Cp2ZrCl2-catalyzed synthesis of 2-aminovinyl benzimidazoles under microwave conditions

Article abstract of DOI:10.1016/j.cclet.2014.11.014

A microwave-assisted general method for the synthesis of 2-aminovinyl benzimidazoles has been developed. Treatment of the 1,2-phenylenediamines and N-arylated/N,N-dialkylated 3-aminoacroleins with bis(cyclopentadienyl)zirconium(IV) dichloride (Cp₂

Full text of DOI:10.1016/j.cclet.2014.11.014

G Model
CCLET-3148; No. of Pages 4
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Cp2ZrCl2-catalyzed synthesis of 2-aminovinyl benzimidazoles under
microwave conditions
a
a
b
b,
Qi Sun a, , Cheng-Jun Wang , Shan-Shan Gong , Yong-Jian Ai , Hong-Bin Sun
*
*
a Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang 330013, China
b Department of Chemistry, Northeastern University, Shenyang 110819, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A microwave-assisted general method for the synthesis of 2-aminovinyl benzimidazoles has been
developed. Treatment of the 1,2-phenylenediamines and N-arylated/N,N-dialkylated 3-aminoacroleins
with bis(cyclopentadienyl)zirconium(IV) dichloride (Cp2ZrCl2) as the catalyst under microwave
irradiation for 3–5 min followed by in situ MnO2 oxidation afforded thirteen 2-aminovinyl
benzimidazoles in good yields.
Received 15 August 2014
Received in revised form 15 September 2014
Accepted 13 October 2014
Available online xxx
ß 2014 Qi Sun and Hong-Bin Sun. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
rights reserved.
Keywords:
Benzimidazoles
Cp2ZrCl2
3-Aminoacroleins
Microwave
1. Introduction
dramatic catalytic effect on the reactions of 1,2-phenylenedia-
mines with 1 and improved the yields to 50%–70% [3]. However,
1,2-Disubstituted benzimidazoles have been recognized as
valuable scaffolds in the development of novel pharmaceutical
agents and functional materials [1]. In modern drug discovery, a
myriad of benzimidazole-based compounds have been synthe-
sized and displayed a variety of pharmacological effects, such as
anti-infective, anti-inflammatory, anti-tumor, and anti-diabetic
activities [2].
the understanding of this metal-catalyzed condensation/cycliza-
tion reaction is still very limited and the extension of this
approach to N,N-dialkylated 3-aminoacroleins has never been
explored. We report herein a microwave-assisted method for the
synthesis of a diversity of 2-aminovinyl benzimidazoles with
bis(cyclopentadienyl)zirconium(IV) dichloride (Cp2ZrCl2) as a
more effective catalyst.
In our previous research on the synthesis of AKT inhibitor IV
(ChemBridge 5233705), the unique 2-aminovinyl benzimidazole
core structure posed a huge challenge to the existing synthetic
methods for benzimidazoles [3]. The conventional condensation
of 1,2-phenylenediamines with an N-arylated 3-aminoacrolein
(1) in refluxing ethanol followed by in situ oxidation only afforded
the products in low yields (<20%) [1,4]. Our attempt to promote
the reaction by adding oxidants (e.g., potassium peroxymono-
sulfate [5], I2 [6], MnO2 [7], and 2,3-dichloro-5,6-dicyano-
p-benzoquinone (DDQ) [8]), acidic catalysts (e.g., BF3ÁEt2O [9]
and polyphosphoric acid (PPA) [10]), or reducing agents (e.g.,
SnCl2 [11]) according to precedent reports failed to generate the
desired product. Interestingly, in our search for potential metal
catalyst [12], we found that ZrOCl2Á8H2O and ZrCl4 exhibited a
2. Experimental
1,2-Phenylenediamines (7–12) were prepared according to the
reported procedures [3]. All NMR spectra were obtained with a
400 MHz instrument with chemical shifts reported in parts per
million (ppm, d) and referenced to CDCl3 or DMSO-d6. IR spectra
were recorded on a FT-IR spectrometer. High-resolution mass
spectra were obtained with a TOFQ mass spectrometer and
reported as m/z. Microwave reactions were performed on an Anton
Paar Monowave 300 instrument with 30 mL reaction vials. The
characterization data of known compounds (1–3, 5, and 13–18)
and 1H NMR and 13C NMR spectra of new compounds (4, 6, and 19–
25) were included in the Supporting information.
2.1. General procedure for the synthesis of 3-aminoacroleins (1–6)
*
Corresponding author.
To a solution of amine (10 mmol) and propargyl alcohol
(20 mmol) in toluene (20 mL) was slowly added activated MnO2
E-mail addresses: sunqi96@tsinghua.org.cn (Q. Sun), sunhb@mail.neu.edu.cn
(H.-B. Sun).
http://dx.doi.org/10.1016/j.cclet.2014.11.014
1001-8417/ß 2014 Qi Sun and Hong-Bin Sun. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: Q. Sun, et al., Cp2ZrCl2-catalyzed synthesis of 2-aminovinyl benzimidazoles under microwave
conditions, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.11.014

G Model
CCLET-3148; No. of Pages 4
2
Q. Sun et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
(200 mmol) at 0 8C. The reaction was stirred for 2 h and then
warmed up to 22 8C. After 24 h, MnO2 was filtered off and washed
with ethyl acetate (10 mL). The combined filtrate was concentrated
in vacuo. Flash column chromatography on silica gel afforded the
product.
121.5, 122.8, 124.6, 126.0, 127.6, 128.0, 128.5, 129.8, 135.1, 136.3,
138.9, 144.3, 144.7, 154.5, 157.6, 169.8; IR (neat, cmÀ1): 3674,
1622, 1497, 1460, 1395, 1275, 1218, 1067, 809, 754; HRMS (ESI+):
m/z calcd. for C30H30N4S [M+H]+: 479.2191; found: 479.2184.
4-[(E)-2-(5-Benzothiazol-2-yl-1-phenyl-1H-benzoimidazol-2-
(E)-3-N-Cyclohexyl-N-ethylaminoacrolein (4): Yellow solid; mp
yl)ethenyl]morpholine (22): Yellow solid; mp 172–174 8C (decomp.);
58–60 8C; 1H NMR (400 MHz, CDCl3):
d
0.94–1.26 (m, 6H), 1.26–
1H NMR (400 MHz, CDCl3):
d 3.12–3.24 (m, 4H), 3.71 (t, 4H,
1.40 (m, 2H), 1.50–1.61 (m, 1H), 1.74 (d, 4H, J = 10.6 Hz), 2.90–3.19
(m, 3H), 5.06 (dd, 1H, J1 = 8.7 Hz, J2 = 12.5 Hz), 6.98 (d, 1H,
J = 12.8 Hz), 8.92 (d, 1H, J = 8.6 Hz); 13C NMR (100 MHz, CDCl3):
J = 4.6 Hz), 4.95 (d, 1H, J = 13.3 Hz), 7.10 (d, 1H, J = 8.4 Hz), 7.34 (dd,
1H, J1 = J2 = 7.7 Hz), 7.39–7.49 (m, 3H), 7.52 (dd, 1H, J1 = J2 = 7.2 Hz),
7.60 (dd, 2H, J1 = J2 = 7.2 Hz), 7.73 (d, 1H, J = 13.3 Hz), 7.88 (d, 1H,
J = 7.9 Hz), 7.95(d,1H, J = 8.3 Hz), 8.05(d, 1H,J = 8.0 Hz), 8.26(s, 1H);
d
12.3, 25.0, 25.5, 32.3, 42.1, 65.1, 100.9, 156.7, 189.1; IR (neat,
cmÀ1):
nmax 2927, 2848, 1595, 1442, 1350, 1161, 893, 795; HRMS
13C NMR (100 MHz, CDCl3):
d 48.6, 66.3, 83.3, 109.5, 117.2, 120.9,
(ESI+): m/z calcd. for C11H19NO [M+H]+: 182.1467; found:
182.1458.
121.6, 123.0, 124.8, 126.2, 127.7, 128.5, 128.9, 130.1, 135.3, 136.0,
138.9, 144.0, 147.0, 154.6, 156.1, 169.5; IR (neat, cmÀ1): 3674, 1624,
1498, 1443, 1392, 1081, 890, 759; HRMS (ESI+): m/z calcd. for
(E)-3-(4-Methylpiperazin-1-yl)acrylaldehyde (6): Yellow oil; 1H
NMR (400 MHz, CDCl3):
2.74–3.28 (m, 4H), 4.76–4.89 (m, 1H), 6.64–6.78 (m, 1H), 8.65–8.75
(m, 1H); 13C NMR (100 MHz, CDCl3):
44.4, 45.3, 53.5, 100.4, 158.4,
d
1.88–1.99 (m, 3H), 2.00–2.21 (m, 4H),
C
26H22N4OS [M+H]+: 439.1514; found: 439.1506.
4-Methyl-[(E)-2-(5-benzothiazol-2-yl-1-phenyl-1H-benzoimida-
d
zol-2-yl)ethenyl]piperazine (23): Yellow solid; mp 180–182 8C
(decomp.); 1H NMR (400 MHz, CDCl3):
2.29 (s, 3H), 2.40 (t, 4H,
188.6; IR (neat, cmÀ1): nmax 2944, 1597, 1435, 1317, 1173, 767;
HRMS (ESI+): m/z calcd. for C8H14N2O [M+H]+: 155.1106; found:
155.1112.
d
J = 4.7 Hz), 3.19 (t, 4H, J = 4.6 Hz), 4.89 (d, 1H, J = 13.2 Hz), 7.07 (d,
1H, J = 8.4 Hz), 7.33 (dd, 1H, J1 = J2 = 7.7 Hz), 7.37–7.47 (m, 3H),
7.50 (dd, 1H, J1 = J2 = 7.2 Hz), 7.58 (dd, 2H, J1 = J2 = 7.4 Hz), 7.74 (d,
1H, J = 13.2 Hz), 7.87 (d, 1H, J = 7.9 Hz), 7.93 (d, 1H, J = 8.4 Hz), 8.03
2.2. General procedure for the synthesis of 2-aminovinyl
benzimidazoles (13–25)
(d, 1H, J = 8.1 Hz), 8.24 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 46.3,
48.3, 54.4, 82.3, 109.4, 117.0, 120.6, 121.5, 122.9, 124.7, 126.1,
127.6, 128.2, 128.8, 130.0, 135.2, 136.0, 138.8, 144.0, 146.8, 154.5,
156.5, 169.6; IR (neat, cmÀ1): 3680, 1623, 1495, 1408, 1380, 1240,
1056, 899, 751; HRMS (ESI+): m/z calcd. for C27H25N5S [M+H]+:
452.1831; found: 452.1841.
To a solution of 1,2-phenylenediamine (0.1 mmol) and 3-
aminoacrolein (0.12–0.15 mmol) in ethanol (15 mL) was added
Cp2ZrCl2 (0.05 mmol). The solution was subjected to microwave
heating at 80 8C for 3–5 min. Then, MnO2 (0.5 mmol) was added,
and the reaction was stirred for 5 min. MnO2 was filtered off and
washed with ethanol (5 mL). The combined filtrate was concen-
trated in vacuo. Flash column chromatography on silica gel
afforded the product.
4-[(E)-2-Phenyl-1H-benzoimidazole-2-yl)ethenyl]morpholine
(24): Yellow solid; mp 64–66 8C; 1H NMR (400 MHz, CDCl3):
d 3.11
(t, 4H, J = 4.8 Hz), 3.68 (t, 4H, J = 4.8 Hz), 4.97 (d, 1H, J = 13.4 Hz),
7.00–7.09 (m, 2H), 7.19 (dd, 1H, J1 = J2 = 7.6 Hz), 7.39 (d, 2H,
J = 7.2 Hz), 7.48 (dd, 1H, J1 = J2 = 7.3 Hz), 7.56 (dd, 2H,
J1 = J2 = 7.2 Hz), 7.63 (d, 1H, J = 7.6 Hz), 7.66 (d, 1H, J = 13.2 Hz);
[(E)-2-(5-Benzothiazole-2-yl-1-phenyl-1H-benzoimidazole-2-
yl)ethenyl]isopropylphenylamine (19): Yellow solid; mp 172–
174 8C; 1H NMR (400 MHz, CDCl3):
d
1.24 (d, 6H, J = 6.7 Hz), 3.
13C NMR (100 MHz, CDCl3):
d 48.5, 66.3, 84.0, 109.2, 117.5, 121.0,
84–3. 98 (m, 1H), 4.84 (d, 1H, J = 13.3 Hz), 7.08 (d, 1H, J = 8.4 Hz),
7.13 (d, 2H, J = 7.8 Hz), 7.21 (dd, 1H, J1 = J2 = 7.2 Hz), 7.27–7.52 (m,
9H), 7.86 (d, 1H, J = 7.9 Hz), 7.93 (d, 1H, J = 8.4 Hz), 8.00–8.10 (m,
122.4, 127.7, 128.5, 129.8, 136.4, 136.6, 143.6, 146.3, 154.3; IR (neat,
cmÀ1): 3406, 1624, 1585, 1459, 1381, 1254, 1027, 956, 767; HRMS
(ESI+): m/z calcd. forC19H19N3S [M+H]+: 306.1528;found: 306.1519.
{(E)-2-[5-Benzothiazole-2-yl-1-(4-methoxyphenyl)-1H-benzoimi-
dazole-2-yl]ethenyl}methylbenzylamine (25): Yellow solid; mp 76–
2H), 8.27 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 21.8, 54.7, 84.2,
109.3, 117.0, 120.5, 121.5, 122.9, 124.6, 126.1, 126.9, 127.3, 128.0,
128.1, 128.5, 129.3, 129.7, 135.1, 135.9, 138.7, 142.5, 144.1, 145.0,
78 8C; 1H NMR (400 MHz, CDCl3):
d 2.71 (s, 3H), 3.88 (s, 3H), 4.36 (s,
154.5, 156.6, 169.6; IR (neat, cmÀ1):
nmax 3651, 1619, 1586, 1502,
2H), 4.80 (d, 1H, J = 13.0 Hz), 7.04 (d, 3H, J = 8.3 Hz), 7.20 (d, 2H,
J = 7.6 Hz), 7.27–7.36 (m, 6H), 7.45 (dd, 1H, J1 = J2 = 7.3 Hz), 7.87 (d,
1H, J = 7.9 Hz), 7.94 (d, 1H, J = 8.3 Hz), 8.02 (d, 1H, J = 8.0 Hz), 8.04–
8.06 (m, 1H), 8.25 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 29.8, 36.6,
1460, 1412, 1071, 869, 754; HRMS (ESI+): m/z calcd. for C31H26N4S
[M+H]+: 487.1878; found: 487.1869.
[(E)-2-(5-Benzothiazole-2-yl-1-phenyl-1H-benzoimidazole-2-
yl)ethenyl]methylbenzylamine (20): Yellow solid; mp 72–74 8C; 1
H
55.7, 59.5, 81.8, 109.2, 115.1, 116.8, 120.4, 121.5, 122.9, 124.6,
126.1, 127.5, 127.8, 128.0, 128.6, 128.8, 135.2, 136.9, 139.3, 144.1,
147.5, 154.5, 157.1, 159.6, 169.8; IR (neat, cmÀ1): 3046, 1631,
1514, 1467, 1278, 1027, 839, 760; HRMS (ESI+): m/z calcd. for
NMR (400 MHz, CDCl3):
d 2.72 (s, 3H), 4.36 (s, 2H), 4.84 (d, 1H,
J = 13.0 Hz), 7.08 (d, 1H, J = 8.4 Hz), 7.20 (d, 2H, J = 7.2 Hz), 7.27–
7.36 (m, 4H), 7.38–7.51 (m, 4H), 7.52–7. 63 (m, 2H), 7.87 (d, 1H,
J = 7.9 Hz), 7.94 (d, 1H, J = 8.2 Hz), 8.05 (d, 2H, J = 10.6 Hz), 8.27 (s,
C
31H26N4OS [M+H]+: 503.1827; found: 503.1819.
1H); 13C NMR (100 MHz, CDCl3):
d 36.7, 59.5, 81.7, 109.3, 116.9,
120.5, 121.5, 122.9, 124.7, 126.1, 127.5, 127.6, 127.8, 128.2, 128.7,
128.8, 129.9, 135.2, 136.1, 136.9, 139.9, 144.1, 147.7, 154.5, 156.7,
169.7; IR (neat, cmÀ1): 3674, 1626, 1595, 1497, 1466, 1276, 1052,
895, 755; HRMS (ESI+): m/z calcd. for C34H24N4S [M+H]+:
473.1722; found: 473.1716.
3. Results and discussion
To explore the scope of the reaction, a series of N-arylated and
N,N-dialkylated 3-aminoacroleins 1–6 were synthesized via a
modified procedure described in Scheme 1 [13]. Treatment of
1.0 equiv. of propargyl alcohol with 0.5 equiv. of amino compounds
in the presence of 10 equiv. of activated MnO2 afforded 1–6 in 53%–
75% yields. Compared to the dH values of the aldehyde protons of
benzaldehyde (10.02), n-hexyl aldehyde (9.66), and cinnamalde-
[(E)-2-(5-Benzothiazole-2-yl-1-phenyl-1H-benzoimidazole-2-
yl)ethenyl]ethylcyclohexylamine (21): Yellow solid; mp 132–134 8C;
1H NMR (400 MHz, CDCl3):
d 0.98–1.16 (m, 3H), 1.18–1.36 (m, 3H),
1.37–1.52 (m, 2H), 1.58–1.70 (m, 1H), 1.82 (d, 4H, J = 10.8 Hz),
3.03–3.31 (m, 3H), 4.74 (d, 1H, J = 13.1 Hz), 7.05 (d, 1H, J = 8.3 Hz),
7.31 (dd, 1H, J1 = J2 = 7.6 Hz), 7.39–7.50 (m, 4H), 7.56 (dd, 2H,
J1 = J2 = 7.6 Hz), 7.84 (d, 1H, J = 3.4 Hz), 7.87 (s, 1H), 7.90 (d, 1H,
J = 8.4 Hz), 8.03 (d, 1H, J = 8.2 Hz), 8.23 (s, 1H); 13C NMR (100 MHz,
hyde (9.74), the dH value of 3-(N-phenyl-N-methyl)aminoacrolein
(1) was much smaller (9.27), indicating that the electropositivity of
the carbonyl group was remarkably lowered due to the conjuga-
tion of electron-donating aniline moiety. This result explained
why the conventional condensation methods for regular aldehyde
CDCl3): d 13.3, 25.4, 26.0, 32.4, 41.2, 64.1, 79.8, 109.0, 116.5, 120.1,
Please cite this article in press as: Q. Sun, et al., Cp2ZrCl2-catalyzed synthesis of 2-aminovinyl benzimidazoles under microwave
conditions, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.11.014

G Model
CCLET-3148; No. of Pages 4
Q. Sun et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
higher yield (78%). The solvent effect on this reaction was also
investigated. The data in Table 1 (entries 16–22) showed that the
catalytic effect of Cp2ZrCl2 was specific in ethanol and not simply
related the dielectric constants and polarity of the solvents,
suggesting that Zr(IV) salts might go through a solvolysis process
and ethanol was possibly involved in reactive metal complex that
promoted the condensation of 1 and 7. It was also confirmed that
a minimum of 0.5 equiv. of Cp2ZrCl2 was required for complete
consumption of 7.
As shown in Scheme 2, the reactions of a variety of 1,2-
phenylenediamines 7–12 and N-arylated 3-aminoacroleins 1 and 2
with Cp2ZrCl2 as the catalyst under microwave conditions followed
by MnO2 oxidation yielded the corresponding 2-aminovinyl
benzimidazoles 14–19 in 70%–76% yields. In contrast, when N,N-
dialkylated 3-aminoacroleins 3–6 were applied, a higher equivalent
of 3-aminoacroleins (1.5 equiv.) and longer microwave irradiation
time (5 min) were required to afford 20–25 in good yields (68%–
76%). TheseresultswereinagreementwithourspeculationthatN,N-
dialkylated 3-aminoacroleins were less reactive than their N-
arylated counterparts. Moreover, control experiments based on
thermal heating were also performed. The reaction of 7 and N-
arylated 3-aminoacrolein 1 in refluxing ethanol needed 30 min for
the first step, whereasthat of 7 and N,N-dialkylated3-aminoacrolein
5 required 2 h. Compared to thermal heating, microwave irradiation
also improved the yields of 13 (72% for thermal heating and 78% for
MW) and 22 (60% for thermal heating and 70% for MW).
TLC monitoring of the first step reaction of 1 and 7 showed that
the major product spot was an orange-colored polar band, which
was unstable to isolate. After MnO2 oxidation, it was completely
converted to the less polar spot of 13. Due to the fact that
benzimidazoline intermediate is typically less polar than the
corresponding benzimidazole, we proposed that the condensation
of 1 and 7 favored the formation of imine instead of the cyclized
Scheme 1. A general method for the synthesis of N-arylated and N,N-dialkylated
3-aminoacroleins 1–6.
substrates were not applicable on 1. The aldehyde proton peaks of
N,N-dialkyl 3-aminoacroleins 3–6 moved toward higher magnetic
field (8.92–8.74), suggesting that N,N-dialkylated 3-aminoacro-
leins might be less reactive toward nucleophiles because of the
higher electron-donating capability of the dialkylamino moiety.
Compared to thermal heating, microwave irradiation has
showed positive effects on both reaction time and yield in
precedent synthesis of benzimidazoles [7,14]. In our research,
we explored the possibility to improve the synthetic efficacy of 2-
aminovinyl benzimidazoles under microwave conditions. In the
preliminary experiments, the ethanol solution of 1 (1.2 equiv.) and
4-benzothiazol-2-yl-N1-phenylbenzene-1,2-diamine (7, 1.0 equiv.)
with different Lewis acids (0.5 equiv.) was irradiated with
microwave at 80 8C for 3 min. To the reaction solution was then
added activated MnO2 (5.0 equiv.) to generate the 2-aminovinyl
benzimidazole 13. The experimental results listed in Table 1
(entries 1–16) showed that most tested Lewis acids resulted in no
reaction or only gave 13 in poor yields. In contrast, all of the
zirconium(IV) salts exhibited comparable catalytic effect on the
formation of 13. Compared to the previously reported ZrCl4 and
ZrOCl2Á8H2O, Cp2ZrCl2-catalyzed reaction afforded 13 in even
Table 1
Effects of Lewis acid and solvent on the synthesis of 2-aminovinyl benzimidazole 13.
Entry
Lewis acid
None
Solvent
EtOH
Isolated yield (%)
1
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
5
2
3
ZnCl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
THF
CuCl2
4
MgCl2
5
NiCl2
6
InCl3
7
CeCl3
8
AlCl3
13
9
FeCl3
28
10
11
12
13
14
15
16
17
18
19
20
21
22
TiCl4
15
Et2OÁBF3
ZrO(NO3)2
Zr(NO3)4
ZrOCl2Á8H2O
ZrCl4
18
54
62
67
72
Cp2ZrCl2
Cp2ZrCl2
Cp2ZrCl2
Cp2ZrCl2
Cp2ZrCl2
Cp2ZrCl2
Cp2ZrCl2
78
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
CH3CN
Toluene
DMF
DMSO
Please cite this article in press as: Q. Sun, et al., Cp2ZrCl2-catalyzed synthesis of 2-aminovinyl benzimidazoles under microwave
conditions, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.11.014

G Model
CCLET-3148; No. of Pages 4
4
Q. Sun et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
-
-
-
-
Scheme 2. Microwave-assisted synthesis of 2-aminovinyl benzimidazoles 14–25 with Cp2ZrCl2 as the catalyst.
(b) L.C.R. Carvalho, E. Fernandes, M.M.B. Marques, Developments towards regio-
selective synthesis of 1,2-disubstituted benzimidazoles, Chem. Eur. J. 17 (2011)
12544–12555.
benzimidazolineintermediateinthepresenceofCp2ZrCl2. Onlyafter
oxidant was added to transform the benzimidazoline intermediate
to 13, the cyclization reaction was driven to completion.
[2] M. Alamgir, D.S.C. Black, N. Kumar, Synthesis, reactivity and biological activity
of benzimidazoles, Top. Heterocycl. Chem. 21 (2007) 87–118.
[3] Q. Sun, R.Z. Wu, S.T. Cai, et al., Synthesis and biological evaluation of analogues
of AKT (protein kinase B) inhibitor-IV, J. Med. Chem. 54 (2011) 1126–1139.
[4] J.M. Smith, V. Krchnak, A solid phase traceless synthesis of benzimidazoles with
three combinatorial steps, Tetrahedron Lett. 40 (1999) 7633–7636.
[5] P.L. Beaulieu, B. Hache, E. von Moos, A practical oxone-mediated, high-through-
put, solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines
and aldehydes and its application to preparative scale synthesis, Synthesis
(2003) 1683–1692.
[6] P. Gogoi, D. Konwar, An efficient and one-pot synthesis of imidazolines and
benzimidazoles via anaerobic oxidation of carbon–nitrogen bonds in water,
Tetrahedron Lett. 47 (2006) 79–82.
[7] S.Y. Kim, K.H. Park, Y.K. Chung, Manganese(IV) dioxide-catalyzed synthesis
of quinoxalines under microwave irradiation, Chem. Commun. (2005) 1321–
1323.
4. Conclusion
In summary, we developed a general method for the synthesis of
a variety of 2-aminovinyl benzimidazole compounds. Our experi-
mental results showed that Cp2ZrCl2 exhibited the best catalytic
effect on the condensation of 1,2-phenylenediamine and 3-
aminoacrolein substrates under microwave conditions. This novel
synthetic method provides facile and efficient access to diverse 2-
aminovinyl benzimidazoles and will facilitate the investigation of
their applications in pharmaceutical and material sciences.
[8] J.P. Mayer, G.S. Lewis, C. McGee, et al., Solid-phase synthesis of benzimidazoles,
Tetrahedron Lett. 39 (1998) 6655–6658.
Acknowledgments
[9] R.R. Nagawade, D.B. Shinde, BF3ÁOEt2 promoted solvent-free synthesis of benz-
imidazole derivatives, Chin. Chem. Lett. 17 (2006) 453–456.
We thank the National Natural Science Foundation of China
(Nos. 21262014 to Q. Sun and 21003018 to H.-B. Sun), Key Project of
Chinese Ministry of Education (No. 212092), and Research Funds (Nos.
ky2012zy08 and 2013QNBJRC001) from JXSTNU for financial support.
[10] M.B. Wallace, J. Feng, Z.Y. Zhang, et al., Structure-based design and synthesis
of benzimidazole derivatives as dipeptidyl peptidase IV inhibitors, Bioorg. Med.
Chem. Lett. 18 (2008) 2361–2362.
[11] L.P. Duan, Q. Li, N.B. Wu, et al., Synthesis of 2,5-disubstitued benzimidazole using
SnCl2-catalyzed reduction system at room temperature, Chin. Chem. Lett. 25
(2014) 155–158.
[12] (a) Z.H. Zhang, L. Yin, Y.M. Wang, An expeditious synthesis of benzimidazole
derivatives catalyzed by Lewis acids, Catal. Commun. 8 (2007) 1126–1131;
(b) R.R. Nagawade, D.B. Shinde, Zirconyl(IV) chloride-promoted synthesis of
benzimidazole derivatives, Russ. J. Org. Chem. 42 (2006) 453–454.
[13] K. Deo, S. Kanwar, A. Pandey, et al., Process for the preparation of N-methyl anilino
acrolein, WO 2005090256, Chem. Abstr. 145 (2006) 292712.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.11.014.
´
[14] (a) G. Navarrete-Vazquez, H. Moreno-Diaz, F. Aguirre-Crespo, et al., Design,
microwave-assisted synthesis, and spasmolytic activity of 2-(alkyloxyaryl)-1H-
benzimidazole derivatives as constrained stilbene bioisosteres, Bioorg. Med.
Chem. Lett. 16 (2006) 4169–4173;
References
(b) R.G. Jacob, L.G. Dutra, C.S. Radatz, et al., Synthesis of 1,2-disubstituted
benzimidazoles using SiO2/ZnCl2, Tetrahedron Lett. 50 (2009) 1495–1497.
[1] (a) P.N. Preston, Synthesis, reactions, and spectroscopic properties of benzimi-
dazoles, Chem. Rev. 74 (1974) 279–314;
Please cite this article in press as: Q. Sun, et al., Cp2ZrCl2-catalyzed synthesis of 2-aminovinyl benzimidazoles under microwave
conditions, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.11.014