Synthesis of N-alkoxybenzimidazoles with differentiated C2 and O-substituents

Article abstract of DOI:10.1016/S0040-4039(01)00935-2

N-Alkoxy-, N-aryloxy- and N-allyloxybenzimidazoles (prepared using tandem N-alkylation, heterocyclisation and O-alkylation with in situ alkylating agent) can be selectively O-deprotected and then independently realkylated to provide a protocol for diversification with differentiated substituents at C2 and on oxygen. In addition, carboxamide functionalised derivatives 8 are amenable to staged interruption of the tandem reaction, allowing sequential additions of two different bases and alkylating agents directly affording 9. This 'start-stop-start' tandem process also facilitates diversification to analogues bearing different C2 and N-alkoxy substituents.

Full text of DOI:10.1016/S0040-4039(01)00935-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5109–5111
Synthesis of N-alkoxybenzimidazoles with differentiated C2 and
O-substituents
John M. Gardiner* and Jonathan Procter
Department of Chemistry, UMIST, Manchester M60 1QD, UK
Received 3 April 2001; revised 8 May 2001; accepted 31 May 2001
Abstract—N-Alkoxy-, N-aryloxy- and N-allyloxybenzimidazoles (prepared using tandem N-alkylation, heterocyclisation and
O-alkylation with in situ alkylating agent) can be selectively O-deprotected and then independently realkylated to provide a
protocol for diversification with differentiated substituents at C2 and on oxygen. In addition, carboxamide functionalised
derivatives 8 are amenable to staged interruption of the tandem reaction, allowing sequential additions of two different bases and
alkylating agents directly affording 9. This ‘start–stop–start’ tandem process also facilitates diversification to analogues bearing
different C2 and N-alkoxy substituents. © 2001 Elsevier Science Ltd. All rights reserved.
Benzimidazoles are common units in a range of biolog-
ically active compounds. However, N-alkoxy systems
are relatively uncommon. We have previously reported
that reaction of a range of 2-nitroanilines (1) with
strong base and alkylating agents leads directly to
2-substituted-N-alkoxy-, -N-aryloxy- or -N-allyloxy-
benzimidazoles (2) via a novel tandem one-pot N-alky-
lation–heterocyclisation–O-alkylationsequence (Scheme
1).1 Prior to this work, base-induced heterocylisations
of this type had been limited to N-alkylated nitroani-
lines with an active methylene2 (our method extended
this to non-activated alkyl functionality) and observa-
tion of in situ O-alkylation was previously limited to
poor yielding side product formation in specific
reactions3 (whereas our method generates N-alkoxy
products 2 directly in good yield across all general
electrophile types).
ment of methods to prepare diverse further related
novel structures. Our previously reported protocol,
though versatile for variations in all reagent compo-
nents, requires that the substituents at the 2-position
and on the oxygen are necessarily derived from the
same alkylating agent (see Scheme 1). We thus sought
to develop modifications of this methodology to
provide access to systems with groups on the oxygen
and C2 derived from different alkylating agents. This
would significantly extend the scope of this general
methodology to a far wider range of new analogues.
We report herein two alternative, complementary, prac-
ticable protocols to achieve this objective.
One route to systems bearing different C2 and N-
alkoxy groups would be to remove the substituent from
the oxygen of specific 2-substituted-N-alkoxybenzimi-
dazoles, and then independently realkylate the N–OH
functionality with a variety of different alkylating
agents. This would be applicable to a range of alkyla-
tion agents and so provide a versatile route to diversity
of novel structures.
A number of the new compounds prepared by this
method were active against HIV-1,4 or cancer cell lines
(<10 mM to sub-micromolar EC50s).5 These promising
leads (from a modest screen range) encouraged develop-
Scheme 1.
* Corresponding author: Tel.: +44 (0)161 200 4530; fax: +44 (0)870 169 2995; e-mail: john.gardiner@umist.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00935-2

5110
J. M. Gardiner, J. Procter / Tetrahedron Letters 42 (2001) 5109–5111
We evaluated three types of oxygen substituents for
removal from the N-alkoxy function, specifically O-
allylic, O-benzylic and O-p-methoxybenzylic groups.
To illustrate the viability of this protocol, benzimida-
zoles 3a,1a 3b1b and 3c were employed (available in high
yields from the precursor 2-methyl-6-nitroaniline). The
O-benzylic system 3a was then converted to the desired
N-hydroxy system (4a) in over 90% yield with hydro-
gen/Pd–C. Notably, this required rigorous control of
reaction time, since the reaction was complete in
around 15 min (prolonging the reaction any further
lead to rapid appearance of the further reduced parent
benzimidazole, 6). The O-allyloxy group was also
cleanly removed from 3b by treatment with TMSI
(generated in situ), giving 4b in 92% purified yield,
whilst the O-p-methyoxybenzyloxy group was removed
from 3c by DDQ, affording 4c in 90% purified yield.
The three N-hydroxy products 4a–c were then realky-
lated in parallel with various types of alkylating agents
to give the new N-alkoxybenzimidazoles 5 in 92–98%
isolated yields (Table 1), demonstrating that alkyl
halides, benzylic halides and allylic halides are all suit-
able electrophiles. These reactions were simply
quenched, extracted and the organic solution dried,
filtered and solvent removed to provide high yields of
analytically pure material in all cases, without the need
for any chromatography.
These experiments establish that for three different C2
substituents, the group on the oxygen can be readily
removed and replaced by a range of different elec-
trophile types. This sequence should be generally
extendable to a wide range of further electrophiles, to
provide a wide diversity of N-alkoxy groups (as well as
being applicable to variations in the nature and posi-
tion of the substituent in the benzene ring of the
benzimidazole skeleton (see R2 in Scheme 1).
Table 1. N-Alkoxybenzimidazoles 5a–c produced via
Scheme 2a
We believe that these benzimidazole N-alkoxide form-
ing reactions (Scheme 1) proceed via the intermediacy
of N-alkylated nitroanilines (e.g. 8); however, although
we have previously isolated traces of this type of inter-
mediate in certain reactions, benzimidazole formation
always commences well before all nitroaniline starting
material has been N-alkylated (even using 1 equiv. of
alkylating agents), and so a step-wise process has not
previously been possible. However, we sought a proto-
col for selective N-alkylation of 2-nitroanilines using 1
equiv. of an electrophile, but not converting this on to
benzimidazole. Ideally, we then hoped to be able to add
further (new) base and a second, different, electrophile,
into the same reaction vessel, restarting the tandem
Entry
R
R1
Yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Et
Pr
Ph
97
96
98
93
92
94
95
96
CHꢀCH2
CHꢀCH2
4-MeO-C6H4-
4-MeO-C6H4-
4-MeO-C6H4-
4-MeO-C6H4-
CHꢀCH2
Pr
Ph
a Yields are for 4 to 5. All products 5 are fully characterised and are
analytically pure.
Scheme 2. Reagents and conditions: (i) Pd/C, H2 (1 atm), 15 min; (ii) TMSCl, NaI; (iii) DDQ; (iv) Pd/C, H2 (1 atm), 30 min.
Scheme 3.

J. M. Gardiner, J. Procter / Tetrahedron Letters 42 (2001) 5109–5111
5111
process and converting N-alkylnitroanilines 8 into N-
Acknowledgements
alkoxybenzimidazoles 9 in a ‘one-pot’ ‘start–stop–start’
sequence in which the intermediate is ‘parked’ before
heterocyclisation. Such a protocol would provide access
to a substantially wider range of new analogues akin to
5 above.
NMR and IR characterisations were carried out using
instrumentation funded with support from EPSRC
grants GR/L52246 (NMR) and GR/M30135 (IR).
We report here such a modified protocol from carbox-
amide-bearing substrate nitroanline 7 (Scheme 3). This
protocol relies on discovering that with carboxamide-
bearing nitroaniline 6, use of limited NaH and alkylat-
ing agent (e.g. allyl and p-methoxybenzyl) leads to
clean conversion to the N-alkyl intermediate 8 without
any concurrent benzimidazole formation.6 On addition
of an equivalent of NaHMDS to the reaction mixture
containing 8, followed by an equivalent of a different
alkylating agent, the reaction recommences, converting
8 into 97 in at least 90% overall yield. The carboxamide
functionality should facilitate application of this proto-
col to substrates immobilised through a ring carboxyl,
as well as to solution phase synthesis of ranges of
targets of type 9.
References
1. (a) Gardiner, J. M.; Loyns, C. R.; Schwalbe, C. H.;
Barrett, G. C.; Lowe, P. R. Tetrahedron 1995, 51, 4101; (b)
Gardiner, J. M.; Loyns, C. R. Synth. Commun. 1995, 25,
819.
2. Cafiero, P. A. C.; French, C. S.; McFarlane, M. D.;
Mackie, R. K.; Smith, D. M. J. Chem. Soc., Perkin Trans.
1 1997, 1375 and references cited therein.
3. Machin, J.; Smith, D. M. J. Chem. Soc., Perkin Trans. 1
1979, 1371.
4. (a) Gardiner, J. M.; Loyns, C. R.; Burke, A.; Khan, A.;
Mahmood, N. Bioorg. Med. Chem. Lett. 1995, 5, 1251; (b)
Evans, T. M.; Gardiner, J. M.; Mahmood, N.; Smis, M.
Bioorg. Med. Chem. Lett. 1997, 7, 409.
In summary, C2-vinyl-, -p-methoxyphenyl and -phenyl-
bearing N-alkoxybenzimidazoles (prepared in one-pot
reactions from precursor 2-nitroaniline) can be diversi-
fied to new analogues with various oxygen substituents
by a simple highly efficient two-step alkoxy removal–
5. Gardiner, J. M.; Evans, T. M.; Procter, J.; Smis, M.;
McGown, A. T. 1999, unpublished results.
6. This selectivity was not seen with any other nitroanilines,
where reaction under these conditions leads to unreacted
starting material, N-alkylated intermediate (usually very
small amounts) and benzimidazole product (as observed
previously).1b
7. Use of NaHMDS as the base in the initial stage, with 1
equiv. alkylating agent, leads directly to a mixture of
starting material (ca. 40%), N-alkylated intermediate
(trace) and benzimidazole (ca. 50%).
realkylation. In addition,
a
carboxamide-bearing
nitroaniline provides a step-wise ‘one-pot’ protocol of
sequential addition of NaH/alkylating agent (for C2),
then NaHMDS/second alkylating agent (for N-alkoxy
group). These methodologies significantly expand the
scope of this chemistry and the diversity of targets avail-
able using parallel synthesis.
.