'One-pot' nitro reduction-cyclisation solid phase route to benzimidazoles

Article abstract of DOI:10.1016/S0040-4039(00)01732-9

An improved solid phase synthesis of benzimidazoles is described. A polymer-bound o-nitroaniline was reacted with aldehydes in DMF in the presence of SnCl₂·2H₂O at 60°C for three hours to give benzimidazoles in excellent purity and good yield after TFA cleavage. A library of 25 benzimidazoles was prepared using this 'one-pot' procedure. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01732-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9871–9874
‘
One-pot’ nitro reduction–cyclisation solid phase route to
benzimidazoles
Zemin Wu,* Philip Rea and Geoffrey Wickham
Mimotopes Pty Ltd., 11 Duerdin Street, Clayton, Victoria 3168, Australia
Received 28 September 2000; accepted 4 October 2000
Abstract
An improved solid phase synthesis of benzimidazoles is described. A polymer-bound o-nitroaniline was
reacted with aldehydes in DMF in the presence of SnCl ·2H O at 60°C for three hours to give
2
2
benzimidazoles in excellent purity and good yield after TFA cleavage. A library of 25 benzimidazoles was
prepared using this ‘one-pot’ procedure. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: solid phase synthesis; benzimidazole; SynPhase™ Lantern.
In the course of evaluating our new proprietary products (SynPhase™ Lanterns) for SPOS,
we have developed some new chemistry. Herein we wish to report an improved solid phase
synthesis of benzimidazoles from readily available amines and aldehydes.
1–9
A number of groups have reported solid phase routes to benzimidazoles, and the majority
of these syntheses involve an o-nitroaniline intermediate of the type shown in Scheme 1 (i.e.
1
–4,6–9
9
compound 4).
Smith et al. recently reported a synthesis of 2-arylaminobenzimidazoles on
SynPhase™ Crowns, which involved an intermediate like 4. We, however, intended to use the
3
route reported by Mayer et al. to synthesize 1,2,5-trisubstituted benzimidazoles on our latest
solid phase product SynPhase™ Lanterns.
11a
Thus, the Wang linker was attached to chloromethylpolystyrene Lanterns 1 using a two-
step process. The loading of the Wang Lanterns 2 was established by coupling Fmoc-b-Ala-OH
and then performing a quantitative Fmoc analysis. Coupling of 4-fluoro-3-nitrobenzoic acid
onto the Wang linker was complete in two hours using diisopropylcarbodiimide and 4-dimethyl-
aminopyridine for carboxyl activation. Substitution of the fluorobenzene 3 by n-propylamine
1
gave the corresponding o-nitroaniline 4 (R =ꢀCH CH CH in Scheme 1) in greater than 95%
2
2
3
purity, as judged by HPLC analysis of the cleaved compound. Reduction of the o-nitroaniline
4
with tin(II) chloride dihydrate at room temperature, however, gave inconsistent results in our
*
Corresponding author. Tel: (61-3) 95651185; fax: (61-3) 95651199; e-mail: zemin wu@mimotopes.com
–
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01732-9

9872
t
−
+
Scheme 1. Reagents and conditions: (i) 4-hydroxybenzaldehyde, BuO K , DMA, 60°C, 18 h; (ii) NaBH , EtOH,
4
1
DMF, rt, 18 h; (iii) 4-fluoro-3-nitrobenzoic acid, DIC, DMAP, DMF, rt, 6 h; (iv) R NH , 5% DIEA/DMF, rt, 6 h;
v) SnCl ·2H O, DMF, rt; (vi) R CHO, DDQ, DMF; (vii) SnCl ·2H O, DMF, 60°C, 18 h; (viii) SnCl ·2H O,
2
2
(
2
2
2
2
2
2
2
R CHO, DMF, 60°C, 3 h (ix) 20% TFA/DCM, rt, 1 h
hands. In addition, the use of either SnCl ·2H O or SnCl in either DMF or NMP as solvent
2
2
2
produced only a small amount of the desired product along with other products which were not
characterized.
These results are interesting, given that three out of the eight published solid phase routes to
benzimidazoles involve tin(II) chloride reduction of an o-nitroaniline intermediate using DMF
as solvent at room temperature and four out of eight used NMP as solvent at either room
temperature or 50°C. Some authors specify that they used the hydrate of tin(II) chloride, but
9
others simply mention SnCl . Smith et al. did report, however, that they ‘occasionally observed
2
incomplete reduction of the nitro group’, using 2 M SnCl in NMP at room temperature
2
1
overnight. Phillips and Wei have reported that tin(II) chloride gave inconsistent results, and
they subsequently used NaBH ꢀCu(acac) to carry out the nitro reduction in their benzimidazole
4
2
2
1
synthesis. In a later paper, however, in which they describe the solid phase synthesis of
benzimidazolones, Wei and Phillips report that tin(II) chloride (1.0 M SnCl ·2H O/DMF/30 h)
2
2
13
was superior to NaBH ꢀCu(acac) for o-nitroaniline reduction. In Pan and Sun’s paper, the
4
2
reduction of support-bound o-nitroanilines has also been an intermediate step in the synthesis
1
4
of benzopiperazinones. While Lee et al. obtained complete reduction using SnCl ·2H O in
2
2
10
DMF at room temperature for 24 h, Morales et al. observed incomplete reduction when the
reduction was carried out with tin(II) chloride in aqueous DMF at room temperature, even for
prolonged periods (2 M aqueous SnCl /DMF/25°C/overnight to 4 days). However, they
2
managed to achieve complete reduction on Wang resin by heating the o-nitroanilines with tin(II)
chloride in aqueous DMF at 80°C overnight.

9873
1
In the present case, treatment of the o-nitroaniline 4 (R =ꢀCH CH CH ) with SnCl ·2H O in
2
2
3
2
2
DMF at 60°C overnight produced exclusively 1-propyl-2(H)-benzimidazole 6. This type of
product has been reported previously by Tumelty et al., and is presumably formed via
4
1
5
formylation of the aniline nitrogen, nitro reduction and cyclization. Formylation of the aniline
nitrogen is believed to assist nitro reduction, since neither benzimidazole 6 nor any clean
reduction product of the o-nitroaniline 4 (viz. 5) was obtained when the reduction was
performed in NMP. This prompted us to investigate whether benzimidazoles might be synthe-
sized directly (albeit via a different mechanism) by heating a mixture of the o-nitroaniline 4,
aldehyde and SnCl ·2H O in DMF. In fact, heating a mixture of the N-propylaniline 4
2
2
1
2
(
R =ꢀCH CH CH ), propionaldehyde (R =ꢀCH CH ) and SnCl ·2H O in DMF at 60°C
overnight led to the desired benzimidazole 7 (42%) along with a side-product (53%) after TFA
2
2
3
2
3
2
2
1
cleavage. ESMS and H NMR spectra of the side product are consistent with the benzimida-
1
2
zolium species 8 (R =ꢀCH CH CH , R =ꢀCH CH ).
2
2
3
2
3
1
2
After extensive optimization, the desired product 7 (R =ꢀCH CH CH , R =ꢀCH CH ) was
2
2
3
2
3
1
obtained in 74% purity (by HPLC) along with 25% of the side product 8 (R =ꢀCH CH CH ,
2
2
3
2
16
R =ꢀCH CH ). The optimized conditions for ‘one-pot’ reduction–cyclisation involved using
2
3
two molar equivalents of aldehyde (relative to the loading of the Wang linker: 36 mmol/D-series
Lantern) and 0.75 M SnCl ·2H O (10 molar equivalents) in DMF and heating at 60°C for three
2
2
hours. The optimum concentration of tin(II) chloride (0.75 M) determined for this reaction is
3
,4
well below that typically used (2.0–3.0 M) for the reduction of nitrobenzenes attached to a
solid support. Using the optimized method, a library of 25 benzimidazoles was synthesized from
1
2
five amines (5×R NH in Scheme 1) and five aldehydes (5×R CHO in Scheme 1). For each
2
amine/aldehyde combination, two products were obtained, the desired benzimidazole 7 and the
benzimidazolium side-product 8 (see Table 1). Clearly, this ‘one pot’ method can provide
benzimidazoles of excellent crude purity and in good yield, but it should be noted that the
Table 1
a
Product distribution and HPLC purities of 5×5 benzimidazole library
2
1
R (from aldehydes)
R (from amines)
n-Propyl n-Butyl
Benzyl
4-Methoxy-benzyl
4-Trifluoromethylbenzyl
Ethyl
n-Propyl
Phenyl
74 (25)
77 (20)
93 (4)
91 (3)
93 (3)
56 (32)
72 (24)
92 (5)
88 (5)
93 (4)
73 (25) 72 (27)
72 (24) 70 (25)
76 (20)
73 (20)
83 (9)
79 (6)
87 (4)
88 (7)
85 (4)
90 (3)
89 (4)
89 (3)
92 (3)
4-Methoxyphenyl
3-Trifluoromethylphenyl
a
Notes: (1) HPLC purities are given as area %; (2) all compounds gave the expected molecular ions in positive ion
ESMS; (3) minor products (area % shown in parentheses) were characterized by LCMS; (4) selected samples gave
1
17
satisfactory H NMR spectra; (5) crude yields of benzimidazoles were approximately 85%, based on weights of
cleaved compounds.

9874
aliphatic aldehydes used in our study gave rise to a significantly greater proportion of the
benzimidazolium side-products compared with the benzaldehydes. The product ratios determined
1
by HPLC and shown in Table 1 are consistent with those observed in the H NMR spectra.
In summary, we have demonstrated that benzimidazoles can be efficiently prepared from a
support-bound o-nitroaniline using a ‘one-pot’ reduction–cyclisation method. This approach has
provided the shortest solid phase synthesis of benzimidazoles to date. Since a wide range of amines
and aldehydes are commercially available, a large number of benzimidazoles can be easily prepared
using this method. It is worth noting that this ‘one-pot’ method has also been applied to other
1
1b
11c
Lantern products (e.g. Rink amide and HMP ) and commercially available Wang resins to
produce benzimidazoles in excellent purity.
Acknowledgements
The authors wish to acknowledge the assistance of Heather Patsiouras and Michael FitzGerald
in obtaining mass spectra.
References
1
2
3
4
5
6
7
8
9
. Phillips, G. B.; Wei, G. P. Tetrahedron Lett. 1996, 37, 4887–4890.
. Lee, J.; Gauthier, D.; Rivero, R. A. Tetrahedron Lett. 1998, 39, 201–204.
. Mayer, J. P.; Lewis, G. S.; McGee, C.; Bankaitis-Davis, D. Tetrahedron Lett. 1998, 39, 6655–6658.
. Tumelty, D.; Schwarz, M. K.; Needels, M. C. Tetrahedron Lett. 1998, 39, 7467–7470.
. Sun, Q.; Yan, B. Bioorg. Med. Chem. Lett. 1998, 8, 361–364.
. Huang, W.; Scarborough, R. M. Tetrahedron Lett. 1999, 40, 2665–2668.
. Tumelty, D.; Schwarz, M. K.; Cao, K.; Needels, M. C. Tetrahedron Lett. 1999, 40, 6185–6188.
. Smith, J. M.; Krchnak, V. Tetrahedron Lett. 1999, 40, 7633–7636.
. Smith, J. M.; Gard, J.; Cummings, W.; Kanizsai, A.; Krchnak, V. J. Comb. Chem. 1999, 1, 368–370.
1
1
1
1
1
1
1
0. Morales, G. A.; Corbett, J. W.; DeGrado, W. F. J. Org. Chem. 1998, 63, 1172–1177.
1. (a) Product code: SPPSDCLM. (b) Product code: SPPSDRAM. (c) Product code: SPPSDHMP.
2. Wei, G. P.; Phillips, G. B. Tetrahedron Lett. 1998, 39, 179–182.
3. Pan, P.-C.; Sun, C.-M. Tetrahedron Lett. 1999, 40, 6443–6446.
4. Lee, J.; Murray, W. V.; Rivero, R. A. J. Org. Chem. 1997, 62, 3874–3879.
5. Mataka, S.; Shimojyo, Y.; Hashimoto, I.; Tashiro, M. Liebigs Ann. 1995, 1823–1825.
6. A typical procedure is as follows: each o-nitroaniline D-series Lantern 4 is treated with 0.5 mL of a solution of
aldehyde (0.15 M, 2 molar equivalents) and SnCl ·2H O (0.75 M, 10 molar equivalents) in DMF at 60°C for 3
2
2
h. The reaction mixture was allowed to cool briefly and the reagent solution decanted. The Lanterns were washed
with DMF (3×3 min) and DCM (3×3 min), and air dried. Each Lantern was cleaved in a polypropylene tube with
0
.7 mL of 20% TFA/DCM for 1 h. The Lantern was removed and the cleavage solution evaporated. The residue
was dissolved in 90% CH CN/H O for HPLC and MS analysis.
3
2
1
1
7. For example, compound 9: H NMR (400 MHz, CDCl ) l 8.58, (d, J=1.2 Hz, H ), 8.13 (dd, J =1.2 Hz, J =8.4
3 a 1 2
Hz, H ), 8.00 (s, H ), 7.98 (d, J=8.4 Hz, H ), 7.87 (d, J=8.0 Hz, H ), 7.75 (t, J=8.0 Hz, H ), 7.54 (d, J=8.4
b
d
g
e
f
Hz, H ), 4.43 (t, J=7.6 Hz, NCH CH CH ), 1.90 (m, NCH CH CH ), 0.91 (t, J=7.6 Hz, NCH CH CH ).
c
2
2
3
2
2
3
2
2
3