The First Synthesis of Protected 5-Hydroxymethyl-2-cyanomethylbenzimidazole

Article abstract of DOI:10.3987/COM-07-11133

Protected 5-hydroxymethyl-2-cyanomethylbenzimidazole 4 has successfully been synthesized starting from 3,4-diaminobenzoic acid 1. The benzimidazole 4 is expected to be a useful intermediate for the synthesis of new functional molecules such as drugs, agro

Full text of DOI:10.3987/COM-07-11133

HETEROCYCLES, Vol. 71, No. 11, 2007
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HETEROCYCLES, Vol. 71, No. 11, 2007, pp. 2491 - 2497. © The Japan Institute of Heterocyclic Chemistry
Received, 7th June, 2007, Accepted, 18th July, 2007, Published online, 25th July, 2007. COM-07-11133
THE
FIRST
SYNTHESIS
OF
PROTECTED
5-HYDROXYMETHYL-2-CYANOMETHYLBENZIMIDAZOLE
Isamu Katsuyama*a and Masanori Kubob
aHitec Co., Ltd., 1-8-30 Temmabashi, Kita-ku, Osaka-shi, Osaka 530-6025, Japan
bKaneka Co., Ltd., 3-2-4 Nakanoshima, Kita-ku, Osaka-shi, Osaka 530-8288,
Japan
*Present address: WDB Co., Ltd., 1-40 Wakatake-cho, Kusatsu-shi, Shiga
525-0031, Japan. E-mail: katsuyama_i@ybb.ne.jp
Abstract – Protected 5-hydroxymethyl-2-cyanomethylbenzimidazole 4 has
successfully been synthesized starting from 3,4-diaminobenzoic acid 1. The
benzimidazole 4 is expected to be a useful intermediate for the synthesis of new
functional molecules such as drugs, agrochemicals, dyes, perfumes, and
cosmetics.
INTRODUCTION
Fused heterocycles such as benzimidazoles, benzoxazoles, and benzothiazoles, are quite important
compounds for the development of functional organic molecules such as pharmaceuticals,1 DNA-binding
molecules,2 functional dyes,3 and heteroaromatic polymers.4 Benzimidazoles, in particular,
2-cyanomethylbenzimidazoles are often used as intermediates for the synthesis of numerous
benzimidazole-containing compounds, for example, imidazopyridines as antifungal agents,5
benzimidazolyl-coumarins as fluorecent dyes,6 benzimidazolyl-ethanones as HIV-integrase inhibitors,7
benzimidazolyl-acrylonitriles with cytotoxic activities,8 pyrrolo[1,2-a]benzimidazoles with many
applications,9 and Ln(Ⅲ) and Y(Ⅲ) complexes of benzimidazol-2-acetic acid as plant growth
promoters.10 Some 5-substituted 2-cyanomethylbenzimidazoles are known compounds; the 5-alkyl,

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alkoxy, and carboxy-substituted derivatives are reported to be prepared. 11 Protected
5-hydroxymethyl-2-cyanomethylbenzimidazole was an essential synthetic intermediate for an our project
aimed at the development of a new coloring agent. No papers, however, have been reported for the
5-hydroxymethyl-substituted derivative as far as we know. The hydroxymethyl group is well known to
be a good hydrogen donor/accepter, and more importantly it can be converted into numerous functional
groups. The hydroxymethyl-substituted benzimidazole, therefore, is expected to be a useful
intermediate for the synthesis of benzimidazole-containing functional molecules such as drugs,
agrochemicals, dyes, perfumes, and cosmetics. This paper describes the first synthesis of protected
5-hydroxymethyl-2-cyanomethylbenzimidazole 4 (Figure 1).
CN
N
PGO
N
H
4 (PG=TBDPS)
Figure 1
RESULTS AND DISCUSSION
Two possible routes to 4 (route A and route B) were at first considered starting from 3,4-diaminobenzoic
acid derivatives 1 as shown in Scheme1.
RO2C
CN
route A
N
CN
N
CN
N
HO
PGO
N
H
N
H
N
H
step 2
step 3
4
step 1
RO2C
NH2
NH2
step1
1
NH2
NH2
NH2
NH2
CN
N
PGO
PGO
HO
route B
N
step 3
H
step 2
2
3
4
Scheme 1
Although the route A appears to be a reasonable process with a view to obtaining 4, there are a few
problems that should be resolved: (i) step 1 is reported to give the product in a low yield (34%) according
to a literature,11a (ii) step 2 requires selective reduction of carboxy groups in the presence of cyano group,
(iii) step 2 and/or step 3 may cause side reaction such as self condensation because cyanomethyl group

HETEROCYCLES, Vol. 71, No. 11, 2007
2493
would be activated to react with electron-deficient moieties under acidic and/or basic conditions, which
are usually necessary for reduction of carboxy group and introduction of protective groups. Although
the route B may be an unusual process for this study, it seems to be widely applicable; the precursor 3
should be used not only for the synthesis of the desired 4 but also for that of many 1,3-benzoazoles
including other benzimidazoles. At this time, therefore, we have decided to choose the route B.
A few papers have been reported for the preparation of the intermediate 3,4-diaminobenzyl alcohol 212;
they require severe reaction conditions, expensive starting materials, and/or long step procedures.
Surprisingly, there are no reports for the synthesis of the alcohol 2 starting from the acid derivatives 1 in
spite of a short step protocol. A direct synthesis of 2 was at first attempted by the reduction of
commercially available 3,4-diaminobenzoic acid 1 as a starting material (Scheme 2).
HO2C
NH2
NH2
NH2
NH2
HO
1
2
Scheme 2
The reduction of the acid 1 with LiAlH4 or BH3-THF gave only a trace amount (3-6%) of 2 along with
several by-products including 3,4-diaminotoluene, while that of 1 with Red-Al hardly proceeded. These
results suggest that the conversion of the acid 1 into the alcohol 2 is quite difficult. As an alternative
manner, the synthesis of 2 was tried by the reduction of ethyl 3,4-diaminobenzoate 1’, which was readily
prepared by the esterification of 1 (Scheme 3).
EtO2C
NH2
NH2
NH2
NH2
HO
1'
2
Scheme 3
When the ester 1’ was treated with LiAlH4 or Red-Al, no formation of 2 was observed because of
polymerization and/or decomposition. On the other hand, the reduction of 1’ with LiBH4 finally gave
the desired 2 in a moderate yield (40-45%) along with the starting material 1’ (29%). Although this
method is not quite versatile, this is the first example for a direct synthesis of 2 by the reduction of 1’
without protecting amino groups. When the hydroxy group in 2 was then protected with the TBDPS
group by the reaction with TBDPSCl, diaminobenzyl TBDPS ether 3 was obtained in a high yield (87%).
The synthesis of 4 was subsequently attempted by the reaction of 3 with cyano acetic ester according to a
general method for the preparation of cyanomethylbenzimidazole (Scheme 4).11b, 13

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HETEROCYCLES, Vol. 71, No. 11, 2007
NCCH2CO2R
NH2
NH2
CN
N
TBDPSO
TBDPSO
N
H
3
4
Scheme 4
When the ether 3 was treated with butyl cyanoacetate in phenetole or DMF at 150 °C, substantial
unidentified materials were formed. The reaction at lower temperature was then performed in reflux
toluene or MeCN. Under these conditions, however, no reaction occurred. These results indicate that
the reported method is not suitable for the synthesis of substituted cyanomethylbenzimidazole such as 4.
As an alternative procedure, the reaction of 3 with cyanoacetimidate instead of cyanoacetic ester was then
investigated for the synthesis of 4 (Scheme 5).
NH.HCl
NC
NH2
NH2
CN
N
OR
TBDPSO
TBDPSO
N
H
4
3
Scheme 5
When 3 was treated with methyl cyanoacetimidate hydrochloride14 in reflux EtOH, decomposition
occurred. On the other hand, the reaction in EtOH at room temperature finally provided the desired 4 in
a moderate yield (58%). The use of MeOH instead of EtOH led to a further improvement in the yield of
4 (85%). The reaction conditions have been optimized in MeOH at room temperature.
In conclusion, the first synthesis of TBDPS-protected 5-hydroxymethyl-2-cyanomethylbenzimidazole 4
has been successful in four steps starting from 3,4-diaminobenzoic acid 1. Because the benzimidazole 4
possesses active methylene, cyano, and protected hydroxymethyl groups, this new compound can be
transformed into many kinds of benzimidazole-containing derivatives. The application of 4 to a possible
benzimidazole-containing functional molecule will be reported as a separate paper.
EXPERIMENTAL
13
1H and C NMR spectra were recorded with a Varian VXR-300 spectrometer using tetramethylsilane
(TMS) as an internal standard. IR spectrum was measured with a JASCO FT-IR 4200 spectrometer.

HETEROCYCLES, Vol. 71, No. 11, 2007
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All the commercially available reagents were used without further purification.
cyanoacetimidate hydrochloride was prepared according to a literature method.14a
Methyl
Synthesis of Ethyl 3,4-diaminobenzoate 1’: 3,4-Diaminobenzoic acid 1 (8.0 g, 52.6 mmol) was
suspended in EtOH (150 mL). Sulfuric acid (15.5 g) was added and the mixture was then refluxed while
being stirred for 6 h. After the EtOH was removed, the residue was dissolved in water and basified with
Na2CO3. The formed precipitate was filtrated, and washed with water and acetone/hexane (1/3) to give
1’ (8.05 g, yield: 85%). 1H NMR (CDCl3): δ 1.36 (t, 3H, J = 7.1 Hz), 3.46 (brs, 4H), 4.31 (q, 2H, J =
7.1 Hz), 6.68 (d, 1H, J = 7.8 Hz), 7.42 (d, 1H, J = 2.1 Hz), 7.48 (dd, 1H, J = 7.8 and 2.1 Hz).
Synthesis of 3,4-Diaminobenzyl alcohol 2: To a solution of ethyl 3,4-diaminobenzoate 1’ (3.60 g, 20.0
mmol) in anhydrous THF (40 mL) was added LiBH4 (0.56 g, 25.5 mmol) while being stirred at rt under
nitrogen atmosphere. The mixture was further stirred at 57-60 °C for 6 h. After being cooled to rt, ice
water was gradually added to destroy excess hydride. After filtration of the insoluble material, the
aqueous filtrate was extracted with AcOEt for a few times and then dried over anhydrous sodium sulfate.
After removal of the solvent, the residue was chromatographed on silica gel using AcOEt/MeOH (5/1) as
an eluent to give 2 (1.23 g, yield: 45%) along with starting material 1’ (1.04 g, recovery: 29%). 1H
NMR (CDCl3): δ 2.95 (brs, 4H), 4.52 (s, 2H), 6.65-6.75 (m, 3H).
Synthesis of 4-(tert-Butyldiphenylsilyl)oxymethyl-1,2-benzenediamine 3: To a suspension of the
alcohol 2 (1.18 g, 8.6 mmol) in anhydrous CH2Cl2 (30 mL) were added sequentially Et3N (1.73 g, 17.1
mmol), 4-N, N-dimethylaminopyridine (100 mg, 0.7 mmol), and tert-butyldiphenylchlorosilane (3.53 g,
12.8 mmol) at rt while being stirred under nitrogen atmosphere. The mixture was further stirred for 3 h
at this temperature. The reaction was quenched with sat. aqueous NaHCO3. The organic layer was
separated and washed with brine, and then dried over anhydrous sodium sulfate. After removal of the
solvent, the residue was chromatographed on silica gel using CH2Cl2/AcOEt (1/1) as an eluent to give 3
as an oily semisolid (2.82 g, yield: 87%). 1H NMR (CDCl3): δ 1.08 (s, 9H), 3.30 (brs, 4H), 4.63 (s, 2H),
6.66 (s, 2H), 6.68 (s, 1H), 7.34-7.42 (m, 6H), 7.70 (dd, 4H, J = 7.8 and 1.8 Hz); MS m/z (%) 376 (M+, 21),
301 (100), 241 (58), 199 (95), 121 (89).
Synthesis of 2-Cyanomethyl-5-(tert-butyldiphenylsilyl)oxymethylbenzimidazole 4: To a solution of
the diamine 3 (3.33 g, 8.86 mmol) in MeOH (22 mL) was added methyl 2-cyanoacetimidate
hydrochloride (2.40 g, 17.82 mmol) at rt. The mixture was then stirred for 2 h at this temperature. The

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reaction was quenched with sat. aqueous NaHCO3 and extracted with AcOEt. After filtration of the
insoluble material, the organic layer was separated and washed with water and brine, and then dried over
anhydrous sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel
using CH2Cl2/AcOEt (1/1) as an eluent to give 4 as an oily semisolid (3.21 g, yield: 85%). IR (KBr)
1
ν 2200 cm-1; H NMR (CDCl3): δ 1.09 (s, 9H), 4.12 (s, 2H), 4.88 (s, 2H), 7.22 (d, 1H, J = 8.2 Hz),
7.33-7.44 (m, 6H), 7.54 (d, 1H, J = 8.2 Hz), 7.63 (s, 1H), 7.69 (d, 4H, J = 7.8 Hz); 13C NMR (CDCl3)
δ 19.2, 19.3, 26.8, 65.6, 115.1, 121.9, 127.7, 129.7, 133.5, 135.5, 142.5. HRFABMS: m/z calcd for
C26H28N3OSi (M + H)+ 426.2002, found 426.1963.
ACKNOWLEDGEMENTS
We are grateful to Kansai University for MS measurement and also grateful to Tohoku Pharmaceutical
University for HRFABMS measurement.
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