Liquid-phase synthesis of 2-substituted benzimidazoles, benzoxazoles and benzothiazoles

Article abstract of DOI:10.1016/j.tetlet.2003.10.095

A novel acid fluoride for use in the liquid-phase synthesis of substituted benzimidazoles, benzoxazoles and benzothiazoles was developed. Its synthetic utility is exemplified by a structurally diverse set of aromatic heterocycles. Final cleavage is achiev

Full text of DOI:10.1016/j.tetlet.2003.10.095

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 113–115
Liquid-phase synthesis of 2-substituted benzimidazoles,
benzoxazoles and benzothiazolesq
Chinpiao Chen* and Yi-Jing Chen
Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien 974, Taiwan, ROC
Received 19 September 2003; revised 17 October 2003; accepted 20 October 2003
Abstract—Anovel acid fluoride for use in the liquid-phase synthesis of substituted benzimidazoles, benzoxazoles and benzothiazoles
was developed. Its synthetic utility is exemplified by a structurally diverse set of aromatic heterocycles. Final cleavage is achieved by
treatment with sodium methoxide in methanol for 12 h. The corresponding benzimidazoles, benzoxazoles and benzothiazoles were
obtained in good isolated yields (22–62%, four steps).
Ó 2003 Elsevier Ltd. All rights reserved.
The development of new methods for the synthesis of
heterocyclic compound libraries, both in solution and in
the solid-phase, represents an expanding area of com-
binatorial chemistry. The benzimidazole, benzoxazole
and benzothiazole structural motifs may be found in
numerous pharmaceutical agents with a diverse range of
biological properties.1 Although a wide range of meth-
ods are available for synthesizing benzimidazole,2
benzoxazole3 and benzothiazole,4 a real need exists for
new simple procedures that support many kinds of
structural diversity and various substitution patterns in
the target library.
benzoxazoles and benzothiazoles, utilizing either linkers
or coupling reagents. Furthermore, a number of solu-
tion-phase methods and reagents for converting alde-
hydes into benzimidazoles, benzoxazoles and
benzothiazoles have recently been published.2–4 In
developing a new strategy for synthesizing Ôbenzimid-
azole, benzoxazole and benzothiazoleÕ-based combina-
torial libraries, the ability to synthesize a structurally
distinct form of the benzimidazole, benzoxazole and
benzothiazole precursor, which can easily be attached to
a PEG support before synthesis, is considered here.
Common methods were used in a combinatorial synthe-
sis of benzimidazoles, benzoxazoles and benzothiazoles,
initially, the corresponding 4-fluoro-3-nitrobenzoic acid
was loaded on solid support, and then the fluorine was
substituted for the amino, hydroxyl and mercapto
groups.2c The nitro group was reduced to an amino
group, and then reacted with the aldehydes or acyl
chlorides to generate the desired heterocyclic com-
pounds. In the present work, the acyl fluoride was easily
loaded on PEG, and the remaining acyl fluoride reacted
with the benzene-1,2-diamine, 2-aminophenol and 2-
aminothiophenol under mild conditions to form corre-
sponding heterocyclic compounds.
Compounds that exhibit the functionality of benzimid-
azole, benzoxazole and benzothiazole have been exten-
sively employed in the area of pharmaceuticals. These
compounds are normally synthesized by condensing
benzene-1,2-diamine, 2-aminophenol and 2-aminobenz-
enethiol with acyl chlorides or aldehydes,2–4 but acyl
chlorides and aldehydes are too reactive to load on PEG
without further protection. The stability of acyl fluoride
can even be worked up from ice water,5 but has not been
employed to functionalize the solid supports. The cur-
rent literature presents an increasing number of exam-
ples of solid-phase syntheses of benzimidazoles,
In the present work (Scheme 1), terephthalic acid was
converted to terephthaloyl fluoride by treating it with
hydrogen fluoride–pyridine and dicyclohexylcarbodi-
imide (DCC).5 it was then reacted with polyethylene
glycol methyl ether (PEG, average molecular weight ca.
5000). One of the acyl fluorides on the terephthaloyl
Keywords: Benzimidazole; Benzoxazole; Benzothiazole.
q Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.10.095
* Corresponding author. Tel.: +886-3-8633597; fax: +886-3-8630475;
e-mail: chinpiao@mail.ndhu.edu.tw
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.095

114
C. Chen, Y.-J. Chen / Tetrahedron Letters 45 (2004) 113–115
was filtered, and the filtrate was added to a solution of
F
O
F
OH
HO
O
O
DCC, HF/pyridine
CH2Cl2, rt
poly(ethylene glycol)methyl ether (10 g, 2 mmol, PEG)
and triethylamine (1.38 mL) in dichloromethane (20 mL)
by cannula. The reaction solution was stirred at room
temperature for 12 h, and the solution was concentrated
to a volume of about 30 mL. The solid was removed by
filtration, and the filtrate was added to diethyl ether
(400 mL) to precipitate the PEG-R 1. After the mixture
had been left to stand for 15 min, PEG-R 1 was obtained
by filtration (Fig. 1). To a solution of PEG-R 1 in di-
chloromethane (100 mL) was added a solution of benz-
ene-1,2-diamine (0.65 g, 6 mmol) and triethylamine
(1.39 mL) in dichloromethane (40 mL) by cannula. The
reaction mixture was stirred at room temperature for
12 h, and potassium carbonate (1.5 g) was added. After
1 h, the solution was concentrated to a volume of about
30 mL. The solid was removed by filtration, and the
filtrate was added to diethyl ether (400 mL) to precipi-
tate out PEG-R 5. After the mixture was left to stand for
15 min, PEG-R 5 was obtained by filtration. It was
dissolved in 1,4-dioxane (65 mL) and glacial acetic acid
(5 mL) was added; the resulting solution was refluxed for
12 h. After the solution was cooled to room tempera-
ture, it was concentrated to a volume of about 30 mL,
and added to diethyl ether (400 mL) to precipitate out
PEG-R 8. After the solution had been left to stand for
15 min, PEG-R 8 was obtained by filtration. To a
solution of PEG-R 8 (1 g, 0.2 mmol) in methanol
(10 mL) was added sodium methoxide (1.39 mL, 0.7 M
in methanol), which was stirred at room temperature for
12 h. The reaction was quenched by adding some am-
monium chloride and stirred for 20 min. The reaction
solution was added to diethyl ether (250 mL) to precip-
itate the PEG. After the solution had been left to stand
for 15 min, PEG was removed by filtration, and the fil-
trate was concentrated, which was purified by flash
chromatography on silica gel. The structures and yields
of compound 11–16 are shown in Table 1.
O
OH
TEA, CH2Cl2, rt
O
O
X
O
O
O
F
TEA, CH2Cl2 (or THF), rt
O
HN
X
2: X = NH2
3: X = OH
4: X = SH
1
5: X = NH
6: X = OH
7: X = SH
2
H2N
MeO
O
Y
N
1,4-dioxane
50oC
NaOMe
O
O
Y
N
MeOH
11: X = NH
12: X = O
13: X = S
8: X = NH
9: X = O
10: X = S
O
MeO
Y
N
14: X = NH
15: X = O
16: X = S
Scheme 1.
fluoride reacted with PEG to form an ester, and an-
other acyl fluoride reacted with benzene-1,2-diamine,
2-aminophenol and 2-aminomercaptophenol to form
the corresponding amides 5, 6 and 7. The amides thus
obtained were refluxed in 1,4-dioxane with acetic acid to
produce the corresponding benzimidazole 8, benzoxa-
zole 9 and benzothiazole 10. Then, the PEG was cleaved
by treatment with sodium methoxide to produce com-
pounds 11, 12 and 13. Instead of the terephthalic acid
with isophthalic acid, the corresponding benzimidazole
14, benzoxazole 15 and benzothiazole 16 were obtained.
Phthalic acid was treated in the same way, but the
desired products were not then obtained. When acyl
fluoride was reacted with 2-aminomercaptophenol in
dichloromethane, the mercapto group reacted with di-
chloromethane to form a thioether 17, after which the
PEG was cleaved by sodium methoxide, yielding com-
pound 18 (Scheme 2).
In summary, a new acyl fluoride reagent was developed
as a linker to load on PEG, and incorporated as a
skeleton of a target compound. This compound is used
to synthesize substituted benzimidazoles, benzoxazoles,
and benzothiazoles has not been reported. The reaction
conditions are amendable to synthesize large combina-
torial libraries.
The general procedure was demonstrated by preparing
4-(1H-benzoimidazol-2-yl)-benzoic acid methyl ester 11.
To a solution of DCC (2.26 g, 10.1 mmol) in dichloro-
methane (20 mL) was added HF-pyridine (308 lL,
ꢀ70% HF); followed a solution of terephthalic acid
(1.66 g, 10 mmol) and pyridine (2 mL) in dichloro-
methane (80 mL) was added by cannula. After the reac-
tion mixture was stirred at room temperature for 2 h, it
CH2Cl
TEA,CH2Cl2,rt
HS
O
O
F
O
O
S
O
O
HN
17
H2N
OMe
NaOMe
MeOH
O
O
S
MeO
HN
18
Scheme 2.
Figure 1. The H NMR spectrum of compound PEG-R 1.

C. Chen, Y.-J. Chen / Tetrahedron Letters 45 (2004) 113–115
Table 1. The structures and yields of compound 11–16 via Scheme 1
115
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Compound
Structure
% Yielda
H
N
MeO
O
11
44
N
MeO
O
O
N
12
13
56
22
MeO
O
S
N
O
MeO
H
14
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27
62
N
N
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O
MeO
O
N
O
MeO
S
N
16
37
a The yield was calculated based on the theoretical loading of the PEG,
and the products were purified by flash chromatography on SiO2.
Supplementary material
Supplementary material includes the H NMR and 13C
NMR spectra and data of compounds 11–16 and 18.
1
Acknowledgements
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The authors would like to thank the National Science
Council of the Republic of China for financially sup-
porting this research under contract no. NSC 91-2113-
M-259-006.
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