Synthesis of novel 2,2- and 1,1-linked dimeric 'head-to-head' N-alkoxybenzimidazoles

Article abstract of DOI:10.1016/S0040-4039(02)02590-X

Synthesis of two new types of 'head-to-head' N,N-alkoxy bisbenzimidazoles is described. The proposed intermediate N-oxy benzimidazole from base-induced heterocyclization of N-alkylnitroanilines can be trapped with a biselectrophile (to give an N,N-linked

Full text of DOI:10.1016/S0040-4039(02)02590-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 511–513
Synthesis of novel 2,2- and 1,1-linked dimeric ‘head-to-head’
N-alkoxybenzimidazoles
John M. Gardiner,a,* Andrew D. Goss,a Tahir N. Majidb and Andrew D. Morleyc,†
aDepartment of Chemistry, UMIST, Manchester M60 1QD, UK
bAventis Pharma US, Route 202-206, Bridgewater, NJ 08807, USA
cAventis Pharma, Rainham Road South, Dagenham, Essex RM10 7XS, UK
Received 22 August 2002; revised 30 October 2002; accepted 15 November 2002
Abstract—Synthesis of two new types of ‘head-to-head’ N,N-alkoxy bisbenzimidazoles is described. The proposed intermediate
N-oxy benzimidazole from base-induced heterocyclization of N-alkylnitroanilines can be trapped with a biselectrophile (to give an
N,N-linked dimer), or double heterocyclization of dimeric nitroanilines can be intercepted by electrophile trapping of both
N-oxybenzimidazole termini to give C2,C2-linked dimers. These represent two regioisomeric motifs constituting new classes of
benzimidazole dimers. © 2002 Elsevier Science Ltd. All rights reserved.
Dimeric benzimidazoles have attracted interest in two
primary areas in recent years. A number have been
used as ligands for various metals, including
lanthanides1 and a range of transition metals.2 These
have included systems with useful metal-selective bind-
ing abilities, and some with intriguing solid state struc-
tural features (e.g. triple helical or network assemblies).
Some have also been proposed as ligand mimics of
Cu(I)/Cu(II) biological redox systems. Certain dimeric
systems are effective DNA minor groove binding agents
with significant potential for new drug development,3
and there have also been examples of other bioactivity,
for example as dopamine D3 ligands.4
The ring systems could either be linked between the C2
atoms or via the N-alkoxy substitutents. The former
approach (to generate 3) could be achieved using a
bifunctional electrophile 2 reacting with a standard
N-alkylnitro-aniline 1 intermediate, trapping two equiv-
alents of benzimidazole (Scheme 1). The latter
approach envisages a dimeric N-alkyl nitroaniline (pre-
pared from bisamine 4 and 5) used as the substrate for
a double heterocyclization, both N-alkoxy functions
might be trapped with electrophiles, which would
provide the latter target (6) (Scheme 2). The advantages
of demonstrating either approach are substantial. The
first approach could have applicability to various bisel-
ectrophiles with structural variability in the bridging
We previously reported new methodology for synthesis
of N-alkoxybenzimidazoles from 2-nitroanilines,5 and
have recently established that this reaction can be inter-
cepted via N-alkyl nitroanilines widening its applicabil-
ity.6 Critically, we found evidence that the mechanism
involves heterocyclization to an N-oxybenzimidazole
which is O-alkylated in the final stage. In this context
we saw an opportunity to evaluate whether this
methodology could be applied to generating dimeric
systems. There are two basic linkage formats we wished
to evaluate for generating ‘head-to-head’ dimeric sys-
tems using this methodology.
* Corresponding author. Tel.: +44 (0)161 200 4530; e-mail:
john.gardiner@umist.ac.uk
† Present address: AstraZeneca, Mereside, Alderley Park, Mac-
clesfield, Cheshire, SK10 4TG; tel.: +44 (0)1625 512782.
Scheme 1. Biselectrophile trapping to form N,N-alkoxy-
linked dimers.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02590-X

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J. M. Gardiner et al. / Tetrahedron Letters 44 (2003) 511–513
We then turned to assessing whether the diamine-based
approach could be used for forming a double N-oxy-
benzimidazole with concomitant trapping of the inter-
mediate N-oxy functions of targets of type 6. In this
case, we used examples of both an alkyl diamine and an
aryl containing diamine. Thus, reaction of 1,8-octyldi-
amine with 2-nitrofluorobenzene afforded the bisaniline
9 [X=(CH2)8)] and treatment of this under our N-
alkoxybenzimidazole forming conditions in the pres-
ence of excess allyl bromide led to isolation of the
target bis-N,N-allyloxybenzimidazole 10. To illustrate
that aryl linkers could be employed and also to vary the
nature of the trapping electrophile, an analogous reac-
tion using 1,3-bisaminomethylbenzene, with propyl
iodide as the trapping electrophile, afforded the dimeric
target 11 (Scheme 4).7 In these examples, the overall
two-step yields were usually slightly lower than for
dimer system 8.
Scheme 2. Bisamine strategy towards 2,2-linked dimers.
Although the yields are not optimized,8 the two-step
synthesis offers access to complex, otherwise unavail-
able, dimers in two novel families by elaboration of
simple diamines and 2-nitrofluorobenzene, in adequate
overall yields in short sequences.
Scheme 3. Reagents and conditions: (i) NaH, D, 12 h then
This work demonstrates that our general methodology
for N-alkoxybenzimidazoles is applicable to generation
of both possible modes of dimeric ‘head-to-head’ N-
alkoxybenzimidazoles, and this work coupled with the
versatility demonstrated in the monomeric systems indi-
cates this has potential for wide applicability to genera-
tion of further novel types of 2,2- or N,N-linked
dimeric N-alkoxybenzimidazoles.9 The biological activi-
ties of novel dimeric N-alkoxybenzimidazoles will be
evaluated and reported in due course.
1,3-bis(bromomethyl)benzene.
linker envisaged. The second approach offers the poten-
tial of extension to various diamine-derived bridges, but
also trapping with diverse electrophiles, R1.
Our recent work on monomeric systems indicates that
many different electrophiles can be used for a final
O-alkylation, and such chemistry ought thus to be
extendable to dimers, opening the way to diverse ana-
logue availability.
As an illustration of the potential for synthesis of
1,1-linked dimers of type 3, the 2-pyridylmethyl system
7, (prepared by reaction of 2-nitrofluorobenzene with
3-aminomethyl pyridine), was treated with base, and
then with 1,3-bis(bromomethyl)benzene to afford the
target dimer 8 in ca. 30% purified yield over the two
steps (Scheme 3).7
Acknowledgements
Aventis are thanked for support through a CASE col-
laboration. NMR, HPLC and IR characterization used
instrumentation funded through EPSRC grants GR/
L52246 (NMR), GR/M30135 (IR) and GR/L84391
Scheme 4. Reagents and conditions: (i). K2CO3, DMF, 2-nitrofluorobenzene (2 equiv.), D; (ii) NaH, 18 h then allyl bromide (2
equiv.), 30 min; (iii), NaH, 2 h, then PrI, 2 h.

J. M. Gardiner et al. / Tetrahedron Letters 44 (2003) 511–513
513
(HPLC). The EPSRC Mass Spectrometry Service at
Swansea is thanked for carrying out low and high
resolution analyses on a number of the new compounds
described.
5. (a) Gardiner, J. M.; Loyns, C. R.; Schwalbe, C. H.; Barrett,
G. C.; Lowe, P. R. Tetrahedron 1995, 51, 4101–4110; (b)
Gardiner, J. M.; Loyns, C. R. Synth. Commun. 1995, 25,
819–827; (c) Evans, T. M.; Gardiner, J. M.; Mahmood, N.;
Smis, M. Bioorg. Med. Chem. Lett. 1997, 7, 409–412; (d)
Gardiner, J. M.; Procter, J. Tetrahedron Lett. 2001, 42,
5109–5111.
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7. All the dimeric systems were fully characterized after
purification by column chromatography. In the case of 8,
1
dimerization is evident in H NMR, where a 4H benzylic
singlet is observed, and integration is conclusive.
8. A number of parameters could be systematically evaluated
for changing conditions from those successful for monomers,
including timing and rate of electrophile additions and
concentrations, all of which may effect the efficiency of the
reactions.
9. We have also prepared the dimeric nitroanilines 9 [X=
(CH2)4)], 9 [X=1,4-(CH2)2C6H4], which are precursors to
linker structural analogues of 10 and 11. A precursor to
‘tail-to-tail’ analogues 12, has also been prepared, but pure
bis-benzimidazoles have not yet been isolated from reactions
of this intermediate.
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