 h
O
S
N
OH
Ph
N
Ph
Ph
HS
HO
H2N
H2N
2, 73%
3, 66%
Scheme 2
(entries ii–iv). This demonstrates that the TOP sequence is
applicable to ‘neutral’, electron rich and electron deficient
benzylic systems. Naphthalene-1-methanol also under-
went the TOP sequence smoothly to give benzimidazole
1e, as did pyridine-3-methanol giving 1f (entries v and vi,
respectively). Next, propargylic and allylic alcohols were
examined (entries vii and viii). In these cases, although
the desired products 1g and 1h were obtained, the yields
were lower, possibly due to the formation of Michael-ad-
ducts. An unactivated alcohol was also examined (entry
ix), but conversion into the anticipated heterocyclic sys-
tem was not observed in the usual reaction time period. Fi-
nally, we went on to determine the scope of this reaction
with respect to the diamine. Thus, N-phenyl 1,2-phe-
nylenediamine and benzyl alcohol gave the corresponding
benzimidazole 1i in 76% yield (entry x), although at-
tempts to use 1,2-phenylenediamine itself were unsuc-
cessful. It therefore seems as if this methodology is ideal
for preparing 1-alkylated-2-substituted benzimidazoles
from activated alcohols but not for the direct preparation
of the corresponding parent 1H-benzimidazoles.
Acknowledgment
We are grateful to the Universiti Teknologi, Petronas, Malaysia for
a Scholarship (C. D. W.).
References
(1) For reviews see: (a) Grimmett, M. R. In Comprehensive
Heterocyclic Chemistry II, Vol. 3; Katrizky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Elsevier Science Ltd.: Oxford,
1996, Chap. 3.02. (b) Grimmett, M. R. Imidazole and
Benzimidazole Synthesis; Academic Press: San Diego, 1997.
(2) Figge, A.; Altenbach, H. J.; Brauer, D. J.; Tielmann, P.
Tetrahedron: Asymmetry 2002, 13, 137.
(3) Alcalde, E.; Dinares, I.; Perez-Garcia, L.; Roca, T. Synthesis
1992, 395.
(4) Matsushita, H.; Lee, S. Y.; Joung, M.; Clapham, B.; Janda,
K. D. Tetrahedron Lett. 2004, 45, 313.
(5) (a) Göker, H.; Kus, C.; Boykin, D. W.; Yildiz, S.; Altanar,
N. Bioorg. Med. Chem. 2002, 10, 2589. (b) Kus, C.;
Boykin, D. W.; Göker, H. Heterocycl. Comm. 2002, 8, 215;
and references therein.
(6) Kondo, T.; Yang, S.; Huh, K.-T.; Kobayashi, M.; Kotachi,
S.; Watanabe, Y. Chem. Lett. 1991, 1275.
(7) For recent lead references see: (a) Reid, M.; Rowe, D. J.;
Taylor, R. J. K. Chem. Commun. 2003, 2284. (b) Kanno,
H.; Taylor, R. J. K. Tetrahedron Lett. 2002, 43, 7337.
(8) Raw, S.; Wilfred, C. D.; Taylor, R. J. K. Chem. Commun.
2003, 2286.
We briefly explored the use of aliphatic diamines, which
should lead to imidazolidine/imidazoline/imidazole de-
rivatives. With N-methyl- and N-phenyl-ethylenediamine,
benzyl alcohol and manganese dioxide, the reaction gave
a mixture (ca. 70%) of 1-methyl- and 1-phenyl-2-phe-
nylimidazolidine and the corresponding ring-opened im-
ines,11 but further dehydrogenation was not observed.
(9) Encyclopedia of Reagents for Organic Synthesis, Vol. 5;
Paquette, L. A., Ed.; John Wiley: Chichester, 1995, 3229.
(10) Representative Experimental Procedure:
Activated manganese dioxide (Aldrich 21764-6, 0.653 g,
7.50 mmol) was added to a mixture of benzyl alcohol (0.054
g, 0.50 mmol), N-methyl 1,2-phenylenediamine (0.15 mL,
1.25 mmol), HCl in Et2O (2 M, 0.04 mL, 15 mol%) and 4 Å
molecular sieves (0.5 g) in dry toluene (12 mL). The mixture
was stirred at 105 °C for 18 h. The mixture was cooled to ca.
50 ºC, hot filtered through Celite®, and the residue washed
with excess CH2Cl2. The combined organic fractions were
concentrated in vacuo and the residue purified using column
chromatography on silica (petroleum ether–EtOAc, 3:1) to
give 1-methyl-2-phenylbenzimidazole (1a, 0.094 g, 90%) as
a brown solid, Rf = 0.3 (petroleum ether–EtOAc, 2:1); mp
96 °C, lit.12 mp 94–95 °C. The spectroscopic data obtained
were consistent with those reported in the literature.12
(11) Lázár, L.; Göblyös, A.; Evanics, F.; Bernáth, G.; Fülöp, F.
Tetrahedron 1998, 54, 13639.
Finally, when the N-substituted 1,2-phenylenediamine
was replaced by 2-aminophenol or 2-aminothiophenol in
the reaction with benzyl alcohol, the desired benzoxazole
2 and benzothiazole 3 were produced in good, though un-
optimised, isolated yields (Scheme 2). These results indi-
cate such TOPs should be of general utility for the
synthesis of these types of heterocyclic systems, as long as
the 2-substituent is derived from an activated alcohol.
In summary, we have developed a simple method for the
conversion of a range of activated alcohols directly into 2-
substituted benzimidazoles and analogous heterocycles
by a TOP sequence involving oxidation–double conden-
sation–aromatisation. We are currently applying this
methodolgy and extending it to other heterocyclic sys-
tems.
(12) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
Synlett 2004, No. 9, 1628–1630 © Thieme Stuttgart · New York