Synthesis of 2-arylbenzothiazoles and imidazoles using scandium triflate as a catalyst for both a ring closing and an oxidation steps

Article abstract of DOI:10.3987/COM-04-10215

2-Aminobenzenethiol and an aryl aldehyde were allowed to react to give a 2-arylbenzothiazole in good yield in the presence of a catalytic amount of scandium triflate Sc(OTf)₃. The detailed study showed that Sc(OTf)₃ catalyzed two steps, that is, the formation of a thiazoline ring and the oxidation of the thiazoline to a thiazole ring. This is the first example that scandium(III) ion catalyzed oxidation of an organic compound using molecular oxygen as an oxidant. The reaction was applied to o-phenylenediamine and an aryl aldehyde to give corresponding 2-arylbenzimidazole in moderate to good yields depending upon the structure of aldehyde.

Full text of DOI:10.3987/COM-04-10215

HETEROCYCLES, Vol. 63, No. 12, 2004, pp. 2769 - 2783
Received, 31st August, 2004, Accepted, 18th October, 2004, Published online, 22nd October, 2004
SYNTHESIS OF 2-ARYLBENZOTHIAZOLES AND IMIDAZOLES
USING SCANDIUM TRIFLATE AS A CATALYST FOR BOTH A RING
CLOSING AND AN OXIDATION STEPS
Takashi Itoh, Kazuhiro Nagata, Hiroyuki Ishikawa, and Akio Ohsawa*
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan. E-mail:ohsawa@pharm.showa-u.ac.jp
Abstract – 2-Aminobenzenethiol and an aryl aldehyde were allowed to react to
give a 2-arylbenzothiazole in good yield in the presence of a catalytic amount of
3 3
scandium triflate Sc(OTf) . The detailed study showed that Sc(OTf) catalyzed
two steps, that is, the formation of a thiazoline ring and the oxidation of the
thiazoline to a thiazole ring. This is the first example that scandium(III) ion
catalyzed oxidation of an organic compound using molecular oxygen as an
oxidant. The reaction was applied to o-phenylenediamine and an aryl aldehyde
to give corresponding 2-arylbenzimidazole in moderate to good yields depending
upon the structure of aldehyde.
INTRODUCTION
-Substituted benzothiazole and benzimidazole derivatives are of industrial, biological, and medicinal
1
2
2
3
interest, thus the methods for preparing these compounds have been extensively studied. Although
condensation of 2-aminobenzenethiol or o-phenylenediamine with an appropriate carboxylic acid
provides the most direct synthetic route to the 2-substituted benzothiazoles or imidazoles, respectively,
4
these processes usually require vigorous reaction conditions. Thus, there have been several papers
which report alternative methods. In the cases of benzothiazoles, there is an only study that adopted
2
-aminobenzenethiol and an aldehyde as starting material for 2-substituted benzothiazole in DMSO
5
solvent. Although DMSO was supposed to act as an oxidant in the reaction, the scope and the

mechanism remain unclear. On the other hand, several methods for the synthesis of benzimidazoles
have been recently reported which involve palladium-catalyzed carbonylation reaction of an
6
o-phenylenediamine followed by cyclodehydration, palladium-catalyzed intramolecular N-arylation
7
reaction of (o-bromophenyl)amidines, and rhodium-catalyzed hydroformylation of N-alkenyl-
8
phenylenediamines. However, there are seldom studies in which the syntheses of both heterocycles
are carried out in the same reaction system.
In the course of our study for the application of lanthanide and related rare earth metal triflates as a
catalyst of the synthesis of azaaromatic compounds, 2-aminobenzenethiol and an aryl aldehyde were
found to react to give a 2-arylbenzothiazole in good yield in the presence of a catalytic amount of
scandium triflate Sc(OTf)
3
.
In addition, the same reaction procedure was applied to
o-phenylenediamine to give benzimidazole derivatives. The reaction was found to proceed via
9
scandium (III) catalyzed oxidation step. This paper describes these results in detail.
RESULTS AND DISCUSSION
It is well known that lanthanide and related rare earth metal triflates function as Lewis acid catalysts
1
0
even in the presence of water, and there are several works which applied these acids to the synthesis of
1
1
aza compounds.
We supposed that the property of these Lewis acids was suitable for the construction
of azaaromatics whose syntheses involve an initial formation of an imine from carbonyl and amino
groups, since the process was inevitably accompanied by generation of an equimolar amount of water.
As the first attempt, 2-aminobenzenethiol (1) and an aldehyde were allowed to react at room temperature
in the presence of a catalytic amount of Sc(OTf) under O to give corresponding benzothiazole (2) in
3
2
excellent yield (Scheme 1 and Table 1, entry 1).
Although the corresponding imine was formed even in the absence of the Lewis acid, the reaction did
1
not proceed to the next step. That is, by the H-NMR spectrum, formation of the corresponding imine
was observed (y. 75%) accompanied by a small amount of 2, and 2-arylbenzothiazoline was not
3
identified in this reaction. (Table 1, entry 2). Thus, it was suggested that Sc(OTf) was a catalyst for

RCHO
Lewis acid
1.5 equiv.), (2 mol%)
SH
S
N
(
R
Scheme 1
NH2
THF, under O2
2
1
Table 1 The Reaction of 2-Aminobenzenethiol with Aryl Aldehyde
in the Presence of Lewis Acid
entry
R
product Lewis acid
time
(h)
yield of 2
(
2.0 mol%)
(%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
2a
2a
2a
2a
2a
2b
2c
2d
2e
Sc(OTf)3
-
Yb(OTf)3
Sn(OTf)2
Cu(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
2
2
2
2
2
2
2
3
2
98
9
89
84
13
99
99
97
97
p-Me-C H4
p-Cl-C H4
2-naphthyl
p-MeO-C H4
6
6
6
the cyclization process which afforded 2-arylbenzothiazoline. Although other Lewis acids than
Sc(OTf) were used as catalysts, it was shown that Sc(OTf) was superior to the other metal triflate
Table 1, entries 3-5). The reaction system was applied to other aldehydes, and it was shown that
3
3
(
various aryl aldehydes afforded good yields of 2-arylbenzothiazoles (entries 6-9). In addition, the
reaction was found to hardly proceed under Ar, thus molecular oxygen was suggested to react as an
oxidant which transformed the benzothiazoline formed in situ to the product.
In the present reaction, 2-arylbenzothiazoline was supposed to be an intermediate because the signals of
1
it were observed in the H-NMR spectrum of the reaction mixture when the reaction time was shortened.
In order to investigate the oxidation step of 2-arylbenzothiazoline to 2-arylbenzothiazole,
1
2
2-phenylbenzothiazoline (3) was synthesized according to the reported method.
The isolated
compound (3) was allowed to react with O in the presence or absence of Sc(OTf) , and the results are
2 3
shown in Table 2.
3
The data shown in Table 2 suggested that a catalytic amount of Sc(OTf) was necessary for the oxidation
of 3 to 2a. In the absence of Sc(OTf) or oxygen, the reaction seldom proceeded (Table 2, entries 1 and
3

Table 2 Oxidation of 2-Phenylbenzothiazoline (3)
with O in the Presence of Scandium Triflate
2
entry
Sc(OTf)3
(mol %)
O2
( equiv)
yield of 2a
S
H
O , Sc(OTf)
2
(%)
3
2
a
N
H
Ph THF, under Ar
1
2
3
4
5
0
1
2
2
2
excess
excess
excess
0
9
48
95
6
1
h
3
0.1
14
4
). In addition, the limited amount of oxygen afforded only corresponding amount of 2a (entry 5).
These results shown in Table 1 and Table 2 revealed that Sc(OTf) catalyzed both the cyclization step
and the oxidation step which employed molecular oxygen as an oxidant.
2
In order to confirm the above assumption, the effects of Sc(OTf) and O on the progress of the reaction
3
3
3
were investigated, and the results are summarized in Table 3. In the absence of Sc(OTf) , the reaction
PhCHO
SH
(1.5 equiv.)
S
N
S
SH
N
H
Ph
H
Ph
Sc(OTf)3
THF, rt
N
H
NH2
Ph
2
h
2
3
4
Table 3 The Yields of Various Products in the Presence and Absence of the Catalyst or O2
entry
O2
amount of Sc(OTf)3
yield of 2
yield of 3
yield of 4
(
mol%)
(%)
(%)
(%)
1
2
3
(+)
(-)
0
2
2
9
0
76
0
75
0
21
98
(+)
0
ceased to proceed at the formation of the corresponding imine (4), therefore the further reaction was
shown to be catalyzed by the Lewis acid (entry 1). Without O in the presence of Sc(OTf) , the
reaction proceeded to the formation of benzothiazoline (3), thus the cyclization step was catalyzed by
Sc(OTf) (entry 2). Accordingly, the present reaction is the first example in which Sc(OTf) catalyzes
2
3
3
3

two consecutive steps. In particular, the second step is the first example where the Lewis acid catalyzes
the oxidation using molecular oxygen (Scheme 2).
SH
SH
N
S
Ar-CHO
O2
S
N
Ar
H
Ar
N
H
NH2
Ar
+
H O
2
3
2
1
the first Sc(OTf)3
catalyzed step
the second Sc(OTf)3
catalyzed step
Scheme 2
In addition to the mechanistic interest, the reaction seems to be of use because the oxidation step adopts
quite mild conditions. Thus, the reaction was applied to the aldehydes which are sensitive toward the
oxidative reagents, and the reaction proceeded smoothly to give the corresponding thiazole derivatives in
good yields (Scheme 3).
SH
S
N
Sc(OTf) (2 mol%)
3
+
+
6 y. 71%
CHO
N
N
THF, rt
NH2
H
H
24 h
5
Scheme 3
SH
S
N
Sc(OTf) (2 mol%)
3
CHO
N
N
THF, rt
4 h
NH2
H
H
2
7
8
y. 72%
The above results prompted us to investigate the application of the present reaction toward the other
heterocycles, and it was found that benzimidazoles were synthesized by the method. When
o-phenylenediamine (9) was allowed to react with benzaldehyde in THF in air, the corresponding imine
(
10) was obtained in 52% accompanied by 12% of 2-phenylbenzimidazole (11) (Scheme 4). The
addition of Sc(OTf)
3
in the system resulted in quantitative formation of 11.
N
Ph
NH2
N
Sc(OTf) (1 mol%)
3
Ph
+
11
2%
+
PhCHO
H
N
H
THF, O2
rt, 44 h
NH2
THF, O2
rt, 44 h
NH2
1
9
1
0 52%
1
1 97%
Scheme 4

The results indicated that the reaction system found for benzothiazoles was also applicable to a
construction of benzimidazole ring. Thus, we investigated the reaction of o-phenylenediamine and
various aldehydes in the presence of the Lewis acid, and the data are summarized in Table 4 (Scheme 5).
NH2
Sc(OTf)3
N
N
N
RCHO
R
R
Scheme 5
THF, under O2
N
H
NH2
rt, 44 h
9
R
1
1
12
Table 4 Reaction of o-Phenylenediamine with an Aldehyde in the Presence of Sc(OTf) under O
3
2
entry
R
conc. of
the substrate(M)
Sc(OTf)3
(mol%)
aldehyde
(equiv.)
yield of 11
yield of 12
(%)
(%)
1
2
3
4
5
6
7
8
9
Ph
p-Cl-C H
p-Cl-C H
p-Cl-C H
1-naphthyl
1-naphthyl
1-naphthyl
p-Me-C H
p-Me-C H
0.35
0.35
0.35
0.002
0.35
0.01
0.002
0.35
0.01
0.002
0.002
0.002
0.002
0.002
1.0
1.0
10
10
1.0
10
10
1.0
10
10
10
10
10
10
1.0
1.0
1.5
1.5
1.0
1.5
1.5
1.0
1.5
1.5
1.5
1.5
1.5
1.5
97 (11a)
37 (11b)
63 (11b)
95 (11b)
43 (11c)
53 (11c)
82 (11c)
37 (11d)
55 (11d)
72 (11d)
95 (11e)
57 (11f)
52 (11g)
98 (11h)
1 (12a)
6 (12b)
35 (12b)
3 (12b)
9 (12c)
31 (12c)
12 (12c)
19 (12d)
35 (12d)
23 (12d)
-
6
4
4
4
6
6
6
4
4
4
6
1
1
1
1
1
0
1
2*
3**
4
p-Me-C H
p-Br-C H
6
6
4
H
CH3
41 (12f)
42 (12g)
0
(CH ) C
3
3
*
37% aq. HCHO was used. ** 90% CH CHO was used.
3
To our disappointment, however, the yields of 11 were moderate to low (entries 2, 5, and 8) under the
standard conditions used for entry 1, and the side products (12) derived through the reaction of 9 with
two equivalents of the aldehyde were obtained in every case. In order to improve the reaction yields,
we scrutinized the reaction conditions, and found that dilution of the reaction medium improved the
reaction yields considerably (entries 2-4, 5-7, and 8-10). In the cases of aliphatic aldehydes, bulkiness
affected the reaction yields as shown in entries 12 to 14. That is, by using formaldehyde and
acetaldehyde, formation of 12 was inevitable even under the high dilution conditions (entries 12 and 13).
By using 2,2-dimethylpropanal, however, the desired product (11) was obtained in a high yield (entry
1
4).

Although conclusive experimental supports for the reaction mechanism have not been obtained yet, the
plausible one is as follows. The reaction of o-phenylenediamine with an aldehyde is supposed to give
an imine (10). The imine is cyclized to corresponding benzimidazoline (13) under the influence of
Sc(OTf) , and a subsequent oxidation of 13 catalyzed by the same Lewis acid affords the benzimidazole
11). Different from the reaction of aminobenzenethiol, however, side product
N-alkyl-o-phenylenediamine (14) was formed in a considerable yield especially when the reaction rate
3
(
a
1
3
was slow.
We speculated that the compound (14) was obtained from the redox reaction between the
1
4
imine (10) and benzimidazoline (13) catalyzed by Sc(OTf) to afford 14 and 11.
The reaction of 14
3
and aldehyde, and succeeding ring closure and oxidation give 12. When the redox reaction of 10 and 13
resulted in the formation of the side product(s), dilution might be effective for preventing this side
reaction to form 11.
Thus, the results shown in Table 4 (entries 2-4, 5-7, and 8-10) support the present
mechanism.
NH2
N
R
H
NH2
N
RCHO
H
NH2
H
R
N C R
Sc(OTf)3
N
H
H
H
1
0
R
NH2
1
1
4
Sc(OTf)3
H
H
H
N
RCHO
N
N
R
H
R
H
R
N
N
H
N
R
1
1
3
O2
Sc(OTf)3
O2
Sc(OTf)3
N
R
1
1
N
Scheme 6
R
1
2
In this paper, we described that the reaction of 2-aminobenzenethiol with an aryl aldehyde was
accelerated by Sc(OTf) to give a ring closing product, and succeeding aromatization was also carried out
3
by participation of Sc(OTf) as a catalyst to give 2-arylbenzothiazole in a good yield. In addition, the
3
reaction was applied to o-phenylenediamine and aldehyde to give corresponding 2-substituted

benzimidazoles when the concentration of the substrate was sufficiently low. This type of ring
closing-oxidation reaction is a ubiquitous process for the synthesis of heterocycles, thus the present
reaction system is thought to be a new, general synthetic method for various heteroaromatics. Moreover,
the reaction is the first example that Sc(OTf) plays a catalytic role on the oxidation reaction by
3
molecular oxygen. The application to synthesis of other heterocycles is now under investigation.
EXPERIMENTAL
Unless otherwise specified, materials were purchased from commercial suppliers and used without
1
13
further purification.
3
H and C NMR spectra were recorded in CDCl at 500 and 125 MHz,
respectively, using tetramethylsilane as a standard. All melting points are uncorrected.
Reaction of 2-aminobenzenethiol with an aldehyde in the presence of scandium triflate (Table 1):
the typical procedure; 2-Aminobenzenethiol (25 mg, 0.2 mmol) was dissolved in THF (2 mL), and O2
was introduced to the reaction vessel. Then benzaldehyde (30µL, 0.3 mmol) and Sc(OTf)
mmol) were added, and the mixture was allowed to react at rt for 2 h. Thereafter, ethyl acetate (12 mL)
was added, and the organic layer was washed with 5% aq. Na CO (2 mL) and brine (2 mL), dried over
MgSO , and evaporated off. The residue was chromatographed on silica gel (CH Cl ) to give
-phenylbenzothiazole (41 mg, 0.19 mmol).
3
(2 mg, 0.004
2
3
4
2
2
2
2
7
1
-Phenylbenzothiazole (2a). oil; H NMR (CDCl
3
) δ: 7.39 (1H, td, J=7.2, 1.2 Hz), 7.48-7.52 (4H, m),
1
.91 (1H, ddd, J= 8.0, 1.6, 0.8 Hz), 8.10-8.12 (3H, m). The H NMR spectrum of this compound was
identical with that of the commercial compound.
°
15
°
1
2
-(4-Methylphenyl)benzothiazole (2b). mp 81-82 C (lit., 83-85 C). H NMR (CDCl
3
) δ: 2.40 (3H, s),
7
.28 (2H, d, J=7.9 Hz), 7.35 (1H, t, J=7.5 Hz), 7.47 (1H, t, J=7.6 Hz), 7.87 (1H, d, J=7.9 Hz), 7.97 (2H,
1
3
3
d, J=8.1 Hz), 8.05 (1H, d, J=8.2 Hz). C NMR (CDCl ) δ: 21.5, 121.6, 123.0, 125.1, 126.3, 127.5, 129.7,
1
30.8, 134.9, 141.5, 154.0, 168.3.
3
-(4-Chlorophenyl)benzothiazole (2c). mp 114-116 C (lit., 116 C). H NMR (CDCl ) δ: 7.40 (1H, t,
°
16
°
1
2
J=7.6 Hz), 7.47 (2H, d, J=8.4 Hz), 7.50 (1H, t, J=7.7 Hz), 7.90 (1H, d, J=8.1 Hz), 8.03 (2H, d, J=8.4 Hz),

1
3
8
1
2
.07 (1H, d, J=8.2 Hz). C NMR (CDCl ) δ: 121.5, 123.1, 125.3, 126.3, 128.6, 129.1, 132.0, 134.9,
3
+
36.9, 153.9, 166.4. FAB-MS: 246 (M+H) .
°
1
2 3
-(2-Naphthyl)benzothiazole (2d). mp 140.5-141.5 C (EtOH/H O). H NMR (CDCl ) δ: 7.41 (1H, t,
J=7.6 Hz), 7.51-7.59 (3H, m), 7.88-7.91 (1H, m), 7.93-7.99 (3H, m), 8.12 (1H, d, J=8.2 Hz), 8.22 (1H, d,
1
3
J=8.5 Hz), 8.58 (1H, s). C NMR (CDCl
3
) δ: 121.7, 123.2, 124.4, 125.3, 126.5, 126.9, 127.5, 127.7,
+
1
27.9, 128.9, 130.9, 133.2, 134.6, 135.0, 154.0, 168.2. FAB-MS: 262 (M+H) . Anal. Calcd for
C
17
H11NS: C, 78.13; H, 4.24; N, 5.36. Found: C, 77.97; H, 4.11; N, 5.31.
°
1
2
-(4-Methoxyphenyl)benzothiazole (2e). mp 121.5-122.0 C (EtOH/H O). H NMR (CDCl ) δ: 3.88 (3H,
2
3
s), 7.00 (2H, d, J=8.8 Hz), 7.35 (1H, t, J=7.6 Hz), 7.47 (1H, t, J=7.7 Hz), 7.87 (1H, d, J=7.7 Hz),
1
3
8
1
.02-8.05 (3H, m). C NMR (CDCl
3
) δ: 55.4, 114.2, 121.3, 122.7, 124.6, 126.0, 126.3, 128.9, 134.7,
+
54.0, 161.7, 167.6. FAB-MS: 242 (M+H) . Anal. Calcd for C14
H11NOS: C, 69.68; H, 4.59; N, 5.80.
Found: C, 69.50; H, 4.44; N, 5.69.
2 3
Oxidation of 2-phenylbenzothiazoline (3) with O in the presence of Sc(OTf) .
a) In the case of the reaction using an excess amount of O2.
-Phenylbenzothiazoline (43 mg, 0.2 mmol) was dissolved in THF (2 mL), and O
reaction vessel. Then Sc(OTf) (2 mg, 0.004 mmol) was added, and the mixture was allowed to react at
rt for 1 h under O . Thereafter, ethyl acetate (12 mL) was added, and the organic layer was washed with
2
2
was introduced to the
3
2
5% aq. Na
2
CO
3
4
(2 mL) and brine (2 mL), and dried over MgSO . Then the solvent was evaporated off,
1
and the product was analyzed by H NMR spectrum using mesitylene as an internal standard.
b) In the case of reaction using a limited amount of O
-Phenylbenzothiazoline (43 mg, 0.2 mmol) was placed in a two-necked flask (vol. ca. 42 mL) and
THF (2 mL) was added. After the solution was bubbled with Ar gas for 20 min, Sc(OTf) (2 mg, 0.004
2
.
2
3
mmol) was added under Ar atmosphere, and the flask was sealed with a septum rubber and a stopcock.
Then, 8 mL of Ar was added through the septum rubber to raise an inner pressure to ca.1.2 atm. Into
the flask was added 450µL of O (0.1 equiv), and the reaction mixture was allowed to react for 1 h.
2

After the addition of ethyl acetate (12 mL), the organic layer was washed with 5% aq. Na CO (2 mL)
2
3
4
and brine (2 mL), and dried over MgSO . After the solvent was evaporated off, the product was
1
analyzed by H NMR spectrum using mesitylene as an internal standard.
2
-(1H-Pyrrol-2-yl)benzothiazole (6). To a THF (5 mL) solution of pyrrole-2-carboxaldehyde (95 mg,
.0 mmol) were added 2-aminobenzenethiole (53µL, 0.5 mmol) and Sc(OTf) (5 mg, 0.01 mmol), and
. Then ethyl acetate (20 mL) was added, and the
organic layer was washed with 5% aq. Na CO (4 mL) and brine (2 mL), dried over MgSO , and
1
3
the mixture was allowed to react for 24 h at rt under O
2
2
3
4
evaporated off. The residue was chromatographed on silica gel (hexane:AcOEt=2:1) to give 6 (71 mg,
°
1
7
1%). mp 167-168 C (AcOEt/hexane). H NMR (CDCl
.23 (1H, t, J=7.6 Hz), 7.43 (1H, t, J=7.6 Hz), 7.83 (1H, d, J=7.4 Hz), 7.89(1H, d, J=8.0 Hz). C NMR
) δ: 110.7, 112.6, 121.5, 121.8, 122.2, 124.5, 126.3, 133.8, 153.3, 160.4. Anal. Calcd for
S: C, 65.97; H, 4.03; N, 13.99. Found: C, 65.86; H, 3.80; N, 13.89.
-(1H-Indol-3-yl)benzothiazole (8). To a THF (5 mL) solution of indole-3-carboxaldehyde (43 mg, 0.3
mmol) was added 2-aminobenzenethiol (21µL, 0.2 mmol) and Sc(OTf) (2 mg, 0.004 mmol), and the
mixture were allowed to react for 24 h at rt under O . Then ethyl acetate (12 mL) was added, and the
organic layer was washed with 5% aq. Na CO (2 mL) and brine (2 mL), dried over MgSO , and
evaporated off. The residue was chromatographed on silica gel (hexane:AcOEt=2:1) to give 8 (36 mg,
3
) δ: 6.32 (1H, m), 6.87 (1H, m), 6.95 (1H, m),
1
3
7
(CDCl
3
C
11 8 2
H N
2
3
2
2
3
4
°
1
7
7
2%). mp 168-169 C (AcOEt/hexane). H NMR (CDCl ) δ: 7.26-7.36 (3H, m), 7.42 (1H, d, J=8.0 Hz),
3
.45 (1H, t, J=8.3 Hz), 7.88 (1H, d, J=8.0 Hz), 7.99 (1H, d, J=2.9 Hz), 8.04 (1H, d, J=8.6 Hz), 8.42 (1H,
1
3
d, J=7.5 Hz), 9.06 (1H, br s). C NMR (CDCl
24.9, 126.2, 126.8, 133.5, 136.5, 153.1, 163.1. Anal. Calcd for C15
Found: C, 71.83; H, 3.77; N, 11.14.
3
) δ: 111.8, 112.2, 121.0, 121.3, 121.9, 122.0, 123.5, 124.4,
1
10 2
H N
S: C, 71.97; H, 4.03; N, 11.19.
Reaction of o-phenylenediamine with an aldehyde in the presence of scandium triflate under O
2
(
Table 4): the typical procedure; a) In the case of the reaction in 0.35 M solution; to a THF (1.5 mL)

solution of o-phenylenediamine (56 mg, 0.52 mmol) were added Sc(OTf) (3 mg, 0.006 mmol) and
3
benzaldehyde (55µL, 0.54 mmol), and the mixture was allowed to react for 44 h at rt under O
2
. Then
ethyl acetate (15 mL) was added, and the organic layer was washed with 5% aq. Na CO (2 mL) and
2
3
brine (2 mL), dried over MgSO
4
, and evaporated off. The residue was chromatographed on silica gel
(
CH Cl :ether=4:1) to give 11a (98 mg, 97%). b) In the case of the reaction in 0.002 M solution; to a
2
2
THF (100 mL) solution of o-phenylenediamine (22 mg, 0.2 mmol) were added Sc(OTf) (10 mg, 0.02
3
mmol) and p-chlorobenzaldehyde (42 mg, 0.3 mmol), and the mixture was allowed to react for 44 h at rt
under O . Then the solvent was evaporated off, and ethyl acetate (30 mL) was added. The organic
2
2 3 4
layer was washed with 5% aq. Na CO (6 mL) and brine (2 mL), dried over MgSO , and evaporated off.
The residue was chromatographed on silica gel (AcOEt:hexane=1:1) to give 11b (43 mg, 95%).
1
2
-Phenylbenzimidazole (11a). oil; H NMR (CDCl
3
) δ: 7.28 (2H, dd, J=6.0, 3.2 Hz), 7.46-7.51 (3H, m),
1
7
.65 (2H, dd, J=6.0, 3.2 Hz), 8.05-8.08 (2H, m). The H NMR spectrum of this compound was identical
with that of the commercial compound.
1
2
-(4-Chlorophenyl)benzimidazole (11b). H NMR (DMSO-d
6
) δ: 7.21-7.23 (2H, m), 7.59-7.65 (2H, m),
1
7
.63 (2H, d, J= 8.6 Hz), 8.19 (2H, d, J=8.4 Hz). The H NMR spectrum of this compound was identical
1
7
with the reported one.
°
18
°
1
2
-(1-Naphthyl)benzimidazole (11c). mp 272-274 C (lit., 284 C). H NMR (DMSO- d
6
) δ: 7.23-7.28
(
2H, m), 7.59-7.70 (5H, m), 8.00-8.05 (2H, m), 8.09 (1H, d, J=8.2 Hz), 9.10 (1H, d, J=8.2 Hz).
°
19
°
1
2
2
2
7
-(4-Methylphenyl)benzimidazole (11d). mp 277-279 C (lit., 275-276 C). H NMR (DMSO- d ) δ:
6
.37 (3H, s), 7.15-7.24 (2H, m), 7.35 (2H, d, J=8.2 Hz), 7.56 (2H, brs), 8.05 (2H, d, J=8.1 Hz).
°
20
°
1
6
-(4-Bromophenyl)benzimidazole (11e). mp 291-294 C (lit., 296-298 C). H NMR (DMSO-d ) δ:
.25-7.29 (2H, m), 7.60-7.62 (2H, m), 7.71 (2H, d, J=8.8 Hz), 7.99 (2H, d, J=8.8 Hz).
1
Benzimidazole (11f). oil; H NMR (MeOH-d
4
) δ: 7.25 (2H, dd, J=6.0, 2.8 Hz), 7.63 (2H, dd, J=6.0, 3.2
1
Hz), 8.02 (1H, s). The H NMR spectrum of this compound was identical with that of commercial
compound.
1
2
-Methylbenzimidazole (11g). oil; H NMR (CDCl
3
) δ: 2.63 (3H, s), 6.80 (1H, br s), 7.20 (2H, dd,

1
J=6.1, 3.1 Hz), 7.54 (2H, dd, J=6.1, 3.1 Hz). The H NMR spectrum of this compound was identical with
that of commercial compound.
°
21
°
1
2
d
1
1
7
-(1,1-Dimethylethyl)benzimidazole (11h). mp > 300 C (EtOH) (lit., 331-333 C). H NMR (MeOH-
1
3
4
) δ: 1.47 (9H, s), 7.17 (2H, dd, J=5.8, 3.2 Hz), 7.50 (2H, br s). C-NMR (MeOH- d
23.0, 164.0. Anal. Calcd for C11 : C, 75.82; H, 8.10; N, 16.08. Found: C, 75.77; H, 8.26; N, 16.04.
-Benzyl-2-phenylbenzimidazole (12a). oil; H NMR(CDCl
.19-7.37 (6H, m), 7.43-7.50 (3H, m), 7.69 (2H, d, J=7.6 Hz), 7.87 (1H, d, J=8.0 Hz). C-NMR(CDCl
4
) δ: 29.7, 34.4,
14 2
H N
1
3
) δ: 5.46 (2H, s), 7.11 (2H, d, J=7.6 Hz),
1
3
3
)
δ: 48.40, 110.53, 119.97, 122.70, 123.06, 125.98, 127.78, 128.75, 129.06, 129.27, 129.93, 130.04, 136.04,
+
1
36.38, 143.13, 154.17. HRMS (FAB): Calcd for C H N (M+H) : 285.1392. Found 285.1380.
2
0
17
2
°
1
1
-(4-Chlorophenyl)methyl-2-(4-chlorophenyl)benzimidazole (12b). mp 139.7-140.1 C (hexane). H
) δ: 5.40 (2H, s), 7.02 (2H, d, J=8.6 Hz), 7.20 (1H, d, J=7.7 Hz), 7.25-7.34 (4H, m), 7.44
NMR (CDCl
3
1
3
(
3
2H, d, J=8.8 Hz), 7.59 (2H, d, J=8.6 Hz), 7.87 (1H, d, J=7.7 Hz). C NMR (CDCl ) δ: 47.7, 110.1,
1
20.1, 122.9, 123.3, 127.1, 128.3, 129.0, 129.2, 130.3, 133.7, 134.5, 135.8, 136.2, 143.0, 152.7.
+
FAB-MS: 353 (M+H) . Anal. Calcd for C20
H
14
N
2
Cl
2
: C, 68.00; H, 3.99; N, 7.93. Found: C, 67.86; H,
3
.76; N, 7.83.
1
1
-(1-Naphthylmethyl)-2-(1-naphthyl)benzimidazole (12c). oil; H NMR (CDCl
3
) δ: 5.72 (2H, s), 6.83
(1H, dd, J=7.1, 0.9 Hz), 7.20-7.29 (3H, m), 7.35-7.57 (7H, m), 7.73 (2H, d, J=8.2 Hz), 7.84-7.92 (3H, m),
1
3
7
1
1
3
.99 (2H, d, J=7.7 Hz). C NMR (CDCl ) δ: 46.1, 110.8, 120.3, 122.1, 122.7, 123.1, 123.6, 124.8, 125.4,
25.6, 126.0, 126.4, 126.5, 127.2, 127.4, 128.17, 128.21, 128.3, 129.0, 130.2, 130.4, 131.2, 132.3, 133.6,
+
33.7, 135.4, 143.4, 153.1. HRMS (FAB): Calcd for C28
H
21
N
2
(M+H) : 385.1705. Found 385.1702.
°
1
-(4-Methylphenyl)methyl-2-(4-methylphenyl)benzimidazole (12d). mp 128-129 C (AcOEt/hexane).
1
3
H NMR (CDCl ) δ: 2.31 (3H, s), 2.38 (3H, s), 5.38 (2H, s), 6.98 (2H, d, J=7.9 Hz), 7.11 (2H, d, J=7.9
1
3
Hz), 7.16-7.30 (5H, m), 7.58 (2H, d, J=8.1 Hz), 7.85 (1H, d, J=7.9 Hz). C-NMR (CDCl
3
) δ: 21.05,
1.40, 48.21, 110.52, 119.69, 122.66, 122.92, 125.87, 126.90, 129.17, 129.45, 129.69, 133.34, 135.96,
37.47, 140.15, 142.75, 154.17. Anal. Calcd for C H N : C, 84.58; H, 6.45; N, 8.97. Found: C, 84.69;
2
1
2
2
20
2
H, 6.48; N, 8.97.

1
1
-Methylbenzimidazole (12f). oil; H NMR (CDCl ) δ: 3.79 (3H, s), 7.25-7.40 (3H, m), 7.78 (1H, dd,
3
1
J=8.4, 1.2 Hz), 7.85 (1H, s). The H NMR spectrum of this compound was identical with that of the
commercial compound.
1
1
-Ethyl-2-methylbenzimidazole (12g). oil; H NMR (CDCl
3
) δ: 1.41 (3H, t, J=7.4 Hz), 2.61 (3H, s),
1
3
4
.16 (2H, q, J=7.4 Hz), 7.22-7.26 (2H, m), 7.32 (1H, dd, J=6.1, 1.5 Hz), 7.68 (1H, dd, J=6.8, 2.2 Hz). C
NMR (CDCl ) δ: 13.57, 14.79, 38.36, 108.85, 118.88, 121.65, 121.84, 134.55, 142.49, 150.97. HRMS
3
+
(
FAB): Calcd for C10
H
13
N
2
(M+H) : 161.1079. Found 161.1069.
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