Solid-phase combinatorial synthesis of benzothiazoles, benzimidazoles, and benzoxazoles using a traceless linker

Article abstract of DOI:10.1016/j.tet.2007.08.073

New methodology for the solid-phase synthesis of benzothiazoles, benzimidazoles, and benzoxazoles has been developed by using a traceless 4-alkoxy-aniline linker. The desired products were released from the polymer support by imine-exchange process couple

Full text of DOI:10.1016/j.tet.2007.08.073

Tetrahedron 63 (2007) 11315–11324
Solid-phase combinatorial synthesis of benzothiazoles,
benzimidazoles, and benzoxazoles using a traceless linker
*
Hideaki Hioki, Kimihito Matsushita, Miwa Kubo, Kenichi Harada,
Mitsuaki Kodama and Yoshiyasu Fukuyama
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 3 August 2007; revised 23 August 2007; accepted 24 August 2007
Available online 26 August 2007
Abstract—New methodology for the solid-phase synthesis of benzothiazoles, benzimidazoles, and benzoxazoles has been developed by
using a traceless 4-alkoxy-aniline linker. The desired products were released from the polymer support by imine-exchange process coupled
with air oxidation. Combinatorial library consisting of 36 members has been synthesized using this linker. The yields are low to good, which
highly depend on the building blocks. Recycling of the polymer support was also investigated.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
advantageous because the functional group attached on
a solid support is not necessary for the target molecules.7
We recently developed a new traceless linker 2 suitable for
the synthesis of compounds possessing azomethines and
applied it to the synthesis of a rod-shaped liquid crystalline
library (Fig. 2).8 In previous studies, the product yields were
dependent on the stability balance of the resin-bound azome-
thines. The overall yields of azomethines were low to mod-
erate because the resin-bound azomethine 4 suffered partial
alcoholysis during condensation with alcohols. On the other
hand, a resin-bound azomethine 6, which was loaded on the
4-alkoxyaniline linker 3, was more stable against alcoholy-
sis than 4, but the equilibrium for the imine-exchange pro-
cess was not shifted effectively in favor of the final
product 7 at the cleaving step due to comparable stability
of 6 and 7 (Scheme 1). In the latter case, it is expected to im-
prove product yields if the resin-bound substrates are
cleaved by an irreversible process.
Benz-fused azoles 1, such as benzothioazoles, benzimid-
azoles, and benzoxazoles are an important class of com-
pounds (Fig. 1). They provide a common scaffold to
various derivatives, which can be utilized as not only
a wide variety of biologically active and medicinally signif-
icant compounds1 but also advanced materials including
non-linear optics (NLO),2 organic light-emitting diodes
(OLED),3 and liquid crystals.4 Hence, facile preparation of
various benz-fused azole derivatives for rapid discovering
of new drugs and materials is highly desirable. Solid-phase
synthesis is particularly effective for split/mix combinatorial
synthesis to generate a large number of compounds. There-
fore, solid-phase combinatorial syntheses of these com-
pounds have been reported by some groups.5
The selection of an adequate linker in the solid-phase syn-
thesis is one of the key factors for efficiently building
the desired libraries.6 Traceless linkers, in particular, are
In general, oxidation is an irreversible process and thus is
most likely to be suitable for our solid-phase synthesis. Re-
cently, Hayashi and co-workers reported practical synthesis
of 2-arylbenzoxazoles by oxidative coupling of 2-aminophe-
nols and aldehydes in the presence of DarcoÒ KB (a sort of
activated carbon) and air.9 This oxidation does not require
any oxidation reagents at cleaving step, and also DarcoÒ
KB can be easily removed by simple filtration. This oxida-
tive protocol would be highly advantageous to develop an
imine-exchange irreversible process in our solid-phase syn-
thesis of benz-fuzed azoles 1.
N
X
1
X = O, S, NR
Figure 1. Benz-fused azoles.
Keywords: Combinatorial synthesis; Traceless linker; Benzoxazole; Benzo-
thiazole; Benzimidazole.
In this paper, we report the solid-phase combinatorial
synthesis of 2-arylbenzothiazoles, benzimidazoles, and
* Corresponding author. Tel.: +81 88 602 8437; fax: +81 88 6553051;
e-mail: hioki@ph.bunri-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.073

11316
H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
O
O
OC9H19
OH
N
N
O
a
b, c
2
C8H17
O
N
H
4
5
66%
O
O
OMe
OMe
N
N
c
d
O
3
N
H
O
C8H17
O
4
6
7
70%
Scheme 1. Synthesis of azomethines using traceless aniline linkers. Reagents: (a) 4-formylbenzoic acid; (b) 1-nonanol, DIC, DMAP; (c) 4-octyloxyaniline; (d)
methyl 4-formylbenzoate.
2-aminophenol was obtained in the absence of DarcoÒ KB
NH2
NH2
O
O
(entry 3). The results showed that DarcoÒ KB promoted
not only oxidative cleavage of a resin-bound substrate but
also oxidative decomposition of 2-aminophenol. Unexpect-
edly, treatment of 8 with 4 equiv of 2-aminothiophenol at
room temperature for 18 h produced corresponding 2-aryl-
benzothiazole 9 (Y¼S) in 68% yield under an air atmosphere
even in the absence of DarcoÒ KB (entry 4). The yield was
improved to 90% on reacting at elevated temperature (entries
N
H
N
H
O
4
2
3
Figure 2. Two traceless aniline linkers.
benzoxazoles by applying oxidative cleavage to release
them from a solid support connected through azomethine
linkage.10
Table 1. Isolated yields in three-step synthesis of benzoxazole 9 (Y¼O),
benzothiazole 9 (Y¼S), benzimidazole 9 (Y¼NH), and N-methylbenzimid-
azole 9 (Y¼NMe) on a solid support
2. Results and discussions
Entry
Y
Conditionsa
Temp (ꢀC)
Yield
(%)
2.1. Oxidative cleavage of resin-bound azomethines
using various 2-heteroatom-substituted anilines
Period
Additive
1
2
3
4
5
6
7
8
O
S
1 h
100
100
100
rt
DarcoÒ KB
22
58 (79)b
1
18 h
18 h
18 h
18 h
18 h
5 min
20 min
1 h
20 min
20 min
1 h
18 h
18 h
48 h
72 h
DarcoÒ KB
First of all, oxidative release of resin-bound azomethines
with various 2-heteroatom-substituted anilines was exam-
ined to afford benz-fused azoles by applying the Hayashi’s
process.9 Solid supported azomethine esters 8 were prepared
according to the previously reported procedure (Scheme 2).8
Yields of three-step synthesis of 2-aryl-benz-fused azoles are
summarized in Table 1. By treating 8 with 4 equiv of 2-ami-
nophenol at 100 ꢀC for 1 h in the presence of DarcoÒ KB, 2-
arylbenzoxazole 9 (Y¼O) was obtained in 22% yield (entry
1). Air oxidation was concomitant with imine-exchange as
expected to release the product. The yield was improved up
to 58% in a longer period of time (entry 2). Excess 2-amino-
phenol was consumed during the reaction period. When the
resulting resin was treated with 4 equiv of 2-aminophenol
again, an additional compound 9 (Y¼O) was isolated in
21% yield. Only a trace amount of the product along with
—
—
—
—
—
—
—
—
—
—
—
—
—
—
68
82
90
76
91
90
51
5
14
84
42
76
73
50
100
100
100
100
100
100
100
100
100
100
100
9
10c
11
12
13
14
15
16
NH
NMe
a
Conditions for oxidative cleavage from a solid support (step 3).
A value in a parenthesis refers to combined yield after successive treat-
ment of 2-aminophenol.
b
c
Two equivalents of 2-aminothiophenol were used.
O
O
OBu
OBu
N
N
c
a, b
O
3
Y
N
H
O
4
Y = O, S, NH, NMe
8
9
Scheme 2. Three-step synthesis of 2-aryl benz-fuzed azoles including oxidative cleavage of azomethines in the presence or absence of DarcoÒ KB. Reagents and
conditions: (a) 4 equiv of 4-formylbenzoic acid, DMF, rt, 24 h; (b) 4 equiv of 1-butanol, DIC, DMAP, DCM, rt, 3 h; (c) 4 equiv of 2-aminophenol (Y¼O),
2-aminothiophenol (Y¼S), 1,2-phenylenediamine (Y¼NH), or N-methyl-1,2-phenylenediamine (Y¼NMe), air, (DarcoÒ KB), DMF. Yields are shown in Table 1.

H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
11317
5 and 6). The reaction was completed within 20 min at
100 ꢀC (entries 6–9). Two equivalents of 2-aminothiophenol
resulted in the decrease of yield (entry 10), indicating that
a substantial amount of 2-aminothiophenol was still decom-
posed under the air oxidation conditions. In the absence
of DarcoÒ KB, 2-arylbenzimidazole (Y¼NH) was also
obtained in good yield, in the case of running the reaction
over a longer period of time (entries 11–13). N-Methyl-2-
arylbenzimidazole (Y¼NMe) was also obtained in good
yield although much longer reaction time was required
(entries 14–16).
synthesis because molecular weight per unit function con-
necting the substrate is very high. In addition, solid supports
are generally expensive. Thus, recycling of the solid support
is highly desirable. It should be noted that the solid support 3
can be easily recovered and recycled after cleavage of the
resin-bound azomethines 8 as shown in Scheme 3. Thus it
is interesting to explore how many times the solid support 3
can be recycled and reused. The synthesis of 2-arylbenzothi-
azole 9 (Y¼S) and 2-arylbenzimidazole 9 (Y¼NH) was re-
peated under optimized conditions by recycling. As results,
yields were decreased by 10–20% lower at every recycling
(table in Scheme 3). The decreases related to the overall
yields were presumed to be due to some decomposition of
4-alkoxyaniline linker 3 during oxidativecleavage of the sub-
strate. However, the recycling process without esterification
did not cause the decrease of the yields (table in Scheme 4).
2.2. Recycling of an 4-alkoxyaniline linker
From a point of view of an atom economy, solid-phase
synthesis is less efficient than conventional solution-phase
NH2
O
O
COOH
1)
OBu
N
O
O
4
H
N
H
3
Y
DMF, rt, 24 h
O
9
Y = S, NH
OH
Oxidative decomposition of 3
N
O
N
H
O
10
4
n-BuOH
2)
3)
NH2
YH
DMAP, DIC
DCM, rt, 3 h
DMF, air, 100 °C
Y = S, 20 min
Y = NH, 14 h
O
OBu
+
3
OBu
OBu
N
HO
O
11
O
N
H
O
8
4
OBu
OBu
H
N
Yields of 9 (%)
Cycle
O
Y = NH
Y = S
O
N
O
4
1st
2nd
3rd
86
77
48
84
69
45
H
12 (Acylation of 3)
Scheme 3. Recyclability of solid support 3 for the three-step synthesis of 9.
COOMe
1)
O
DMF, rt, 24 h
H
O
OMe
N
NH2
O
O
N
H
O
N
H
O
4
4
6
3
O
NH2
SH
Cycle
Yields (%) of 13
2)
OMe
1st
2nd
3rd
97
95
98
N
DMF, air, 100 °C, 20 min
S
13
Scheme 4. Recycling of solid support 3 for two-step synthesis of 13.

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H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
Judging from both the results, the drawback to the recycling
of 3 is ascribable to partial formation of amide 12 on the solid
support via alcoholysis of 10, followed by consecutive con-
densation between 3 and 11. This means that there remains
the problem that 4-alkoxyanline linker 3 is not stable enough
to suppress a competing alcoholysis of 10. Recycling is lim-
ited to two or three times in the present study.
provided a library consisting of 36 members. Oxidative
cleavage was performed at 100 ꢀC for 18 h except for
N-methylbenzimidazole series, which were reacted for 48 h.
DarcoÒ KB was employed for the synthesis of 2-arylbenz-
oxazoles. The reaction rate in the final step highly depended
on the substituents at aromatic nuclei. When X was a methoxy
group, the reaction rate was the fastest in all the series. On the
other hand, when X was bromine, the reaction rate was the
slowest. The order of reaction rate seems to reflect the oxidiz-
ing potential of cyclic acetal intermediates 16. The final prod-
ucts were separated from excess reagents and their oxidative
decomposition products by silica gel column chromato-
graphy. Most of library members were easily purified.
The yields are summarized in Table 2. When X was hydro-
gen, esters and thioesters with 2-arylbenzothiazoles or
2-arylbenzimidazoles were obtained in good yields. When
X was bromine or a methoxy group, the yields were slightly
reduced. This is presumably explained due to the instability
of resin-bound azomethines 14 and 15 in which steric hin-
drance between X and azomethine linkage causes out-of-
plane distortion of the two aromatic rings. Partial aminolysis
of thioesters in N-methylbenzimidazoles reduced yields, be-
cause the reaction time was longest among all the series. Am-
ides were synthesized in low to moderate yields, indicating
that substantial amount of imine-exchange reaction between
15 and diisobutylamine was unavoidable even if 4-alkoxyani-
line linker 3 was used.
2.3. Split synthesis of benz-fuzed azole library consisting
of 36 members
Next, we attempted combinatorial library synthesis to dem-
onstrate the scope and versatility of our solid-phase reactions
(Scheme 5). Three kinds of 4-formylbenzoic acid derivatives
(4-formylbenzoic acid, 4-formyl-3-methoxybenzoic acid,
and 3-bromo-4-formylbenzoic acid) were prepared. They
condensed with a 4-alkoxyaniline linker 3 on the solid sup-
port to afford resin-bound azomethines 14 (step 1). In the
second step, n-butanol, nonanethiols, and diisobutylamines
were reacted with 14 to give azomethines 15 (step 2). Fi-
nally, the azomethines on the solid support were cleaved
by four kinds of 2-heteroatom substituted anilines (2-amino-
phenol, 2-aminothiophenol, 1,2-phenylenediamine, and
N-methyl-1,2-phenylenediamine) through an imine-exchange
process coupled with air oxidation to give 2-arylbenz-
oxazoles 17 (Y¼O), 2-arylbenzothiazoles 17 (Y¼S), and
2-arylbenzimidazoles 17 (Y¼NH, NMe) (step 3), which
O
b
O
X
X
OH
R1
N
N
O
O
a
3
N
H
N
H
O
O
4
4
14 3 members
X = H, OMe, Br
15 9 members
R
1 = OC4H9, SC9H19, N(CH2CHMe2)2
O
O
X
R1
X
R1
N
Y
H
N
c
Y
36 members
16
17
Y = O, S, NH, NMe
Scheme 5. Split synthesis of benzothiazoles, benzimidazoles and benzoxazoles library consisting of 36 members. Reagents and conditions: (a) three kinds of
4-formylbenzoic acids (4-formylbenzoic acid, 4-formyl-3-methoxybenzoic acid, and 3-bromo-4-formylbenzoic acid), DMF, rt, 24 h; (b) n-C4H9OH,
n-C9H19SH, or (Me2CHCH2)2NH, DIC, DMAP, DCM, rt, 3 h; (c) four kinds of 2-substituted anilines (2-aminophenol, 2-aminothiophenol, 1,2-phenylenedi-
amine, N-methyl-1,2-phenylenediamine), air, DarcoÒ KB (only for Y¼O), DMF, 100 ꢀC, 18–48 h.
Table 2. Isolated yields (%) of all library members 17
R1
X
Benzoxazole
Benzothiazole
Benzimdazole
N-Methyl benzimidazole
Y¼NMe
Y¼O
Y¼S
Y¼NH
OBu
H
OMe
Br
H
OMe
Br
H
OMe
Br
58
44
30
44
30
32
15
7
87
72
70
88
70
60
47
33
31
84
80
64
82
70
74
40
38
37
77
54
77
30
25
23
23
17
19
SC9H19
N(CH2CHMe2)2
8

H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
11319
3. Conclusion
with DMF (3ꢁ2 min) and DCM (3ꢁ2 min). The combined
DMF and DCM solutions were filtered. The filtrate was
evaporated and purified by silica gel chromatography (hex-
ane/EtOAc¼2:1) to give 9 (Y¼O) in 58% yield (12.8 mg,
43.5 mmol) as colorless solid. Butyl 4-(benzothiazol-2-yl)-
benzoate 9 (Y¼S), butyl 4-(benzimidazol-2-yl)benzoate 9
(Y¼NH), and butyl 4-(1-methyl-benzimidazol-2-yl)benzo-
ate 9 (Y¼NMe) were synthesized employing the almost
same manner as described above. Yields are shown in Table
1 under various reaction conditions.
We have demonstrated that an 4-alkoxyaniline unit is
employed as a versatile traceless linker for solid-phase com-
binatorial syntheses of 2-arylbenzoxazoles, 2-arylbenzo-
thioazoles, and 2-arylbenzimidazoles, which are frequently
involved in a number of drugs and advanced materials. It
should be emphasized that the products can be released
from the solid support only by exposing it to an air atmo-
sphere without any kinds of oxidants under neutral condi-
tions. This new methodology will be widely applicable for
combinatorial synthesis because time-consuming work-up
is avoided to obtain the final products. Although the
recycling of the solid support is limited, the present studies
would provide a primary insight into the possibility of
increasing the number of recycling the solid support. Further
efforts for developing traceless linkers that can stabilize
a solid supported azomethine intermediate are under
investigation.
4.2.2.1. Butyl 4-(benzoxazol-2-yl)benzoate 9 (Y=O).
1
Colorless solid, mp 127 ꢀC; H NMR (300 MHz, CDCl3)
d 1.01 (3H, t, J¼7.1 Hz), 1.51 (2H, tq, J¼7.1, 7.1 Hz),
1.80 (2H, tt, J¼6.6, 7.1 Hz), 4.37 (2H, t, J¼6.6 Hz), 7.38–
7.41 (2H, m), 7.60–7.63 (1H, m), 7.80–7.83 (1H, m), 8.19
(2H, d, J¼8.5 Hz), 8.33 (2H, d, J¼8.5 Hz); IR (ATR)
1713 cmꢂ1; MS (CI): m/z 296 ([M+H]+, 100%); HRMS
(CI): calcd for C18H18NO3 ([M+H]+) 296.1287, found
296.1279.
4. Experimental
4.1. General
4.2.2.2. Butyl 4-(benzothiazol-2-yl)benzoate 9 (Y=S).
1
Colorless solid, mp 84 ꢀC; H NMR (300 MHz, CDCl3)
d 1.00 (3H, t, J¼7.4 Hz), 1.50 (2H, tq, J¼7.4, 7.4 Hz),
1.79 (2H, tt, J¼6.6, 7.4 Hz), 4.37 (2H, t, J¼6.6 Hz), 7.42
(1H, ddd, J¼1.1, 7.1, 8.0 Hz), 7.52 (1H, ddd, J¼1.4, 7.1,
8.2 Hz), 7.93 (1H, ddd, J¼0.6, 1.4, 8.0 Hz), 8.11 (1H, ddd,
All commercially available chemicals were used without
further purification. Solid support 3 was prepared from
aminomethylated SynPhase LanternÒ purchased from
Mimotopes Pty Ltd. (Victoria, Australia) according to the
previously reported procedure.8 Melting points were deter-
J¼0.6, 1.1, 8.2 Hz), 8.16 (4H, s); IR (ATR) 1710 cmꢂ1
calcd for C18H17NO2S ([M]+) 311.0980, found 311.0983.
;
MS (EI): m/z 255 (100%), 311 ([M]+, 53%); HRMS (EI):
€
mined using a Buchi B-545 apparatus and are uncorrected.
IR spectra were recorded with a JASCO FT/IR410 spectro-
photometer equipped with SensIR Technologies Dura-
scopeÒ for ATR (attenuated total reflectance) and only
4.2.2.3. Butyl 4-(benzimidazol-2-yl)benzoate 9 (Y=NH).
1
Colorless solid, mp 211 ꢀC; H NMR (300 MHz, CDCl3)
d 0.98 (3H, t, J¼7.1 Hz), 1.48 (2H, tq, J¼7.1, 7.1 Hz),
1.76 (2H, tt, J¼6.6, 7.1 Hz), 4.34 (2H, t, J¼6.6 Hz), 7.26–
7.31 (2H, m), 7.66 (2H, br s), 8.09 (2H, d, J¼7.7 Hz), 8.15
(2H, d, J¼7.7 Hz), 10.9 (1H, s); IR (ATR) 1707 cmꢂ1; MS
(EI): m/z 238 (100%), 294 ([M]+, 94%); HRMS (EI): calcd
for C18H18N2O2 ([M]+) 294.1368, found 294.1371.
1
characteristic peaks are reported. H NMR spectra were
recorded at 200 or 300 MHz with Varian Gemini-200 or
Mercury-300 spectrometers, using tetramethylsilane as
the internal standard. Mass spectra were taken on JEOL
AX-500.
4.2. Oxidative cleavage of resin-bound azomethines with
2-hetroatom-substituted anilines
4.2.2.4. Butyl 4-(1-methyl-benzimidazol-2-yl)benzoate
9 (Y=NMe). Colorless solid, mp 66 ꢀC; 1H NMR (300 MHz,
CDCl3) d 1.00 (3H, t, J¼7.4 Hz), 1.51 (2H, tq, J¼7.4,
7.4 Hz), 1.79 (2H, tt, J¼6.6, 7.4 Hz), 3.89 (3H, s), 4.38
(2H, t, J¼6.6 Hz), 7.31–7.43 (3H, m), 7.82–7.86 (1H, m),
7.86 (2H, d, J¼8.0 Hz), 8.20 (2H, d, J¼8.0 Hz); IR (ATR)
1715 cmꢂ1; MS (CI): m/z 309 ([M+H]+, 100%); HRMS
(CI): calcd for C19H21N2O2 ([M+H]+) 309.1603, found
309.1606.
4.2.1. Preparation of a solid supported azomethine 8. Six
pieces of the solid supported aniline 3 (loading: 75 mmolꢁ6,
450 mmol) were reacted with 4-formylbenzoic acid (270 mg,
1.8 mmol, 4 equiv) in DMF solution (6 mL) at room temper-
ature for 24 h. The solution was removed by decantation and
the resulting resins were washed with DMF (3ꢁ0.5 min) and
DCM (3ꢁ0.5 min). The resulting solid supported azo-
methine 10 (loading: 75 mmolꢁ6, 450 mmol) was reacted
with 4-N,N-dimethylaminopyridine (13.7 mg, 0.113 mmol,
0.25 equiv), n-butanol (133 mg, 1.8 mmol, 4 equiv), and
1,3-diisopropylcarbodiimide (564 mL, 3.6 mmol, 8 equiv)
in DCM at room temperature for 3 h. The solution was re-
moved by decantation and the resulting resins were washed
with DMF (3ꢁ0.5 min) and DCM (3ꢁ0.5 min).
4.3. Recycling of the solid support 3
4.3.1. Recycling for the three-step synthesis of 9. The solid
supported ester 8 was prepared as described above. It (load-
ing: 75 mmolꢁ1, 75 mmol) was reacted with 2-aminothio-
phenol (32.1 mL, 0.3 mmol, 4 equiv) in DMF (3 mL) at
100 ꢀC under an air atmosphere for 20 min. The resulting
resins were washed with DMF (3ꢁ2 min) and DCM
(3ꢁ2 min). The combined DMF and DCM solutions were
evaporated and purified by silica gel chromatography (hex-
ane/EtOAc¼15:1) to give 9 (Y¼S) in 86% yield (21.0 mg,
64.5 mmol) as colorless solid. The resulting resins, which
were washed with 15% TFA in DCM (1ꢁ30 min), DMF
4.2.2. Oxidative cleavage of 8. The solid supported azo-
methine ester 8 (loading: 75 mmolꢁ1, 75 mmol) was reacted
with 2-aminophenol (32.7 mg, 0.3 mmol, 4 equiv) and
DarcoÒ KB (450 mg) in DMF (3 mL) at 100 ꢀC under an
air atmosphere for 18 h. The resulting resins were washed

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H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
(3ꢁ2 min) and DCM (3ꢁ2 min), were treated twice in the
same manner as described above to give 9 (Y¼S) in 77%
yield (18.0 mg, 57.8 mmol) at second recycling and in 48%
yield (11.2 mg, 36.0 mmol) at third recycling. Oxidative
cleavage to give 9 (Y¼NH) was performed at 100 ꢀC under
an air atmosphere for 14 h by employing 1,2-phenylene-
diamine. Work-up and recycling were accomplished in
the same manner. Yields for each recycling are shown in
Scheme 3.
(2.05 g, 8.46 mmol) were added by portions to a refluxing
solution of methyl 3-bromo-4-methylbenzoate (25.3 g,
0.11 mol) in benzene (250 mL). After refluxing for 1.5 h, the
reaction mixture was cooled to room temperature. The precipi-
tate was filtered and the filtrate was evaporated to leave the res-
idue to which 200 mL of brine was added. The mixture was
extracted with toluene (3ꢁ150 mL). The combined organic
layers were dried over sodium sulfate and concentrated to af-
ford the crude methyl 3-bromo-4-(dibromomethyl)benzoate.
Water (100 mL) and sodium carbonate (116 g, 1.1 mol) were
added to a solution of the crude product in ethanol
(120 mL). The reaction mixture was stirred at 90 ꢀC for
72 h. After being cooled to room temperature, the reaction
mixture was quenched slowly by addition of 10 mol Lꢂ1
HCl (250 mL) at 0 ꢀC. After stirring for 16 h at room temper-
ature, 500 mL of water was added to the mixture, which was
filtered to afford the solid crude product. Brine of 200 mL
was added to the solid and extracted with ethyl acetate
(3ꢁ100 mL). The combined organic layers were washed
with brine (2ꢁ50 mL), dried over sodium sulfate, and concen-
trated to furnish crude product, which was purified by flash
chromatography followed by recrystallization (DMF/EtOAc/
hexane). The product (12.4 g, 54.3 mmol, 49% for two steps)
4.3.2. Simple loading and cleavage on the solid support 3.
One piece of the solid supported aniline 3 (loading:
75 mmolꢁ1, 75 mmol) was reacted with methyl 4-formyl-
benzoate (49.2 mg, 0.3 mmol, 4 equiv) in DMF solution
(3 mL) at room temperature for 24 h. The solution was re-
moved by decantation and the resulting resins 6 were washed
with DMF (3ꢁ0.5 min) and DCM (3ꢁ0.5 min). Oxidative
cleavage and purification of the compound were accom-
plished in the same manner as described above to give 13
in 97% yield (19.6 mg, 72.8 mmol) as colorless solid. The
resulting resins, which were washed with 15% TFA in
DCM (1ꢁ30 min), DMF (3ꢁ2 min), and DCM (3ꢁ2 min)
were treated twice following the same procedure as above
to give 13 in 95% yield (19.2 mg, 71.3 mmol) at second
recycling and in 98% yield (19.8 mg, 73.5 mmol) at third
recycling.
1
was obtained as light brown needles; mp 239 ꢀC. H NMR
(300 MHz, DMSO-d6) d 8.06 (1H, d, J¼8.0 Hz), 8.17 (1H,
dd, J¼1.6, 8.0 Hz), 8.32 (1H, d, J¼1.6 Hz), 10.4 (1H, s); IR
(ATR) 1680 cmꢂ1; MS (CI): m/z 229 ([M+H]+, 100%);
HRMS (CI): calcd for C8H6BrO3 ([M+H]+) 228.9500, found
228.9492.
4.3.2.1. Methyl 4-(benzothiazol-2-yl)benzoate 13. Col-
orless solid, mp 164 ꢀC; 1H NMR (300 MHz, CDCl3) d 3.96
(3H, s), 7.42 (1H, ddd, J¼1.1, 7.4, 8.0 Hz), 7.52 (1H, ddd,
J¼1.4, 7.4, 8.2 Hz), 7.93 (1H, ddd, J¼0.6, 1.4, 8.0 Hz),
8.10 (1H, ddd, J¼0.6, 1.1, 8.2 Hz), 8.16 (4H, s); IR (ATR)
1715 cmꢂ1; MS (EI): m/z 269 ([M]+, 53%); HRMS (EI):
calcd for C15H11NO2S ([M]+) 269.0511, found 269.0511.
4.4.2. General procedures for the synthesis of the library.
The library was prepared by general ‘Split and Pool Syn-
thesis’ using color coded tags.12
4.4.2.1. Synthesis of 14 (X=OMe) on solid support 3.
Six pieces of the solid supported aniline 3 (loading:
75 mmolꢁ6, 450 mmol) were reacted with 4-formyl-3-
methoxybenzoic acid (325 mg, 1.8 mmol, 4 equiv) in DMF
(6 mL) at room temperature for 24 h. The solution was re-
moved by decantation and the resulting resins were washed
with DMF (3ꢁ0.5 min) and DCM (3ꢁ0.5 min). 4-Formyl-
benzoic acid and 3-bromo-4-formylbenzoic acid were also
loaded by the same procedure.
4.4. Library synthesis
4.4.1. Syntheses of building blocks. All building blocks
except for the following two reagents are commercially
available.
4.4.1.1. Synthesis of 3-methoxy-4-formylbenzoic
acid. Water (120 mL) and sodium carbonate (4.68 g,
44.2 mmol) were added to a solution of methyl 4-formyl-
3-methoxybenzoate11 (4.29 g, 22.1 mmol) in ethanol
(140 mL). The mixture was refluxed for 2.5 h. After being
cooled to room temperature, the reaction mixture was
quenched slowly by addition of 1 mol Lꢂ1 HCl (100 mL).
The mixture was extracted with diethyl ether (3ꢁ100 mL).
The combined organic layers were washed with brine
(2ꢁ50 mL), dried over sodium sulfate, and concentrated to
furnish the crude product, which was purified by flash chro-
matography (silica gel 40 g, EtOAc) followed by recrystalli-
zation (EtOAc). The product (2.47 g, 13.7 mmol, 62%) was
obtained as light yellow needles; mp 233 ꢀC. 1H NMR
(300 MHz, DMSO-d6) d 4.10 (3H, s), 7.73 (1H, dd, J¼1.4,
8.0 Hz), 7.79 (1H, d, J¼1.4 Hz), 7.91 (1H, d, J¼8.0 Hz),
10.5 (1H, s); IR (ATR) 1699, 1651 cmꢂ1; MS (EI): m/z
180 ([M]+, 100%); HRMS (EI): calcd for C9H8O4 ([M]+)
180.0422, found 180.0430.
4.4.2.2. Synthesis of 15 (R1=SC9H19) on solid support
14 with 1-nonanethiol. Six pieces of the solid supported
azomethine 14 (loading: 75 mmolꢁ6, 450 mmol) were reacted
with 4-N,N-dimethylaminopyridine (13.7 mg, 0.113 mmol,
0.25 equiv), 1-nonanethiol (289 mg, 1.8 mmol, 4 equiv),
and 1,3-diisopropylcarbodiimide (564 mL, 3.6 mmol, 8 equiv)
in DCM at room temperature for 3 h. The solution was
removed by decantation and the resulting resins were
washed with DMF (3ꢁ0.5 min) and DCM (3ꢁ0.5 min).
Butylesters 15 (R1¼OBu) and N,N-diisobutylamides 15
(R1¼N(CH2CHMe2)2) were also prepared by the same
procedure described above.
4.4.2.3. Oxidative cleavage from the solid support. The
solid supported ester 15 (X¼H, R1¼OBu, loading:
75 mmolꢁ1, 75 mmol) was reacted with 2-aminophenol
(32.7 mg, 0.3 mmol, 4 equiv) and DarcoÒ KB (450 mg) in
DMF (3 mL) at 100 ꢀC under an air atmosphere for 18 h.
The resulting resins were washed with DMF (3ꢁ2 min) and
4.4.1.2. Synthesis of 3-bromo-4-formylbenzoic acid. N-
Bromosuccinimide (46.9 g, 0.264 mol) and benzoyl peroxide

H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
11321
DCM (3ꢁ2 min). The combined DMF and DCM solutions
were filtered. The filtrate was evaporated and purified by
silica gel chromatography (hexane/EtOAc¼10:1) to give 17
(X¼H, R1¼OBu, Y¼O) in 58% yield (12.8 mg, 43.3 mmol)
as colorless solid. Benzothiazoles 17 (Y¼S) and benzimid-
azoles 17 (Y¼NH) were synthesized by the same procedure
described above but in the absence of DarcoÒ KB. N-Methyl-
benzimidazoles 17 (Y¼NMe) were synthesized in the same
manner as the preparation of benzimidazoles 17 (Y¼NH)
but for longer reaction period (48 h). Yields for all library
members are shown in Table 2.
(ATR) 1633 cmꢂ1; MS (CI): m/z 429 ([M+H]+, 100%);
HRMS (CI): calcd for C22H26BrN2O2 ([M+H]+) 429.1178,
found 429.1184.
4.4.2.3.6. Butyl 4-(2-benzoxazol-2-yl)-3-methoxyben-
zoate 17 (X=OMe, R1=OBu, Y=O). Colorless solid, mp
98 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.01 (3H, t, J¼
7.1 Hz), 1.51 (2H, tq, J¼7.1, 7.1 Hz), 1.80 (2H, tt, J¼6.6,
7.1 Hz), 4.10 (3H, s), 4.38 (2H, t, J¼6.6 Hz), 7.36–7.40
(2H, m), 7.60–7.64 (1H, m), 7.75–7.78 (2H, m), 7.84–7.87
(1H, m), 8.22 (1H, d, J¼8.2 Hz); IR (ATR) 1717 cmꢂ1
C19H20NO4 ([M+H]+) 326.1392, found 326.1396.
;
MS (CI): m/z 326 ([M+H]+, 100%); HRMS (CI): calcd for
4.4.2.3.1. S-Nonyl 4-(2-benzoxazol-2-yl)benzoate 17
(X=H, R1=SC9H19, Y=O). Colorless solid, mp 111 ꢀC;
1H NMR (300 MHz, CDCl3) d 0.88 (3H, t, J¼7.1 Hz),
1.28 (10H, m), 1.44 (2H, m), 1.70 (2H, tt, J¼6.9,
7.1 Hz), 3.11 (2H, t, J¼7.1 Hz), 7.38–7.41 (2H, m), 7.60–
7.63 (1H, m), 7.80–7.83 (1H, m), 8.12 (2H, d, J¼
4.4.2.3.7. S-Nonyl 4-(benzoxazol-2-yl)-3-methoxyben-
zoate 17 (X=OMe, R1=SC9H19, Y=O). Colorless solid, mp
77 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.89 (3H, t, J¼
7.1 Hz), 1.28 (10H, m), 1.45 (2H, m), 1.71 (2H, tt, J¼7.4,
7.4 Hz), 3.12 (2H, t, J¼7.4 Hz), 4.10 (3H, s), 7.35–7.42
(2H, m), 7.60–7.63 (1H, m), 7.65 (1H, s), 7.72 (1H, d,
J¼8.0 Hz), 7.84–7.87 (1H, m), 8.24 (1H, d, J¼8.0 Hz); IR
(ATR) 1662 cmꢂ1; MS (CI): m/z 252 (100%), 412
([M+H]+, 70%); HRMS (CI): calcd for C24H30NO3S
([M+H]+) 412.1946, found 412.1939.
8.8 Hz), 8.34 (2H, d, J¼8.8 Hz); IR (ATR) 1657 cmꢂ1
;
MS (CI): m/z 222 (100%), 382 ([M+H]+, 70%); HRMS
(CI): calcd for C23H28NO2S ([M+H]+) 382.1841, found
382.1847.
4.4.2.3.2. N,N-Diisobutyl 4-(benzoxazol-2-yl)benzamide
17 (X=H, R1=N(CH2CHMe2)2, Y=O). Colorless solid, mp
158 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.76 (6H, d,
J¼6.6 Hz), 1.02 (6H, d, J¼6.6 Hz), 1.87 (1H, m), 2.15
(1H, m), 3.11 (2H, d, J¼7.4 Hz), 3.39 (2H, d, J¼7.7 Hz),
7.36–7.41 (2H, m), 7.52 (2H, d, J¼8.2 Hz), 7.60–7.63
(1H, m), 7.78–7.81 (1H, m), 8.29 (2H, d, J¼8.0 Hz); IR
(ATR) 1632 cmꢂ1; MS (CI): m/z 351 ([M+H]+, 100%);
HRMS (CI): calcd for C22H27N2O2 ([M+H]+) 351.2073,
found 351.2070.
4.4.2.3.8. N,N-Diisobutyl 4-(benzoxazol-2-yl)-3-
methoxybenzamide 17 (X=OMe, R1=N(CH2CHMe2)2,
Y=O). Pale yellow oil; H NMR (300 MHz, CDCl3) d 0.78
1
(6H, d, J¼6.6 Hz), 1.02 (6H, d, J¼6.9 Hz), 1.89 (1H, m),
2.15 (1H, m), 3.12 (2H, d, J¼7.4 Hz), 3.39 (2H, d,
J¼7.4 Hz), 4.04 (3H, s), 7.05 (1H, dd, J¼4.4, 7.7 Hz),
7.08 (1H, d, J¼1.4 Hz), 7.58–7.63 (1H, m), 7.78–7.86
(1H, m), 8.15 (1H, d, J¼8.0 Hz); IR (ATR) 1631 cmꢂ1
C23H29N2O3 ([M+H]+) 381.2178, found 381.2180.
;
MS (CI): m/z 381 ([M+H]+, 100%); HRMS (CI): calcd for
4.4.2.3.3. Butyl 4-(2-benzoxazol-2-yl)-3-bromobenzoate
1
17 (X=Br, R1=OBu, Y=O). Colorless solid, mp 115 ꢀC; H
NMR (300 MHz, CDCl3) d 1.00 (3H, t, J¼7.1 Hz), 1.50
(2H, tq, J¼7.1, 7.1 Hz), 1.79 (2H, tt, J¼6.6, 7.1 Hz), 4.38
(2H, t, J¼6.6 Hz), 7.39–7.47 (2H, m), 7.63–7.67 (1H, m),
7.87–7.90 (1H, m), 8.11 (1H, dd, J¼1.6, 8.2 Hz), 8.20
(1H, d, J¼8.2 Hz), 8.43 (1H, d, J¼1.6 Hz); IR (ATR)
1720 cmꢂ1; MS (CI): m/z 374 ([M+H]+, 100%); HRMS
(CI): calcd for C18H17BrNO3 ([M+H]+) 374.0391, found
374.0389.
4.4.2.3.9. S-Nonyl 4-(benzothiazol-2-yl)benzoate 17
1
(X=H, R1=SC9H19, Y=S). Colorless solid, mp 83 ꢀC; H
NMR (300 MHz, CDCl3) d 0.88 (3H, t, J¼6.6 Hz), 1.22–
1.39 (10H, m), 1.44 (2H, m), 1.70 (2H, tt, J¼7.4, 7.4 Hz),
3.10 (2H, t, J¼7.4 Hz), 7.42 (1H, ddd, J¼1.1, 7.1, 8.0 Hz),
7.52 (1H, ddd, J¼1.1, 7.1, 8.0 Hz), 7.93 (1H, ddd, J¼0.6,
1.1, 8.0 Hz), 8.08 (2H, d, J¼8.8 Hz), 8.11 (1H, d, J¼0.6,
1.1, 8.0 Hz), 8.17 (2H, d, J¼8.8 Hz); IR (ATR)
1645 cmꢂ1; MS (EI): m/z 238 (100%), 397 ([M]+, 7.0%);
HRMS (EI): calcd for C23H27NOS2 ([M]+) 397.1534, found
397.1549.
4.4.2.3.4. S-Nonyl 4-(benzoxazol-2-yl)-3-bromobenzoate
17 (X=Br, R1=SC9H19, Y=O). Colorless solid, mp 68 ꢀC;
1H NMR (300 MHz, CDCl3) d 0.89 (3H, t, J¼6.9 Hz),
1.28 (10H, m), 1.44 (2H, m), 1.70 (2H, tt, J¼6.9, 7.4 Hz),
3.12 (2H, t, J¼7.4 Hz), 7.39–7.48 (2H, m), 7.63–7.67 (1H,
m), 7.87–7.90 (1H, m), 8.03 (1H, dd, J¼1.6, 8.2 Hz), 8.21
(1H, d, J¼8.2 Hz), 8.35 (1H, d, J¼1.6 Hz); IR (ATR)
1657 cmꢂ1; MS (CI): m/z 460 ([M+H]+, 97%); HRMS
(CI): calcd for C23H27BrNO2S ([M+H]+) 460.0946, found
460.0944.
4.4.2.3.10. N,N-Diisobutyl 4-(benzothiazol-2-yl)benz-
amide 17 (X=H, R1=N(CH2CHMe2)2, Y=S). Colorless solid,
1
mp 142 ꢀC; H NMR (300 MHz, CDCl3) d 0.76 (6H, d,
J¼6.3 Hz), 1.01 (6H, d, J¼6.3 Hz), 1.87 (1H, m), 2.15
(1H, m), 3.12 (2H, d, J¼7.4 Hz), 3.39 (2H, d, J¼7.4 Hz),
7.41 (1H, dd, J¼7.4, 8.0 Hz), 7.48 (2H, d, J¼8.2 Hz), 7.52
(1H, dd, J¼7.4, 7.4 Hz), 7.93 (1H, d, J¼8.0 Hz), 8.09 (1H,
d, J¼7.4 Hz), 8.12 (2H, d, J¼8.2 Hz); IR (ATR)
1623 cmꢂ1; MS (EI): m/z 238 (100%), 366 ([M]+, 71%);
HRMS (EI): calcd for C22H26N2OS ([M]+) 366.1766, found
366.1769.
4.4.2.3.5. N,N-Diisobutyl 4-(benzoxazol-2-yl)-3-bromo-
benzamide 17 (X=Br, R1=N(CH2CHMe2)2, Y=O). Pale yel-
low oil; 1H NMR (300 MHz, CDCl3) d 0.78 (6H, d,
J¼6.6 Hz), 1.01 (6H, t, J¼6.6 Hz), 1.89 (1H, m), 2.13
(1H, m), 3.10 (2H, d, J¼7.7 Hz), 3.37 (2H, d, J¼7.4 Hz),
7.40–7.45 (3H, m), 7.62–7.65 (1H, m), 7.74 (1H, d,
J¼1.6 Hz), 7.85–7.88 (1H, m), 8.13 (1H, d, J¼8.0 Hz); IR
4.4.2.3.11. Butyl 4-(benzothiazol-2-yl)-3-bromobenzoate
1
17 (X=Br, R1=OBu, Y=S). Colorless solid, mp 95 ꢀC; H
NMR (300 MHz, CDCl3) d 1.00 (3H, t, J¼7.4 Hz), 1.49

11322
H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
(2H, tq, J¼7.4, 7.4 Hz), 1.79 (2H, tt, J¼6.9, 7.4 Hz), 4.37
(2H, t, J¼6.9 Hz), 7.47 (1H, dd, J¼7.1, 7.4 Hz), 7.56 (1H,
dd, J¼7.1, 8.2 Hz), 7.97 (1H, d, J¼7.4 Hz), 8.08 (1H, dd,
J¼1.6, 7.4 Hz), 8.15 (1H, d, J¼7.4 Hz), 8.16 (1H, d,
MS (EI): m/z 333 (92%), 335 (100%), 389 ([M]+, 67%),
391 ([M+2]+, 69%); HRMS (EI): calcd for C18H16BrNO2S
([M]+) 389.0085, found 389.0089.
J¼6.3 Hz), 1.02 (6H, d, J¼6.3 Hz), 1.89 (1H, m), 2.15
(1H, m), 3.14 (2H, d, J¼7.4 Hz), 3.39 (2H, d, J¼7.4 Hz),
4.08 (3H, s), 7.08 (1H, d, J¼8.6 Hz), 7.09 (1H, s), 7.39
(1H, ddd, J¼1.4, 7.4, 8.0 Hz), 7.50 (1H, ddd, J¼1.4, 7.4,
8.0 Hz), 7.94 (1H, ddd, J¼0.8, 1.4, 8.0 Hz), 8.10 (1H, ddd,
J¼0.8, 1.4, 8.0 Hz), 8.54 (1H, d, J¼8.6 Hz); IR (ATR)
1628 cmꢂ1; MS (EI): m/z 268 (100%), 396 ([M]+, 45%);
HRMS (EI): calcd for C23H28N2O2S ([M]+) 396.1871, found
396.1881.
J¼8.2 Hz), 8.40 (1H, d, J¼1.6 Hz); IR (ATR) 1712 cmꢂ1
;
4.4.2.3.12. S-Nonyl 4-(benzothiazol-2-yl)-3-bromoben-
zoate 17 (X=Br, R1=SC9H19, Y=S). Colorless solid, mp
64 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.89 (3H, t, J¼
6.6 Hz), 1.28–1.38 (10H, m), 1.44 (2H, m), 1.70 (2H, tt, J¼
7.4, 7.4 Hz), 3.11 (2H, t, J¼7.4 Hz), 7.47 (1H, ddd, J¼1.4,
7.4, 8.0 Hz), 7.56 (1H, ddd, J¼1.4, 7.4, 8.0 Hz), 7.97 (1H,
ddd, J¼0.6, 1.4, 8.0 Hz), 8.01 (1H, dd, J¼1.4, 8.1 Hz),
8.16 (1H, ddd, J¼0.6, 1.4, 8.0 Hz), 8.18 (1H, d,
4.4.2.3.17. S-Nonyl 4-(benzimidazol-2-yl)benzoate 17
(X=H, R1=SC9H19, Y=NH). Colorless solid, mp 190 ꢀC;
1H NMR (300 MHz, CDCl3) d 0.87 (3H, t, J¼6.6 Hz),
1.26–1.36 (10H, m), 1.41 (2H, m), 1.66 (2H, tt, J¼7.1,
7.1 Hz), 3.07 (2H, t, J¼7.1 Hz), 7.26–7.31 (2H, m), 7.65
(2H, br s), 7.98 (2H, d, J¼8.0 Hz), 8.16 (2H, d,
J¼8.0 Hz); IR (ATR) 1660 cmꢂ1; MS (EI): m/z 221
(100%), 380 ([M]+, 44%); HRMS (EI): calcd for
C23H28N2OS ([M]+) 380.1922, found 380.1919.
J¼8.2 Hz), 8.32 (1H, d, J¼1.4 Hz); IR (ATR) 1662 cmꢂ1
;
MS (EI): m/z 316 (97%), 318 (100%), 475 ([M]+, 11%),
477 ([M+2]+, 12%); HRMS (EI): calcd for C23H26BrNOS2
([M]+) 475.0639, found 475.0639.
4.4.2.3.18. N,N-Diisobutyl 4-(benzimidazol-2-yl)benz-
amide 17 (X=H, R1=N(CH2CHMe2)2, Y=NH). Colorless
solid, mp 192 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.70 (6H,
d, J¼6.6 Hz), 1.03 (6H, d, J¼6.6 Hz), 1.84 (1H, m), 2.19
(1H, m), 3.09 (2H, d, J¼7.4 Hz), 3.46 (2H, d, J¼7.7 Hz),
7.21–7.27 (2H, m), 7.22 (2H, d, J¼8.5 Hz), 7.63 (2H, br
s), 7.89 (2H, d, J¼8.5 Hz), 12.15 (1H, br s); IR (ATR)
1606 cmꢂ1; MS (EI): m/z 221 (100%), 349 ([M]+, 16%);
HRMS (EI): calcd for C22H27N3O ([M]+) 349.2154, found
349.2153.
4.4.2.3.13. N,N-Diisobutyl 4-(benzothiazol-2-yl)-3-bro-
mobenzamide 17 (X=Br, R1=N(CH2CHMe2)2, Y=S). Color-
less oil; 1H NMR (300 MHz, CDCl3) d 0.80 (6H, d,
J¼6.3 Hz), 1.01 (6H, t, J¼6.4 Hz), 1.90 (1H, m), 2.14
(1H, m), 3.12 (2H, d, J¼7.4 Hz), 3.38 (2H, d, J¼7.4 Hz),
7.42 (1H, dd, J¼1.4, 8.0 Hz), 7.46 (1H, ddd, J¼1.1, 7.1,
8.0 Hz), 7.56 (1H, ddd, J¼1.1, 7.1, 8.2 Hz), 7.72 (1H, d,
J¼1.4 Hz), 7.97 (1H, d, J¼8.0 Hz), 8.06 (1H, d,
J¼8.0 Hz), 8.15 (1H, d, J¼8.2 Hz); IR (ATR) 1628 cmꢂ1
;
MS (EI): m/z 316 (99%), 318 (100%), 444 ([M]+, 13%),
446 ([M+2]+, 13%); HRMS (EI): calcd for C22H25BrN2OS
([M]+) 444.0871, found 444.0854.
4.4.2.3.19. Butyl 4-(benzimidazol-2-yl)-3-bromobenzoate
17 (X=Br, R1=OBu, Y=NH). Colorless solid, mp 143 ꢀC; 1H
NMR (300 MHz, CDCl3) d 1.00 (3H, t, J¼7.1 Hz), 1.49 (2H,
tq, J¼7.1, 7.1 Hz), 1.78 (2H, tt J¼6.6, 7.1 Hz), 4.36 (2H, t
J¼6.6 Hz), 7.31–7.36 (2H, m), 7.60 (1H, br s), 7.81 (1H,
br s), 8.03 (1H, d, J¼8.2 Hz), 8.31 (1H, s), 8.33 (1H, d,
J¼8.2 Hz), 10.64 (1H, br s); IR (ATR) 1724 cmꢂ1; MS
(EI): m/z 372 ([M]+, 100%), 374 ([M+2]+, 99%); HRMS
(EI): calcd for C18H17BrN2O2 ([M]+) 372.0473, found
372.0482.
4.4.2.3.14. Butyl 4-(benzothiazol-2-yl)-3-methoxyben-
zoate 17 (X=OMe, R1=OBu, Y=S). Colorless solid, mp
92 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.01 (3H, t,
J¼7.4 Hz), 1.50 (2H, tq, J¼7.4, 7.4 Hz), 1.79 (2H, tt,
J¼6.6, 7.4 Hz), 4.12 (3H, s), 4.37 (2H, t, J¼6.6 Hz), 7.40
(1H, ddd, J¼1.1, 7.1, 8.0 Hz), 7.51 (1H, ddd, J¼1.4, 7.1,
8.2 Hz), 7.74 (1H, d, J¼1.4 Hz), 7.78 (1H, dd, J¼1.4,
8.2 Hz), 7.94 (1H, ddd, J¼0.6, 1.4, 8.0 Hz), 8.12 (1H,
ddd, J¼0.6, 1.1, 8.2 Hz), 8.61 (1H, d, J¼8.2 Hz); IR
(ATR) 1705 cmꢂ1; MS (EI): m/z 341 ([M]+, 100%);
HRMS (EI): calcd for C19H19NO3S ([M]+) 341.1086, found
341.1069.
4.4.2.3.20. S-Nonyl 4-(benzimidazol-2-yl)-3-bromoben-
zoate 17 (X=Br, R1=SC9H19, Y=NH). Colorless solid, mp
144 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.88 (3H, t,
J¼7.1 Hz), 1.28–1.38 (10H, m), 1.43 (2H, m), 1.69 (2H,
tt, J¼7.1, 7.1 Hz), 3.10 (2H, t, J¼7.1 Hz), 7.30–7.36
(2H, m), 7.70 (2H, br s), 7.94 (1H, dd, J¼1.6, 8.2 Hz),
8.21 (1H, d, J¼1.6 Hz), 8.30 (1H, d, J¼8.2 Hz), 10.76
(1H, br s); IR (ATR) 1657 cmꢂ1; MS (EI): m/z 299
(100%), 301 (96%), 458 ([M]+, 18%), 460 ([M+2]+, 19%);
HRMS (EI): calcd for C23H27BrN2OS ([M]+) 458.1027,
found 458.1013.
4.4.2.3.15. S-Nonyl 4-(benzothiazol-2-yl)-3-methoxyben-
zoate 17 (X=OMe, R1=SC9H19, Y=S). Colorless solid, mp
80 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.88 (3H, t,
J¼6.6 Hz), 1.28–1.38 (10H, m), 1.44 (2H, m), 1.70 (2H, tt,
J¼7.1, 7.1 Hz), 3.10 (2H, t, J¼7.1 Hz), 4.12 (3H, s), 7.40
(1H, ddd, J¼1.0, 7.1, 7.7 Hz), 7.51 (1H, ddd, J¼1.0, 7.1,
8.0 Hz), 7.63 (1H, d, J¼1.6 Hz), 7.74 (1H, dd, J¼1.6,
8.2 Hz), 7.94 (1H, d, J¼7.7 Hz), 8.11 (1H, d, J¼8.0 Hz),
8.62 (1H, d, J¼8.2 Hz); IR (ATR) 1645 cmꢂ1; MS (EI):
m/z 268 (100%), 427 ([M]+, 18%); HRMS (EI): calcd for
C24H29NO2S2 ([M]+) 427.1640, found 427.1624.
4.4.2.3.21. N,N-Diisobutyl 4-(benzimidazol-2-yl)-3-bro-
mobenzamide 17 (X=Br, R1=N(CH2CHMe2)2, Y=NH). Col-
orless solid, mp 173 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.77
(6H, d, J¼6.3 Hz), 1.02 (6H, d, J¼6.6 Hz), 1.89 (1H, m),
2.16 (1H, m), 3.10 (2H, d, J¼7.4 Hz), 3.42 (2H, d,
J¼7.4 Hz), 7.31–7.34 (2H, m), 7.33 (1H, d, J¼8.0 Hz),
7.62 (1H, br s), 7.64 (1H, s), 7.83 (1H, br s), 8.10 (1H, d,
J¼8.0 Hz), 11.10 (1H, br s); IR (ATR) 1627 cmꢂ1; MS
(EI): m/z 299 (99%), 301 (100%), 427 ([M]+, 16%), 429
4.4.2.3.16. N,N-Diisobutyl 4-(benzothiazol-2-yl)-3-me-
thoxybenzamide 17 (X=OMe, R1=N(CH2CHMe2)2, Y=S).
Colorless oil; H NMR (300 MHz, CDCl3) d 0.77 (6H, d,
1

H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
11323
([M+2]+, 16%); HRMS (EI): calcd for C22H26BrN3O ([M]+)
427.1259, found 427.1240.
1.50 (2H, tq, J¼7.4, 7.4 Hz), 1.80 (2H, tt, J¼6.6, 7.4 Hz),
3.68 (3H, s), 4.39 (2H, t, J¼6.6 Hz), 7.32–7.46 (3H, m),
7.63 (1H, d, J¼8.0 Hz), 7.82–7.88 (1H, m), 8.12 (1H, dd,
J¼1.7, 8.0 Hz), 8.38 (1H, d, J¼1.7 Hz); IR (ATR)
1717 cmꢂ1; MS (CI): m/z 388 (100%), 387 ([M+H]+,
96%); HRMS (CI): calcd for C19H20BrN2O2 ([M+H]+)
387.0709, found 387.0709.
4.4.2.3.22. Butyl 4-(benzimidazol-2-yl)-3-methoxyben-
zoate 17 (X=OMe, R1=OBu, Y=NH). Colorless solid, mp
220 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.01 (3H, t,
J¼7.4 Hz), 1.50 (2H, tq, J¼7.4, 7.4 Hz), 1.79 (2H, tt,
J¼6.9, 7.4 Hz), 4.16 (3H, s), 4.37 (2H, t, J¼6.9 Hz), 7.28–
7.33 (2H, m), 7.52–7.54 (1H, m), 7.76 (1H, d, J¼1.4 Hz),
7.80 (1H, dd, J¼1.4, 8.2 Hz), 7.83–7.85 (1H, m),
8.67 (1H, d, J¼8.2 Hz), 10.70 (1H, br s); IR (ATR)
1701 cmꢂ1; MS (EI): m/z 324 ([M]+, 100%); HRMS
(EI): calcd for C19H20N2O3 ([M]+) 324.1474, found
324.1470.
4.4.2.3.28. S-Nonyl 4-(1-methyl-benzimidazol-2-yl)-3-
bromobenzoate 17 (X=Br, R1=SC9H19, Y=NMe). Colorless
solid, mp 104 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.89
(3H, t, J¼6.9 Hz), 1.28 (10H, m), 1.45 (2H, m), 1.70
(2H, tt, J¼7.1, 7.4 Hz), 3.12 (2H, t, J¼7.4 Hz), 3.66
(3H, s), 7.31–7.37 (2H, m), 7.39–7.44 (1H, m), 7.63
(1H, d, J¼8.0 Hz), 7.83–7.86 (1H, m), 8.03 (1H, dd
J¼1.6, 8.0 Hz), 8.29 (1H, d, J¼1.6 Hz); IR (ATR)
1655 cmꢂ1; MS (CI): m/z 473 ([M+H]+, 100%); HRMS
(CI): calcd for C24H30BrN2OS ([M+H]+) 473.1263, found
473.1262.
4.4.2.3.23. S-Nonyl 4-(benzimidazol-2-yl)-3-methoxy-
benzoate 17 (X=OMe, R1=SC9H19, Y=NH). Colorless solid,
1
mp 145 ꢀC; H NMR (300 MHz, CDCl3) d 0.88 (3H, t,
J¼6.6 Hz), 1.26–1.39 (10H, m), 1.45 (2H, m), 1.70 (2H, tt,
J¼7.4, 7.4 Hz), 3.10 (2H, t, J¼7.4 Hz), 4.15 (3H, s), 7.28–
7.32 (2H, m), 7.52 (1H, m), 7.64 (1H, d, J¼1.4 Hz), 7.77
(1H, dd, J¼1.4, 8.2 Hz), 7.84 (1H, br s), 8.67 (1H, d,
4.4.2.3.29. N,N-Diisobutyl 4-(1-methyl-benzimidazol-2-
yl)-3-bromobenzamide 17 (X=Br, R1=N(CH2CHMe2)2,
Y=NMe). Colorless solid, mp 125 ꢀC; 1H NMR (300 MHz,
CDCl3) d 0.80 (6H, d, J¼6.9 Hz), 1.01 (6H, t, J¼6.6 Hz),
1.91 (1H, m), 2.14 (1H, m), 3.12 (2H, d, J¼7.7 Hz), 3.39
(2H, d, J¼7.7 Hz), 3.67 (3H, s), 7.32–7.39 (2H, m), 7.40–
7.46 (1H, m), 7.43 (1H, dd, J¼1.6, 7.7 Hz), 7.58 (1H, d,
J¼7.7 Hz), 7.70 (1H, d, J¼1.6 Hz), 7.81–7.87 (1H, m); IR
(ATR) 1630 cmꢂ1; MS (CI): m/z 442 ([M+H]+, 100%);
HRMS (CI): calcd for C23H29BrN3O ([M+H]+) 442.1494,
found 442.1490.
J¼8.2 Hz), 10.68 (1H, br s); IR (ATR) 1661 cmꢂ1
;
MS (EI): m/z 251 (100%), 410 ([M]+, 55%); HRMS
(EI): calcd for C24H30N2O2S ([M]+) 410.2028, found
410.2029.
4.4.2.3.24. N,N-Diisobutyl 4-(benzimidazol-2-yl)-3-me-
thoxybenzamide 17 (X=OMe, R1=N(CH2CHMe2)2,
1
Y=NH). Colorless solid, mp 173 ꢀC; H NMR (300 MHz,
CDCl3) d 0.77 (6H, d, J¼6.0 Hz), 1.02 (6H, d, J¼6.0 Hz),
1.88 (1H, m), 2.15 (1H, m), 3.15 (2H, d, J¼6.9 Hz),
3.39 (2H, d, J¼7.1 Hz), 4.08 (3H, s), 7.09 (1H, d,
J¼8.2 Hz), 7.10 (1H, s), 7.26–7.31 (2H, m), 7.66 (2H, br
s), 8.58 (1H, d, J¼8.2 Hz), 10.67 (1H, br s); IR (ATR)
1617 cmꢂ1; MS (EI): m/z 251 (100%), 379 ([M]+, 41%);
HRMS (EI): calcd for C23H29N3O2 ([M]+) 379.2260, found
379.2268.
4.4.2.3.30. Butyl 4-(1-methyl-benzimidazol-2-yl)-3-me-
thoxybenzoate 17 (X=OMe, R1=OBu, Y=NMe). Colorless
1
oil; H NMR (300 MHz, CDCl3) d 1.01 (3H, t, J¼7.1 Hz),
1.50 (2H, tq, J¼7.1, 7.1 Hz), 1.80 (2H, tt, J¼6.6, 7.1 Hz),
3.66 (3H, s), 3.90 (3H, s), 4.38 (2H, t, J¼6.6 Hz), 7.28–
7.43 (3H, m), 7.67 (1H, d, J¼7.7 Hz), 7.71 (1H, s), 7.79
(1H, d, J¼7.7 Hz), 7.82–7.85 (1H, m); IR (ATR)
1714 cmꢂ1; MS (CI): m/z 339 ([M+H]+, 100%); HRMS
(CI): calcd for C20H23N2O3 ([M+H]+) 339.1708, found
339.1701.
4.4.2.3.25. S-Nonyl 4-(1-methyl-benzimidazol-2-yl)ben-
zoate 17 (X=H, R1=SC9H19, Y=NMe). Colorless solid, mp
64 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.89 (3H, t,
J¼6.9 Hz), 1.25–1.37 (10H, m), 1.45 (2H, m), 1.71 (2H, tt,
J¼7.4, 7.4 Hz), 3.12 (2H, t, J¼7.4 Hz), 3.90 (3H, s), 7.31–
7.44 (3H, m), 7.82–7.86 (1H, m), 7.88 (2H, d, J¼8.2 Hz),
8.13 (2H, d, J¼8.2 Hz); IR (ATR) 1658 cmꢂ1; MS (CI):
m/z 395 ([M+H]+, 100%); HRMS (CI): calcd for
C24H31N2OS ([M+H]+) 395.2157, found 395.2167.
4.4.2.3.31. S-Nonyl 4-(1-methyl-benzimidazol-2-yl)-3-
methoxybenzoate 17 (X=OMe, R1=SC9H19, Y=NMe). Col-
orless solid, mp 54 ꢀC; 1H NMR (300 MHz, CDCl3) d 0.89
(3H, t, J¼6.9 Hz), 1.26–1.37 (10H, m), 1.45 (2H, m), 1.68
(2H, m), 3.12 (2H, t, J¼7.4 Hz), 3.66 (3H, s), 3.90 (3H, s),
7.28–7.43 (3H, m), 7.60 (1H, d, J¼1.4 Hz), 7.68 (1H, d,
J¼8.0 Hz), 7.75 (1H, dd, J¼1.4, 8.0 Hz), 7.82–7.85 (1H,
m); IR (ATR) 1662 cmꢂ1; MS (CI): m/z 425 ([M+H]+,
100%); HRMS (CI): calcd for C25H33N2O2S ([M+H]+)
425.2262, found 425.2244.
4.4.2.3.26. N,N-Diisobutyl 4-(1-methyl-1-methyl-benz-
imidazol-2-yl)benzamide 17 (X=H, R1=N(CH2CHMe2)2,
Y=NMe). Colorless oil; 1H NMR (300 MHz, CDCl3)
d 0.76 (6H, d, J¼6.6 Hz), 1.02 (6H, d, J¼6.9 Hz), 1.89
(1H, m), 2.16 (1H, m), 3.14 (2H, d, J¼7.4 Hz), 3.40 (2H,
d, J¼7.7 Hz), 3.88 (3H, s), 7.30–7.44 (3H, m), 7.52 (2H,
d, J¼8.2 Hz), 7.80 (2H, d, J¼8.2 Hz), 7.80–7.86 (1H, m);
IR (ATR) 1631 cmꢂ1; MS (CI): m/z 364 ([M+H]+, 100%);
HRMS (CI): calcd for C23H30N3O ([M+H]+) 364.2389,
found 364.2389.
4.4.2.3.32. N,N-Diisobutyl 4-(1-methyl-benzimidazol-2-
yl)-3-methoxybenzamide 17 (X=OMe, R1=N(CH2CHMe2)2,
Y=NMe). Colorless oil; 1H NMR (300 MHz, CDCl3) d 0.79
(6H, d, J¼6.6 Hz), 1.02 (6H, d, J¼6.3 Hz), 1.91 (1H, m),
2.15 (1H, m), 3.16 (2H, d, J¼7.1 Hz), 3.40 (2H, d,
J¼7.4 Hz), 3.65 (3H, s), 3.84 (3H, s), 7.04 (1H, s), 7.06
(1H, d, J¼7.4 Hz), 7.28–7.37 (2H, m), 7.39–7.43 (1H, m),
7.60 (1H, d, J¼7.4 Hz), 7.79–7.84 (1H, m); IR (ATR)
1626 cmꢂ1; MS (CI): m/z 394 ([M+H]+, 100%); HRMS
4.4.2.3.27. Butyl 4-(1-methyl-benzimidazol-2-yl)-3-bro-
mobenzoate 17 (X=Br, R1=OBu, Y=NMe). Colorless oil;
1H NMR (300 MHz, CDCl3) d 1.01 (3H, t, J¼7.4 Hz),

11324
H. Hioki et al. / Tetrahedron 63 (2007) 11315–11324
(CI): calcd for C24H32N3O2 ([M+H]+) 394.2494, found
394.2494.
S. J.; Park, H. J.; Lee, S. K.; Kim, S. W.; Han, G.; Choo,
H.-Y. P. Bioorg. Med. Chem. 2006, 14, 1229–1235; (e)
Beebe, X.; Wodka, D.; Sowin, T. J. J. Comb. Chem. 2001, 3,
360–366; (f) Hwang, J. Y.; Gong, Y.-D. J. Comb. Chem.
2006, 8, 297–303; (g) Matsushita, H.; Lee, S.-H.; Joung, M.;
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Chem. 2000, 2, 282–292; (i) Wu, Z.; Ede, N. J.; Mathieu,
M. N. Tetrahedron Lett. 2003, 44, 2293–2296; (j) Kilburn,
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5419–5421.
Acknowledgements
This study was financially supported by a Grant-in-Aid from
the Ministry of Education, Culture, Sports, Science, and
Technology of the Japanese Government, and a MEXT.HAI-
TEKU, 2003–2007.
6. For some examples, see: (a) Guillier, F.; Orain, D.; Bradley, M.
Chem. Rev. 2000, 100, 2091–2158; (b) Scott, P. J. H.; Steel,
P. G. Eur. J. Org. Chem. 2006, 2251–2268.
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12. See the following web site for generating a LanternÒ library
using color coded tags; http://www.mimotopes.com/
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