Copper-catalyzed, one-pot, three-component synthesis of benzimidazoles by condensation and C-N bond formation

Article abstract of DOI:10.1021/jo2019416

Benzimidazoles were synthesized by the copper-catalyzed, one-pot, three-component reaction of 2-haloanilines, aldehydes, and NaN₃. The reaction was optimized when 2-iodo- or 2-bromoanilines (1.0 equiv), aldehydes (1.2 equiv), NaN₃ (2.0 equiv), 5 mol% of CuCl, and 5 mol % of TMEDA were reacted in DMSO at 120 °C for 12 h. Good yields resulted, and the reaction showed tolerance toward functional groups such as ester, nitro, and chloro. Aliphatic and heteroaromatic aldehydes also afforded the desired products in moderate to good yields.

Full text of DOI:10.1021/jo2019416

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Copper-Catalyzed, One-Pot, Three-Component Synthesis of
Benzimidazoles by Condensation and C−N Bond Formation
Yong Kim, Manian Rajesh Kumar, Namjin Park, Yumi Heo, and Sunwoo Lee*
Department of Chemistry, Institute of Basic Science, Chonnam National University, 300 Yongbong-dong, Buk-gu, Gwangju 500-757,
Republic of Korea
S
* Supporting Information
ABSTRACT: Benzimidazoles were synthesized by the
copper-catalyzed, one-pot, three-component reaction of 2-
haloanilines, aldehydes, and NaN3. The reaction was optimized
when 2-iodo- or 2-bromoanilines (1.0 equiv), aldehydes (1.2
equiv), NaN3 (2.0 equiv), 5 mol% of CuCl, and 5 mol % of
TMEDA were reacted in DMSO at 120 °C for 12 h. Good
yields resulted, and the reaction showed tolerance toward functional groups such as ester, nitro, and chloro. Aliphatic and
heteroaromatic aldehydes also afforded the desired products in moderate to good yields.
2H-indazoles suggests the possibility of the one-pot synthesis of
benzimidazoles from sodium azide. Here, we report one-pot,
three-component coupling reactions for the syntheses of
benzimidazoles (Scheme 1).
INTRODUCTION
■
N-Containing heteroaromatic compounds are important
structures found in natural and synthetic compounds. Among
them, benzimidazole and its derivatives are crucial core
structures used to create drugs and materials. They exhibit
biological activities such as anticancer,1 antiulcer,2 antihyper-
tensive,3 antibacterial,4 and enzyme inhibition.5 They have also
been applied in dyes,6 chemosensing,7 fluorescence, and
corrosion science.8
Scheme 1. Synthesis of Benzimidazoles from Azides
Benzimidazole has various reported syntheses, with two
methods used extensively that employ 1,2-diaminoarenes as
starting materials. One is the coupling of carboxylic acids,9 and
the other is the condensation of aldehydes.10 They both have
some drawbacks; the former requires strongly acidic conditions
and sometimes high reaction temperatures; the latter method
requires a stoichiometric oxidant for dehydration. Both
syntheses result in side products such as regioisomers and
disubstituted products from the 1,2-diaminoarene. Efficient
syntheses of benzimidazoles from 2-haloacetanilides,11 N-
arylbenzimidamide,12 2-haloarylamidine,13 and arylamino ox-
imes14 have recently been reported. However, each requires
multistep reactions for the preparation of the starting materials.
Despite these recent advances including reusable catalytic
systems,15 the development of a simpler method is still required
to overcome the limitations of the existing procedures.
In 2008, Driver’s group reported the FeBr2-catalyzed
synthesis of benzimidazole from 2-azidoaniline and achieved
good yields under mild conditions.16 However, their method
has some drawbacks; the starting materials, 2-azidoanilines,
require a four-step preparation from 2-nitroaniline and an
additional two steps are required for the synthesis of the
benzimidazoles. Very recently, the copper-catalyzed, three-
component coupling of 2-bromoaldehyde, primary amines, and
sodium azide has recently been reported to construct 2H-
indazoles in high yields by our group.17 The successful use of
sodium azide as a nitrogen source in the one-pot synthesis of
RESULTS AND DISCUSSION
■
As a model reaction, 2-iodoaniline, benzaldehyde, and sodium
azide were reacted under a variety of reaction conditions (Table
1).
As expected, the desired product was not obtained in the
absence of metal catalyst (entry 1); therefore, we employed and
tested several transition metals as catalysts. FeBr2, which
Driver’s group reported as having good activity for the
production of 2-azidoarylimine,15 did not afford the desired
products (entry 2). Palladium complexes did not produce the
benzimidazole, despite catalyzing the coupling reactions of aryl
halides and azide (entries 3 and 4). Nickel catalyst was similarly
ineffective (entry 5). Copper complexes afforded 2-phenyl-
benzimidazole in moderate yields,18 with CuCl showing the
best yield (entry 10), which was improved in the presence of
Received: September 20, 2011
Published: October 30, 2011
© 2011 American Chemical Society
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Table 1. Optimized Conditions for the Synthesis of
Benzimidazoles
Table 2. Screening of Coppers in the Synthesis of
Benzimidazoles
a
a
b
yield (%)
d
f
entry ArX
cat.
ligand
solvent
yield (%)
c
entry
catalyst
without ligand
with ligand (TMEDA )
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a′
1a′
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
diglyme
DMF
0
1
2
Cu powder
Cu2O
34
24
35
36
64
38
34
26
40
47
36
32
31
40
69
42
32
28
42
52
FeBr2
0
3
Pd(OAc)2
Pd(CH3CN)2Cl2
Ni(OAc)2
CuCl2
0
3
Cu2S
4
0
4
Cu2Se
5
0
5
Cu(OAc)2
Cu(acac)2
CuO
6
44
49
70
71
76
72
65
98
trace
trace
62
68
71
98
72
94
91
6
7
Cu(OTf)2
CuI
7
8
8
CuS
9
CuBr
9
CuCO3
CuSO4
10
11
12
13
14
15
16
17
18
19
20
21
22
CuCl
10
CuCl
DMEDA
Phenanth
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
a
e
Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), 3 (0.60
mmol), and catalyst (0.03 mmol) were reacted in DMSO (1.0 mL) at
120 °C for 12 h. Determined by HPLC with internal standard. 0.03
CuCl
CuCl
b
c
CuCl
mmol of ligand was used.
CuCl
CuCl
forming C−N bonds and undergoing cyclization for the
synthesis of benzimidazoles (Table 3).
CuCl
NMP
CuCl
DMAc
DMSO
DMSO
DMSO
DMSO
As expected, all of the aldehydes formed corresponding
benzimidazoles in good yields. Benzaldehyde showed 90%
product yield (entry 1). Aromatic aldehydes with electron-
withdrawing groups such as chloro and nitro gave the
corresponding benzimidazoles in 75% and 55% yields,
respectively (entries 2 and 3). Benzaldehydes with electron-
donating groups such as dimethylamino, methyl, and methoxy
formed the desired products in good yields (entries 4−6). 2,3-
and 3,4-(Methylenedioxyl)benzaldehydes produced the desired
benzimidazoles in 62% and 66% yields, respectively (entries 7
and 8). The heteroaryl aldehydes 2-furaldehyde (2i) and 2-
thiophenecarboxaldehyde (2j) reacted smoothly, giving the
coupling products in good to excellent yields (entries 9 and
10). 6-Methoxy-2-naphthaldehyde showed product in 98%
yield (entry 11). Alkyl aldehydes with bulky groups at the α
position afforded the desired products in moderate to good
yields (entries 12 and 13). However, butyraldehyde did not give
the desired product (entry 14). Formaldehyde afforded
benzimidazole in 42% yield (entry 15).
The use of 2-bromoaniline resulted in the desired products
with good yields, similar to 2-iodoanilines. Attempts to employ
N,N-dimethylformamide and N-methylformamide failed as
their imine products did not form. In general, no strong
dependence of product yield on the donating or withdrawing
character of the substituted aldehydes was observed.
Anilines bearing ester, chloride, and heteroaromatic groups
were next studied (Table 4). Methyl 4-amino-3-iodobenzoate
(1b), with a base-sensitive group, was condensed with
aldehydes and coupled with NaN3 to produce the desired
benzimidazoles in moderate to good yields (entries 1−3). The
coupling of benzaldehyde (2a) produced a mixture of
benzimidazole tautomers (entry 1). The coupling reaction of
5-chloro-2-iodoaniline occurred at the iodide site via copper
catalysis. 3-Bromo-2-aminopyridine (1d) and 2-bromo-3-
aminopyridine (1e) afforded products with the same structures
(entries 7, 8, and 10 vs entries 12, 13, and 14, respectively).
These results are similar to Driver’s.16,19 This reaction
b
b
CuCl
TMEDA
TMEDA
TMEDA
TMEDA
c
c
CuCl
CuCl
b
b
CuCl
a
Reaction conditions: 1a or 1a′ (0.30 mmol), 2a (0.36 mmol), 3 (0.60
mmol), and catalyst (0.03 mmol) were reacted in solvent (1.0 mL) at
120 °C for 12 h. CuCl (0.015 mmol)/TMEDA (0.015 mmol) was
used. CuCl (0.006 mmol)/TMEDA (0.006 mmol) was used. 0.03
b
c
d
e
f
mmol of ligand was used. 1,10-Phenanthroline. Determined by
HPLC with internal standard.
TMEDA ligands (entry 13). The solvent affected the yield of
the desired product, with no product obtained in toluene and
diglyme (entries 14 and 15). Polar solvents, such as DMF,
NMP, and DMAc, showed fair performance, but DMSO was
best (entries 16−18). Using the catalyst at 5 mol% and 2 mol %
gave yields of 98% and 72%, respectively (entries 19 and 20).
The reaction of 2-bromoaniline and aldehydes at 120 °C in the
presence of 5 mol% catalyst gave good yields (entry 22).
Compared with 2-iodoaniline, 2-bromoaniline showed similar
activity in the synthesis of benzimidazole.
To investigate the role of copper and ligand in the synthesis
of benzimidazole, we tested a variety of copper sources in the
absence or presence of ligand as shown in Table 2. Copper(I)
provided the desired product in the range of 24−40% yields
(entries 2−4), and copper(II) showed similar yields (entries 6−
10) except in the case of Cu(OAc)2 (entry 5). From these
results, we found that the oxidation state of copper was not a
crucial factor, and the effects of ligands on most of the copper
catalysts were weak.
The reaction was optimized when 2-haloanilines (1.0 equiv),
aldehydes (1.2 equiv), and NaN3 (2.0 equiv) reacted in the
presence of 5 mol% of CuCl/TMEDA and DMSO at 120 °C
for 12 h.
Next, 2-iodo- and 2-bromoanilines were tested in con-
densation reactions with a variety of substituted aldehydes,
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Table 3. Synthesis of Benzimidazoles from 2-Haloanilines
and Aldehydes
Table 4. Synthesis of Benzimidazole from Substituted 2-
Haloanilines
a
a
a
Reaction conditions: 2-haloanilines 1 (2.0 mmol), aldehydes 2 (2.4
mmol), NaN3 (4.0 mmol), CuCl (0.1 mmol), and TMEDA (0.1
b
mmol) were reacted in DMSO (6.0 mL) at 120 °C for 12 h. The
ratio of tautomers is 53:47, which was calculated from the 2D NMR.
a
Reaction conditions: 1a or 1a′ (2.0 mmol), aldehydes 2 (2.4 mmol),
NaN3 (4.0 mmol), CuCl (0.1 mmol), and TMEDA (0.1 mmol) were
b
c
reacted in DMSO (6.0 mL) at 120 °C for 12 h. Yield from 1a′. Only
N-butylidenebenzene-1,2-diamine was found in 20% yield in the
reaction mixture.
Figure 1. Three tautomers.
mechanism is not regiospecific and produced the more stable
tautomer.20
Scheme 2. One-Pot Synthesis of Tiabendazole
When 1d and 1e were employed as anilines, there were three
tautomers in their products as shown in Figure 1. These
structures were fully optimized at the DFT-B3LYP level and 6-
31++G(d,p) basis set in Gaussian 03 suite of programs.21 These
calculations showed that tautomer A is the most stable one in
most cases; however, tautomer B is more stable than tautomer
A in the case of 4da and 4ea.
copper appeared to be much more important in the coupling
reactions of aryl halides and azide than in cyclization. These
results allow the mechanism in Scheme 4 to be proposed. The
condensation of 2-haloaniline and aldehyde afforded 2-
halobenzimine I. The copper-catalyzed coupling of aryl halides
with azide23 was then followed by cyclization. Two possible
paths are suggested; the formation of intermediate III (path A)
and the direct formation of intermediate IV without the
formation of azidoimine III (path B). In Scheme 3, the result of
(2) supports path B, but path A was not excluded due to the
result of (3). Further mechanistic studies of this reaction system
are in progress.24
Finally, tiabendazole,22 a fungicide and parasiticide with the
trade names Mintezol and Tesaderm, was synthesized from this
one-pot method in good yields (Scheme 2).
To understand the reaction mechanism, several competitive
reactions were conducted (Scheme 3). 2-Azidoaniline was not
formed from 2-haloaniline under CuCl catalysis. 2-Azido-N-
benzylideneaniline was not detected in the reaction mixture;
only benzimidazole was formed in 98% yield.
However, 2-azido-N-benzylideneaniline produced the desired
product in the presence of copper catalysts (Cu2O: 97%, CuCl:
98% yields). Cu2O and CuCl showed different product yields in
the one-pot reactions (Cu2O: 32%, CuCl: 98%). The source of
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2-Phenyl-1H-benzimidazole25 (4aa) (Entry 1 in Table 3). 2-
Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with benzaldehyde
(255 mg, 2.4 mmol) (2a) to give 350 mg (1.8 mmol, 90%) of 4aa as a
pale yellow solid after chromatography [342 mg (1.8 mmol, 88%) of
4a′a was obtained from 2-bromoaniline (344 mg, 2.0 mmol) (1a′)]:
Scheme 3. Cu-Catalyzed Couplings and Cyclization
1
mp 292−294 °C; H NMR (300 MHz, DMSO) δ 12.92 (br s, 1H),
8.22−8.17 (m, 2H), 7.68 (d, J = 6.6 Hz, 1H), 7.58−7.46 (m, 4H), 7.21
(dd, J = 8.7, 3.6 Hz, 2H); 13C NMR (75 MHz, DMSO) δ 151.2, 143.8,
135.0, 130.2, 129.8, 128.9, 126.4, 122.5, 121.7, 118.9, 111.3; IR (KBr)
3044, 1622, 1587, 1537, 1458, 1439, 1407, 1312, 1274 cm−1; HRMS
(FAB) calcd for C13H11N2 [M + H]+ 195.0922, found 195.0922.
2-(4-Chlorophenyl)-1H-benzimidazole26 (4ab) (Entry 2 in
Table 3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with
4-chlorobenzaldehyde (337 mg, 2.4 mmol) (2b) to give 343 mg (1.5
mmol, 75%) of 4ab as a pale yellow solid after chromatography [206
mg (0.9 mmol, 45%) of 4a′b was obtained from 2-bromoaniline (344
mg, 2.0 mmol) (1a′)]: mp 289−291 °C; 1H NMR (300 MHz,
DMSO) δ 13.02 (br s, 1H), 8.21 (d, J = 8.7 Hz, 2H), 7.67−7.63 (m,
4H), 7.25−7.22 (m, 2H); 13C NMR (75 MHz, DMSO) δ 150.2, 143.7,
135.0, 134.5, 129.1, 129.1, 128.2, 122.8, 121.9, 119.0, 111.5; IR (KBr)
3051, 1689, 1581, 1555, 1428, 1273, 745, 729 cm−1; HRMS (FAB)
calcd for C13H10ClN2 [M + H]+ 229.0533, found 229.0532.
Scheme 4. Proposed Mechanism
2-(4-Nitrophenyl)-1H-benzimidazole27 (4ac) (Entry 3 in
Table 3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with
4-nitrobenzaldehyde (363 mg, 2.4 mmol) (2c) to give 263 mg (1.1
mmol, 55%) of 4ac as a brown solid after chromatography [196 mg
(0.8 mmol, 41%) of 4a′c was obtained from 2-bromoaniline (344 mg,
1
2.0 mmol) (1a′)]: mp 259−260 °C; H NMR (300 MHz, DMSO) δ
13.05 (br s, 1H), 8.00 (ddd, J = 15.3, 7.8, 1.2 Hz, 2H), 7.87 (td, J = 7.5,
1.2 Hz, 1H), 7.76 (td J = 7.8, 1.5 Hz, 1H), 7.61 (br s, 2H), 7.25 (d, J =
4.8 Hz, 2H); 13C NMR (75 MHz, DMSO) δ 149.0, 147.3, 143.6,
134.6, 132.6, 130.9, 124.3, 123.1, 121.9, 119.2, 111.7; IR (KBr) 3063,
1526, 1445, 1415, 1378, 1347, 1319 cm−1; HRMS (FAB) calcd for
C13H10N3O2 [M + H]+ 240.0773, found 240.0774.
2-(4-Dimethylaminophenyl)-1H-benzimidazole28 (4ad)
(Entry 4 in Table 3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was
coupled with ethyl 4-(dimethylamino)benzaldehyde (358 mg, 2.4
mmol) (2d) to give 460 mg (1.94 mmol, 97%) of 4ad as a pale yellow
solid after chromatography [394 mg (1.7 mmol, 83%) of 4a′d was
obtained from 2-bromoaniline (344 mg, 2.0 mmol) (1a′)]: mp 273−
275 °C; 1H NMR (300 MHz, DMSO) δ 12.53 (br s, 1H), 7.98 (d, J =
9.0 Hz, 2H), 7.55 (br s, 1H), 7.43 (br s, 1H), 7.14−7.08 (m, 2H), 6.82
(d, J = 9.0 Hz, 2H), 2.99 (s, 6H); 13C NMR (75 MHz, DMSO) δ
152.3, 151.3, 144.1, 135.0, 127.6, 121.6, 121.2, 118.0, 117.4, 111.9,
110.7, 39.9 ; IR (KBr) 3051, 2917, 2808, 1609, 1503, 1438, 1400, 1200
cm−1; HRMS (FAB) calcd for C15H16N3 [M + H]+ 238.1344, found
238.1354.
CONCLUSION
■
In summary, an efficient synthesis of benzimidazoles was
developed involving one-pot, three-component reactions of 2-
haloanilines, aldehydes, and NaN3 in the presence of copper
catalysts. This system shows several advantages: it requires no
preparation of the starting materials as they are commercially
available; it does not require the isolation of intermediates; it
provides easy purification procedure by simple column
chromatography; and it shows applicability with a broad
range of substrates. For example, 2-iodo- and 2-bromoanilines,
aliphatic, and heteroaromatic aldehydes afforded the desired
products. In addition, substrates bearing base-sensitive func-
tional groups also showed good yields.
2-p-Tolyl-1H-benzimidazole29 (4ae) (Entry 5 in Table 3). 2-
Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with 4-
methylbenzaldehyde (288 mg, 2.4 mmol) (2e) to give 325 mg (1.56
mmol, 78%) of 4ae as a white solid after chromatography [350 mg
(1.7 mmol, 84%) of 4a′e was obtained from 2-bromoaniline (344 mg,
1
2.0 mmol) (1a′)]: mp 275−277 °C; H NMR (300 MHz, DMSO) δ
EXPERIMENTAL SECTION
12.81 (br s, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.57 (br s, 2H), 7.36 (d, J =
7.8 Hz, 2H), 7.21−7.16 (m, 2H), 2.38 (s, 3H); 13C NMR (75 MHz,
DMSO) δ 151.4, 139.5, 129.5, 127.4, 126.4, 122.0, 21.0; IR (KBr)
3052, 2962, 2914, 1616, 1587, 1501, 1446, 1430, 1273 cm−1; HRMS
(FAB) calcd for C14H13N2 [M + H]+ 209.1079, found 209.1077.
2-(4-Methoxyphenyl)-1H-benzimidazole30 (4af) (Entry 6 in
Table 3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with
4-methoxybenzaldehyde (327 mg, 2.4 mmol) (2f) to give 368 mg
(1.64 mmol, 82%) of 4af as a white solid after chromatography [292
mg (1.3 mmol, 65%) of 4a′f was obtained from 2-bromoaniline (344
mg, 2.0 mmol) (1a′)]: mp 222−225 °C; 1H NMR (300 MHz,
DMSO) δ 12.74 (br s, 1H), 8.14−8.09 (m, 2H), 7.57−7.54 (m, 2H),
7.20−7.14 (m, 2H), 7.13−7.09 (m, 2H), 3.84 (s, 3H); 13C NMR (75
MHz, DMSO) δ 160.6, 151.3, 128.0, 122.7, 121.8, 114.4, 55.3; IR
(KBr) 3053, 2963, 2914, 1616, 1501, 1430, 1321, 1273 cm−1; HRMS
(FAB) calcd for C14H13N2O [M + H]+ 225.1028, found 225.1024.
■
General Method for the Preparation of 1H-Benzimidazole.
CuCl (10 mg, 0.1 mmol), 2-iodoaniline (483 mg, 2.0 mmol) (1a) or 2-
bromoaniline (344 mg, 2.0 mmol) (1a′) or methyl 4-amino-3-
iodobenzoate (554 mg, 2.0 mmol) (1b) or 5-chloro-2-iodoaniline
(507 mg, 2.0 mmol) (1c) or 2-amino-3-bromopyridine (346 mg, 2.0
mmol) (1d) or 3-amino-2-bromopyridine (346 mg, 2.0 mmol) (1e),
NaN3 (260 mg, 4.0 mmol), N,N,N′,N′-tetramethylethylenediamine
(TMEDA) (12 mg, 0.1 mmol), and aldehydes (2.4 mmol) were
reacted in 6.0 mL of DMSO. The reaction mixture was heated to 120
°C for 12 h. After cooling, the mixture was poured into the EtOAc
(50.0 mL), washed with brine (25.0 mL) and water (2 × 25.0 mL),
dried over MgSO4, and passed through a Celite. Evaporation of the
solvent under reduced pressure provided the crude product, which was
purified by column chromatography (hexane/EtOAc = 1:1) to afford
the final product.
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2-(Benzo[1,3]dioxol-4-yl)-1H-benzimidazole (4ag) (Entry 7
in Table 3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled
with 2,3-(methylenedioxy)benzaldehyde (360 mg, 2.4 mmol) (2g) to
give 295 mg (1.24 mmol, 62%) of 4ag as a white solid after
chromatography [267 mg (1.1 mmol, 56%) of 4a′g was obtained from
2-bromoaniline (344 mg, 2.0 mmol) (1a′)]: mp 194−196 °C; 1H
NMR (300 MHz, DMSO) δ 12.25 (s, 1H), 7.66−7.60 (m, 3H), 7.23−
7.18 (m, 2H), 7.07−6.98 (m, 2H), 6.26 (s, 2H); 13C NMR (75 MHz,
DMSO) δ 148.0, 147.0, 144.8, 122.1, 120.1, 112.4, 109.4, 101.7; IR
(KBr) 3046, 2902, 1465, 1396, 1244, 1190, 1056, 933 cm−1; HRMS
(FAB) calcd for C14H11N2O2 [M + H]+ 239.0820, found 239.0804.
2-(Benzo[1,3]dioxol-5-yl)-1H-benzimidazole31 (4ah) (Entry 8
in Table 3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled
with piperonal (360 mg, 2.4 mmol) (2h) to give 314 mg (1.32 mmol,
66%) of 4ah as a pale brown solid after chromatography [343 mg (1.4
mmol, 72%) of 4a′h was obtained from 2-bromoaniline (344 mg, 2.0
3051, 2971, 2883, 1534, 1455, 1415, 1273 cm−1; HRMS (FAB) calcd
for C10H13N2 [M + H]+ 161.1079, found 161.1040.
2-tert-Butyl-1H-benzimidazole33 (4am) (Entry 13 in Table
3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with
pivalaldehyde (207 mg, 2.4 mmol) (2m) to give 342 mg (1.96
mmol, 98%) of 4am as pale yellow solid after chromatography [146
mg (0.8 mmol, 42%) of 4a′m was obtained from 2-bromoaniline (344
mg, 2.0 mmol) (1a′)]: mp 303−306 °C; 1H NMR (300 MHz,
DMSO) δ 12.07 (br s, 1H), 7.54−7.51 (m, 1H), 7.42−7.39 (m, 1H),
7.14−7.06 (m, 2H), 1.39 (s, 9H); 13C NMR (75 MHz, DMSO) δ
162.2, 142.8, 134.6, 121.4, 120.7, 118.3, 110.8, 33.2, 29.3; IR (KBr)
3050, 2964, 2872, 1532, 1451, 1410, 1274, 1220 cm−1; HRMS (FAB)
calcd for C11H15N2 [M + H]+ 175.1235, found 175.1234.
Benzimidazole34 (4an) (Entry 15 in Table 3). 2-Iodoaniline
(438 mg, 2.0 mmol) (1a) was coupled with formaldehyde (72 mg, 2.4
mmol) (2n) and MgSO4 (722 mg, 6.0 mmol) to give 99 mg (0.84
mmol, 42%) of 4an as a white solid after chromatography [128 mg
(1.1 mmol, 54%) of 4a′n was obtained from 2-bromoaniline (344 mg,
1
mmol) (1a′)]: mp 239−240 °C; H NMR (300 MHz, DMSO) δ
12.75 (br s, 1H), 7.75−7.69 (m, 2H), 7.62 (br s, 1H), 7.50 (br s, 1H),
7.18−7.08 (m, 3H), 6.12 (s, 2H); 13C NMR (75 MHz, DMSO) δ
151.2, 148.8, 147.9, 143.8, 135.1, 124.3, 122.0, 120.9, 118.5, 111.3,
108.8, 106.5, 101.6; IR (KBr) 3052, 2907, 1619, 1476, 1453, 1247,
1228, 1039 cm−1; HRMS (FAB) calcd for C14H11N2O2 [M + H]+
239.0820, found 239.0826.
1
2.0 mmol) (1a′)]: mp 169−171 °C; H NMR (300 MHz, DMSO) δ
12.52 (br s, 1H), 8.25 (s, 1H), 7.64−7.58 (m, 2H), 7.22−7.16 (m,
2H); 13C NMR (75 MHz, DMSO) δ 142.0, 138.1, 121.8, 115.4; IR
(KBr) 3113, 3062, 1770, 1581, 1458, 1409, 1245, 747 cm−1; HRMS
(FAB) calcd for C7H7N2 [M + H]+ 119.0609, found 119.0608.
Compound 4ba35 (Entry 1 in Table 4). Methyl 4-amino-3-
iodobenzoate (554 mg, 2.0 mmol) (1b) was coupled with
benzaldehyde (255 mg, 2.4 mmol) (2a) to give 288 mg (1.14
mmol, 57%) of 4ba as a pale brown solid after chromatography: mp
189−191 °C (T: indentified peaks from one tautomer, nd:
2-(Furan-2-yl)-1H-benzimidazole32 (4ai) (Entry 9 in Table
3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with furan-2-
carbaldehyde (231 mg, 2.4 mmol) (2i) to give 265 mg (1.44 mmol,
72%) of 4ai as a pale brown solid after chromatography [250 mg (1.4
mmol, 68%) of 4a′i was obtained from 2-bromoaniline (344 mg, 2.0
1
mmol) (1a′)]: mp 285−287 °C; H NMR (300 MHz, DMSO) δ
1
nonindentified peaks); H NMR (300 MHz, DMSO) δ 13.26 (br s,
12.91 (br s, 1H), 7.94 (dd, J = 1.8, 0.9 Hz, 1H), 7.55 (br s, 2H), 7.22−
7.18 (m, 3H), 6.73 (dd, J = 3.3, 1.8 Hz, 1H); 13C NMR (75 MHz,
DMSO) δ 145.6, 144.6, 143.6, 134.2, 122.4, 121.8, 118.7, 112.3, 111.4,
0.5 H, nd), 13.25 (br s, 0.5 H, nd), 8.27 (br s, 0.5 H, nd), 8.20 (d, J =
4.5 Hz, 2H, nd), 8.12 (br s, 0.5 H, nd), 7.87 (d, J = 4.8 Hz, 0.5H, T),
7.85 (d, J = 5.1 Hz, 0.5H, T), 7.75 (d, J = 5.1 Hz, T), 7.63 (d, J = 4.8
Hz, 0.5 Hz, T), 7.59−7.53 (m, 3H), 3.88 (s, 3H); 13C NMR (75 MHz,
DMSO) δ 166.8 (nd), 166.6 (T), 154.2 (nd), 153.4 (nd), 147.3 (T),
143.4 (nd), 138.5 (T), 134.7 (T), 130.5 (nd), 130.4 (nd), 129.5 (nd),
129.4 (nd), 129.0 (nd), 126.8 (nd), 126.7 (nd), 123.7 (T), 123.5 (nd),
123.3 (nd), 122.8 (T), 120.4 (T), 118.7 (nd), 112.9 (T), 111.4 (nd),
52.0 (nd), 51.9 (nd); IR (KBr) 3315, 2949, 1694, 1542, 1435, 1299,
1229 cm−1; HRMS (FAB) calcd for C15H13N2O2 [M + H]+ 253.0977,
found 253.0977.
110.5; IR (KBr) 3053, 1630, 1525, 1416, 1363, 1278, 1233 cm−1
;
HRMS (FAB) calcd for C11H9N2O [M + H]+ 185.0715, found
185.0715.
2-(Thien-2-yl)-1H-benzimidazole31 (4aj) (Entry 10 in Table
3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with 2-
thiophenecarboxaldehyde (269 mg, 2.4 mmol) (2j) to give 393 mg
(1.96 mmol, 98%) of 4aj as a pale yellow solid after chromatography
[188 mg (1.0 mmol, 51%) of 4a′j was obtained from 2-bromoaniline
1
(344 mg, 2.0 mmol) (1a′)]: mp 342−343 °C; H NMR (300 MHz,
Compound 4bh (Entry 2 in Table 4). Methyl 4-amino-3-
iodobenzoate (554 mg, 2.0 mmol) (1b) was coupled with piperonal
(360 mg, 2.4 mmol) (2h) to give 427 mg (1.44 mmol, 72%) of 4bh as
DMSO) δ 12.94 (br s, 1H), 7.83 (dd, J = 3.6, 1.2 Hz, 1H), 7.72 (dd, J
= 5.0, 1.1 Hz, 1H), 7.62−7.59 (m, 1H), 7.50 (dd, J = 6.9, 2.1 Hz, 1H),
7.24−7.14 (m, 3H); 13C NMR (75 MHz, DMSO) δ 147.0, 143.6,
134.7, 133.7, 128.8, 128.3, 126.7, 122.6, 121.7, 118.5, 111.1; IR (KBr)
3047, 3008, 1569, 1450, 1423, 1312, 1275, 1233 cm−1; HRMS (FAB)
calcd for C11H9N2S [M + H]+ 201.0486, found 201.0484.
1
a pale yellow solid after chromatography: mp 269−271 °C; H NMR
(300 MHz, DMSO) δ 13.10 (br s, 1H), 8.14 (s, 1H), 7.82 (dd, J = 8.4,
1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.8 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H),
7.63 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.13 (s, 2H), 3.86
(s, 3H); 13C NMR (75 MHz, DMSO) δ 166.7, 153.7, 149.2, 147.9,
123.5, 123.2, 121.4, 108.8, 106.7, 101.7, 52.0; IR (KBr) 3291, 2952,
2895, 1692, 1616, 1486, 1287, 1245, 1043 cm−1; HRMS (FAB) calcd
for C16H13N2O4 [M + H]+ 297.0875, found 297.0875.
2-(6-Methoxynaphthalene-2-yl)-1H-benzimidazole (4ak)
(Entry 11 in Table 3). 2-Iodoaniline (438 mg, 2.0 mmol) (1a)
was coupled with 6-methoxy-2-naphthaldehyde (447 mg, 2.4 mmol)
(2k) to give 538 mg (1.96 mmol, 98%) of 4ak as pale brown solid after
chromatography [357 mg (1.3 mmol, 65%) of 4a′k was obtained from
2-bromoaniline (344 mg, 2.0 mmol) (1a′)]: mp 220−222 °C; 1H
NMR (300 MHz, DMSO) δ 12.97 (br s, 1H), 8.65 (s, 1H), 8.25 (d, J
= 7.2 Hz, 1H), 7.96 (dd, J = 8.4, 3.6 Hz, 2H), 7.68(d, J = 6.9 Hz, 1H),
7.54 (d J = 6.3 Hz, 1H), 7.40 (s, 1H), 7.27−7.18 (m, 3H), 3.92 (s,
3H); 13C NMR (75 MHz, DMSO) δ 158.2, 151.5, 144.0, 135.1, 135.0,
130.1, 128.2, 127.4, 125.8, 125.4, 124.4, 122.5, 121.7, 119.5, 118.7,
111.3, 106.1, 55.4; IR (KBr) 3050, 2990, 2943, 1629, 1606, 1429,
1397, 1359, 1318, 1255 cm−1; HRMS (FAB) calcd for C18H15N2O [M
+ H]+ 275.1184, found 275.1187.
Compound 4bi (Entry 3 in Table 4). Methyl 4-amino-3-
iodobenzoate (554 mg, 2.0 mmol) (1b) was coupled with furan-2-
carbaldehyde (231 mg, 2.4 mmol) (2i) to give 460 mg (1.9 mmol,
1
95%) of 4bi as a brown oil after chromatography: H NMR (300
MHz, DMSO) δ 13.30 (br s, 1H), 8.15 (br s, 1H), 8.00 (dd, J = 1.5,
0.6 Hz, 1H), 7.84 (dd, J = 8.4, 1.2 Hz, 1H), 7.65 (br s, 1H), 7.29 (dd, J
= 3.5, 0.8 Hz, 1H), 6.76 (dd, J = 3.6, 1.8 Hz, 1H), 3.87 (s, 3H); 13C
NMR (75 MHz, DMSO) δ 166.7, 145.3, 144.9, 123.5, 112.6, 111.8,
52.1; IR (KBr) 3123, 2951, 1714, 1622, 1435, 1307, 1219 cm−1
;
HRMS (FAB) calcd for C13H11N2O3 [M + H]+ 243.0770, found
243.0771.
2-Isopropyl-1H-benzimidazole33 (4al) (Entry 12 in Table 3).
2-Iodoaniline (438 mg, 2.0 mmol) (1a) was coupled with
isobutyraldehyde (173 mg, 2.4 mmol) (2l) to give 167 mg (1.04
mmol, 52%) of 4al as a white solid after chromatography [195 mg (1.2
mmol, 61%) of 4a′l was obtained from 2-bromoaniline (344 mg, 2.0
Compound 4ca32 (Entry 4 in Table). 5-Chloro-2-iodoaniline
(507 mg, 2.0 mmol) (1c) was coupled with benzaldehyde (255 mg,
2.4 mmol) (2a) to give 183 mg (0.8 mmol, 40%) of 4ca as pale yellow
solid after chromatography: mp 212−213 °C; H NMR (300 MHz,
DMSO) δ 13.09 (br s, 1H), 8.18−8.14 (m, 2H), 7.64−7.47 (m, 5H),
7.23 (dd, J = 8.4, 2.1 Hz, 1H); 13C NMR (75 MHz, DMSO) δ 152.7,
130.2, 129.7, 129.0, 126.6, 122.4; IR (KBr) 3095, 1621, 1584, 1439,
1
mmol) (1a′)]: mp 232−234 °C; H NMR (300 MHz, DMSO) δ
12.12 (br s, 1H), 7.45 (br m, 2H), 7.13−7.07 (m, 2H), 3.13 (hept, J =
6.9 Hz, 1H), 1.34 (d, J = 7.2 Hz, 6H); 13C NMR (75 MHz, DMSO) δ
159.8, 143.0, 134.3, 121.3, 120.7, 118.2, 110.7, 28.4, 21.4; IR (KBr)
9581
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The Journal of Organic Chemistry
Featured Article
1385, 1308, 1275 cm−1; HRMS (FAB) calcd for C13H10ClN2 [M +
H]+ 229.0533, found 229.0534.
7.99−7.95 (m, 2H), 7.31 (dd, J = 3.6, 0.9 Hz, 1H), 7.23 (dd, J = 7.8,
4.8 Hz, 1H), 6.76 (dd, J = 3.6, 1.8 Hz, 1H); 13C NMR (75 MHz,
DMSO) δ 148.7, 145.4, 145.0, 143.9, 135.4, 126.2, 119.1, 118.1, 112.5,
112.0; IR (KBr) 3085, 1631, 1590, 1517, 1415, 1264 cm−1; HRMS
(FAB) calcd for C10H8N3O [M + H]+ 186.0667, found 186.0667.
Compound 4ea37 (Entry 12 in Table 4). 3-Amino-2-bromopyr-
idine (346 mg, 2.0 mmol) (1e) was coupled with benzaldehyde (255
mg, 2.4 mmol) (2a) to give 316 mg (1.62 mmol, 81%) of 4ea as a pale
Compound 4cj36 (Entry 5 in Table 4). 5-Chloro-2-iodoaniline
(507 mg, 2.0 mmol) (1c) was coupled with 2-thiophenecarbox-
aldehyde (269 mg, 2.4 mmol) (2j) to give 352 mg (1.5 mmol, 75%) of
1
4cj as a pale brown solid after chromatography: mp 223−225 °C; H
NMR (300 MHz, DMSO) δ 13.22 (br s, 1H), 7.85 (dd, J = 3.6, 1.2
Hz, 1H), 7.77−7.75 (m, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 8.4
Hz, 1H), 7.26−7.19 (m, 2H); 13C NMR (75 MHz, DMSO) δ 148.4,
133.1, 129.3, 128.4, 127.3, 126.4, 122.4; IR (KBr) 3064, 1620, 1568,
1438, 1416, 1060 cm−1; HRMS (FAB) calcd for C11H8ClN2S [M +
H]+ 235.0097, found 235.0098.
1
yellow solid after chromatography: mp 284−286 °C; H NMR (300
MHz, DMSO) δ 13.48 (br s, 1H), 8.34 (dd, J = 4.8, 1.5 Hz, 1H),
8.25−8.21 (m, 2H), 8.02 (d, J = 7.5 Hz, 1H), 7.61−7.51 (m, 3H), 7.25
(dd, J = 8.1, 4.8 Hz, 1H); 13C NMR (75 MHz, DMSO) δ 152.7, 143.8,
130.5, 129.7, 129.0, 126.7, 118.1; IR (KBr) 3047, 1536, 1462, 1412,
1276, 941, 771, 700 cm−1; HRMS (FAB) calcd for C12H10N3 [M +
H]+ 196.0875, found 196.0875.
Compound 4ck (Entry 6 in Table 4). 5-Chloro-2-iodoaniline
(507 mg, 2.0 mmol) (1c) was coupled with 6-methoxy-2-
naphthaldehyde (447 mg, 2.4 mmol) (2k) to give 451 mg (1.46
mmol, 73%) of 4ck as a pale brown solid after chromatography: mp
Compound 4ef37 (Entry 13 in Table 4). 3-Amino-2-bromopyr-
idine (346 mg, 2.0 mmol) (1e) was coupled with 4-methoxybenzalde-
hyde (327 mg, 2.4 mmol) (2f) to give 441 mg (1.96 mmol, 98%) of
1
205−207 °C; H NMR (300 MHz, DMSO) δ 13.16 (br s, 1H), 8.65
(d, J = 1.2 Hz, 1H), 8.23 (dd, J = 8.7, 1.8 Hz, 1H), 7.97 (dd, J = 8.7,
3.2 Hz, 2H), 7.65−7.60 (m, 2H), 7.41 (d, J = 2.4 Hz, 1H), 7.28−7.21
(m, 2H), 3.92 (s, 3H); 13C NMR (75 MHz, DMSO) δ 158.3, 135.2,
130.1, 128.1, 127.4, 126.1, 124.8, 124.3, 119.5, 106.1, 55.4; IR (KBr)
3066, 1629, 1483, 1394, 1267, 1210 cm−1; HRMS (FAB) calcd for
C18H14ClN2O [M + H]+ 309.0795, found 309.0794.
1
4ef as a pale yellow solid after chromatography: mp 238−240 °C; H
NMR (300 MHz, DMSO) δ 13.34 (br s, 1H), 8.29 (dd, J = 4.8, 1.5
Hz, 1H), 8.20−8.15 (m, 2H), 7.95 (dd, J = 8.1, 1.5 Hz, 1H), 7.20 (dd,
J = 7.8, 4.8 Hz, 1H), 7.15−7.10 (m, 2H), 3.84 (s, 3H); 13C NMR (75
MHz, DMSO) δ 161.1, 152.8, 143.3, 128.4, 122.1, 117.8, 114.4, 55.4;
IR (KBr) 3120, 3058, 1621, 1489, 1439, 1407, 1370, 1253 cm−1
;
Compound 4da37 (Entry 7 in Table 4). 2-Amino-3-bromopyr-
idine (346 mg, 2.0 mmol) (1d) was coupled with benzaldehyde (255
mg, 2.4 mmol) (2a) to give 359 mg (1.84 mmol, 92%) of 4da as a pale
HRMS (FAB) calcd for C13H12N3O [M + H]+ 226.0980, found
226.0978.
Compound 4eo37 (Entry 14 in Table 4). 3-Amino-2-bromopyr-
idine (346 mg, 2.0 mmol) (1e) was coupled with 2-Pyridinecarbox-
aldehyde (257 mg, 2.4 mmol) (2o) to give 157 mg (0.8 mmol, 40%)
of 4eo as a pale yellow solid after chromatography: mp 227−229 °C;
1H NMR (300 MHz, DMSO) δ 13.52 (br s, 1H), 8.78−8.76 (m, 1H),
8.41−8.36 (m, 2H), 8.07−7.99 (m, 2H), 7.59−7.55 (m, 1H), 7.30−
7.25 (m, 1H); 13C NMR (75 MHz, DMSO) δ 152.2, 149.5, 148.0,
144.5, 137.7, 125.3, 121.9, 118.5; IR (KBr) 3053, 1592, 1444, 1412,
1268 cm−1; HRMS (FAB) calcd for C11H9N4 [M + H]+ 197.0827,
found 197.0824.
1
yellow solid after chromatography: mp 284−286 °C; H NMR (300
MHz, DMSO) δ 13.48 (br s, 1H), 8.34 (dd, J = 4.8, 1.5 Hz, 1H),
8.25−8.21 (m, 2H), 8.02 (d, J = 7.5 Hz, 1H), 7.61−7.51 (m, 3H), 7.25
(dd, J = 8.1, 4.8 Hz, 1H); 13C NMR (75 MHz, DMSO) δ 152.7, 143.8,
130.5, 129.7, 129.0, 126.7, 118.1; IR (KBr) 3047, 1536, 1462, 1412,
1276, 941, 771, 700 cm−1; HRMS (FAB) calcd for C12H10N3 [M +
H]+ 196.0875, found 196.0875.
Compound 4df37 (Entry 8 in Table 4). 2-Amino-3-bromopyr-
idine (346 mg, 2.0 mmol) (1d) was coupled with 4-methoxybenzal-
dehyde (327 mg, 2.4 mmol) (2f) to give 360 mg (1.6 mmol, 80%) of
4df as a pale brown solid after chromatography: mp 238−240 °C; 1H
NMR (300 MHz, DMSO) δ 13.34 (br s, 1H), 8.29 (dd, J = 4.8, 1.5
Hz, 1H), 8.20−8.15 (m, 2H), 7.95 (dd, J = 8.1, 1.5 Hz, 1H), 7.20 (dd,
J = 7.8, 4.8 Hz, 1H), 7.15−7.10 (m, 2H), 3.84 (s, 3H); 13C NMR (75
MHz, DMSO) δ 161.1, 152.8, 143.3, 128.4, 122.1, 117.8, 114.4, 55.4;
Synthesis of Tiabendazole.39 2-Iodoaniline (438 mg, 2.0 mmol)
(1a) was coupled with thiazole-4-carboxaldehyde (272 mg, 2.4 mmol)
to give 390 mg (1.94 mmol, 97%) of tiabendazole as a pale yellow
solid after chromatography [354 mg (1.8 mmol, 88%) of Tiabendazole
was obtained from 2-bromoaniline (344 mg, 2.0 mmol) (1a′)]: mp
1
IR (KBr) 3120, 3058, 1621, 1489, 1439, 1407, 1370, 1253 cm−1
;
294−297 °C; H NMR (300 MHz, DMSO) δ 12.96 (br s, 1H), 9.33
HRMS (FAB) calcd for C13H12N3O [M + H]+ 226.0980, found
226.0979.
(d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 7.58 (br s, 2H), 7.23−
7.17 (m, 2H); 13C NMR (75 MHz, DMSO) δ 154.8, 147.4, 146.9,
123.0, 118.8; IR (KBr) 3093, 3045, 1578, 1405, 1306 cm−1; HRMS
(FAB) calcd for C10H8N3S [M + H]+ 202.0439, found 202.0440.
Compound 4dk (Entry 9 in Table 4). 2-Amino-3-bromopyridine
(346 mg, 2.0 mmol) (1d) was coupled with 6-methoxy-2-
naphthaldehyde (447 mg, 2.4 mmol) (2k) to give 441 mg (1.6
mmol, 80%) of 4dk as a pale brown solid after chromatography: mp
ASSOCIATED CONTENT
1
■
282−283 °C; H NMR (300 MHz, DMSO) δ 13.53 (br s, 1H), 8.74
S
* Supporting Information
(s, 1H), 8.35−8.27 (m, 2H), 8.03−7.86 (m, 3H), 7.42 (d, J = 2.7 Hz,
1H), 7.28−7.23 (m, 2H), 3.92 (s, 3H); 13C NMR (75 MHz, DMSO)
δ 158.5, 153.0, 143.7, 135.4, 130.2, 128.1, 127.4, 126.4, 124.8, 124.3,
119.6, 118.0, 106.2, 55.3; IR (KBr) 3075, 1629, 1595, 1519, 1503,
1259, 1211 cm−1; HRMS (FAB) calcd for C17H14N3O [M + H]+
276.1137, found 276.1135.
Stability of tautomers and copies of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Compound 4do37 (Entry 10 in Table 4). 2-Amino-3-bromopyr-
idine (346 mg, 2.0 mmol) (1d) was coupled with 2-pyridinecarbox-
aldehyde (257 mg, 2.4 mmol) (2o) to give 177 mg (0.9 mmol, 45%)
of 4do as a pale yellow solid after chromatography: mp 227−229 °C;
1H NMR (300 MHz, DMSO) δ 13.52 (br s, 1H), 8.78−8.76 (m, 1H),
8.41−8.36 (m, 2H), 8.07−7.99 (m, 2H), 7.59−7.55 (m, 1H), 7.30−
7.25 (m, 1H); 13C NMR (75 MHz, DMSO) δ 152.2, 149.5, 148.0,
144.5, 137.7, 125.3, 121.9, 118.5; IR (KBr) 3053, 1592, 1444, 1412,
1268 cm−1; HRMS (FAB) calcd for C11H9N4 [M + H]+ 197.0827,
found 197.0829 .
Corresponding Author
*E-mail: sunwoo@chonnam.ac.kr.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea Grant funded by the Korean Government (2009-
0072357)
REFERENCES
Compound 4di38 (Entry 11 in Table 4). 2-Amino-3-bromopyr-
idine (346 mg, 2.0 mmol) (1d) was coupled with furan-2-carbaldehyde
(231 mg, 2.4 mmol) (2i) to give 296 mg (1.6 mmol, 80%) of 4di as a
■
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9582
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