Efficient synthesis of functionalized benzimidazoles and perimidines: Ytterbium chloride catalyzed C-C bond cleavage

Article abstract of DOI:10.1002/cjoc.201180328

An efficient method is developed for the synthesis of functionalized benzimidazoles and perimidines by the condensation of aryl diamines with β-carbonyl compounds catalyzed by ytterbium chloride. The reactions give good yields under mild conditions. A mechanism involving a lanthanide activated C-C bond cleavage is proposed. An efficient method is developed for the synthesis of functionalized benzimidazoles and perimidines by the condensation of aryl diamines with β-carbonyl compounds catalyzed by ytterbium chloride. The reactions give good yields under mild conditions. A mechanism involving a lanthanide activated C-C bond cleavage is proposed. Copyright

Full text of DOI:10.1002/cjoc.201180328

FULL PAPER
Efficient Synthesis of Functionalized Benzimidazoles and
Perimidines: Ytterbium Chloride Catalyzed C— C
Bond Cleavage
Cai, Lijian(蔡礼健)
Ji, Xiaofeng(季晓峰)
Yao, Zhigang(姚志刚)
Xu, Fan*(徐凡)
Shen, Qi*(沈琪)
Key Laboratory of Organic Synthesis, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
An efficient method is developed for the synthesis of functionalized benzimidazoles and perimidines by the
condensation of aryl diamines with β-carbonyl compounds catalyzed by ytterbium chloride. The reactions give good
yields under mild conditions. A mechanism involving a lanthanide activated C— C bond cleavage is proposed.
Keywords lanthanide, C— C activation, catalysis, ytterbium chloride, benzimidazole, perimidine
Introduction
Experimental
Benzimidazole exists as an important structural unit
in a great amount of molecules of pharmaceutical or
biological interest.1 Functionalized benzimidazoles are
known to possess a broad-spectrum of biological activi-
ties, and have been used successfully as antiparasitic,
antiviral, antibacterial, and antitumor agents.2 Therefore,
the development of efficient methods for the synthesis
of benzimidazoles has been receiving considerable at-
tention in recent years. Among the routes towards
2-substituted benzimidazoles, two methods are general.
One involves treatment of o-phenylenediamine with
aldehydes,3 which generally requires the participation of
various oxidative reagents. The other is the coupling of
o-phenylenediamine with carboxylic acids4 or their
equivalents including amides, nitriles, orthoesters,5 and
β-ketoesters,6 which requires, in most cases, high tem-
perature, strong proton acids, and/or microwave irradia-
tion for high yields.
Catalyzed C—C bond cleavage is an attractive sub-
ject not only due to its fundamental scientific interest
but also to its potential utility in organic synthesis. As
typical Lewis acids, lanthanide compounds have been
widely used to activate 1,3-dicarbonyl compounds in-
cluding 1,3-diketones and β-ketoesters due to the high
oxophilicity of lanthanide ions, which causes many
useful transformations.7 However, to the best of our
knowledge, the cleavage of C—C bond between 1,3-
dicarbonyl carbon atoms catalyzed by lanthanide com-
pounds has not been reported. Herein, we would like to
report an efficient method for the synthesis of benzimi-
dazoles and relevant compounds via lanthanide-catalyzed
C—C bond cleavage of β-ketoesters.
General
Lanthanide chlorides were synthesized according to
the method described by Taylor and Carter.8 Melting
points were uncorrected. H and 13C NMR spectra were
1
obtained on Varian INOVA-400 and System-300 spec-
trometers using tetramethylsilane (TMS) as an internal
reference. HRMS data were recorded on a Micromass
GCT instrument.
General procedure for the condensation of diamines
and β-ketoesters
A mixture of diamine 1 (1 mmol), β-ketoester 2 (1
mmol) and YbCl3 (0.05 mmol) in ethanol (0.5 mL) was
stirred at the desired temperature for 24 h. Water was
added, and the mixture was extracted with ethyl acetate.
The combined organic layer was dried over anhydrous
Na2SO4, concentrated in vacuo, and purified by chroma-
tography on silica gel [eluent: V(acetone)∶V(petroleum
ether)＝1∶5] to afford the desired product 3.
The spectral data of the known compounds were
found to be identical with those reported in the existent
literature. Data for the new compounds are presented
below.
6-(1H-Benzoimidazol-2-yl)-hexanoic acid ethyl
1
ester (5a) White solid, m.p. 125—126 ℃; H NMR
(CDCl3, 400 MHz) δ: 7.66—7.20 (m, 4H), 4.13 (q, J＝
7.2 Hz, 2H), 2.94 (t, J＝7.6 Hz, 2H), 2.32 (t, J＝7.2 Hz,
2H), 1.91—1.83 (m, 2H), 1.72—1.64 (m, 2H), 1.46—
1.38 (m, 2H), 1.25 (t, J＝7.2 Hz, 3H); 13C NMR
(DMSO-d6, 75 MHz) δ: 172.7, 154.9, 139.1, 120.9,
114.3, 59.5, 33.3, 28.3, 28.0, 27.2, 24.1, 14.0; HRMS
calcd for C15H20N2O2 260.1525, found 260.1525.
*
E-mail: xufan@suda.edu.cn; qshen@suda.edu.cn; Tel.: 0086-0512-65880331; Fax: 0086-0512-65880305
Received March 20, 2011; revised April 29, 2011; accepted May 30, 2011.
Project supported by the National Natural Science Foundation of China (Nos. 20872106, 20972107).
1880
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Chin. J. Chem. 2011, 29, 1880— 1886

Efficient Synthesis of Functionalized Benzimidazoles and Perimidines
Ethyl 6-(1H-benzo[d]imidazol-2-yl)heptanoate (5c)
Light brown solid, m.p. 104—105 ℃; 1H NMR (CDCl3,
300 MHz) δ: 7.55—7.19 (m, 4H), 4.11 (q, J＝7.2 Hz,
2H), 3.17—3.05 (m, 1H), 2.34—2.20 (m, 2H), 1.95—
1.54 (m, 4H), 1.44 (d, J＝7.2 Hz, 3H), 1.38—1.30 (m,
2H), 1.22 (t, J＝7.2 Hz, 3H); 13C NMR (DMSO-d6, 75
MHz) δ: 172.7, 159.0, 140.3, 134.9, 120.9, 117.2, 114.5,
106.6, 59.5, 35.2, 33.7, 33.3, 26.2, 24.3, 19.5, 14.0;
HRMS calcd for C16H22N2O2 274.1681, found 274.1681.
Ethyl 3-[2-(1H-benzo[d]imidazol-2-yl)ethoxy]pro-
NMR (CDCl3, 75 MHz) δ: 154.8, 138.6, 121.6, 114.3,
61.5 (d, J＝6.6 Hz), 28.7, 28.3, 24.7 (d, J＝139.6 Hz),
21.7 (d, J＝4.7 Hz), 16.2, 16.1; HRMS calcd for
C15H23N2O3P 310.1446, found 310.1447.
2-(4-Tosylbutyl)-1H-benzo[d]imidazole (5j) White
solid, m.p. 200—201 ℃; 1H NMR (CDCl3, 400 MHz) δ:
7.72 (d, J＝8.4 Hz, 2H), 7.60—7.46 (m, 2H), 7.30 (d,
J＝8.0 Hz, 2H), 7.24—7.22 (m, 2H), 3.12 (t, J＝7.6 Hz,
2H), 2.93 (t, J＝7.2 Hz, 2H), 2.43 (s, 3H), 2.05—1.98
(m, 2H), 1.87—1.80 (m, 2H); 13C NMR (DMSO-d6, 100
MHz) δ: 154.4, 144.1, 136.0, 129.8, 127.6, 121.0, 114.4,
54.3, 27.7, 25.8, 21.9, 21.0; HRMS calcd for
C18H20N2O2S 328.1245, found 328.1229.
1
panoate (5d) Pale yellow liquid; H NMR (CDCl3,
300 MHz) δ: 7.57—7.17 (m, 4H), 4.24 (q, J＝7.2 Hz,
2H), 3.84 (t, J＝5.4 Hz, 2H), 3.78 (t, J＝5.4 Hz, 2H),
3.20 (t, J＝5.4 Hz, 2H), 2.68 (t, J＝5.4 Hz, 2H), 1.28 (t,
J＝7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 172.7,
153.1, 138.5, 121.7, 114.6, 68.3, 65.6, 60.8, 34.3, 29.2,
14.0; HRMS calcd for C14H18N2O3 262.1317, found
262.1318.
2-(5-Tosylpentyl)-1H-benzo[d]imidazole
(5k)
1
White solid, m.p. 144—145 ℃; H NMR (CDCl3, 300
MHz) δ: 7.75 (d, J＝7.8 Hz, 2H), 7.64—7.44 (m, 2H),
7.34 (d, J＝7.8 Hz, 2H), 7.23—7.21 (m, 2H), 3.06 (t, J＝
7.5 Hz, 2H), 2.89 (t, J＝7.5 Hz, 2H), 2.44 (s, 3H), 1.91—
1.71 (m, 4H), 1.55—1.45 (m, 2H); 13C NMR (DMSO-d6,
75 MHz) δ: 154.8, 144.1, 136.1, 129.8, 127.6, 121.0,
114.3, 54.5, 28.1, 27.0, 26.9, 22.2, 21.0; HRMS calcd
for C19H22N2O2S 342.1402, found 342.1408.
Ethyl 4-[2-(1H-benzo[d]imidazol-2-yl)phenyl]bu-
1
tanoate (5e) White solid, m.p. 148—149 ℃; H
NMR (CDCl3, 300 MHz) δ: 8.07—7.27 (m, 8H), 4.21 (q,
J＝7.2 Hz, 2H), 2.94 (t, J＝8.4 Hz, 2H), 2.51 (t, J＝6.0
Hz, 2H), 2.06—1.99 (m, 2H), 1.28 (t, J＝7.2 Hz, 3H);
13C NMR (DMSO-d6, 75 MHz) δ: 172.5, 151.7, 143.7,
141.0, 134.3, 130.4, 129.9, 129.7, 129.3, 126.1, 122.3,
121.3, 118.9, 111.2, 59.6, 33.0, 32.1, 26.1, 13.9; HRMS
calcd for C19H20N2O2 308.1525, found 308.1524.
Ethyl 5-(1H-perimidin-2-yl)pentanoate (7l) Grey
solid, m.p. 115—116 ℃; 1H NMR (CDCl3, 400 MHz) δ:
7.16—6.30 (m, 6H), 4.16 (q, J＝7.2 Hz, 2H), 2.41—
2.37 (m, 4H), 1.80—1.73 (m, 4H), 1.27 (t, J＝7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ: 173.9, 157.1,
140.7, 135.3, 128.2, 121.7, 119.3, 107.8, 60.5, 35.0,
33.6, 26.4, 24.0, 14.1; HRMS calcd for C18H20N2O2
296.1525, found 296.1527.
Ethyl
6-[6-methyl-1H-benzo[d]imidazol-2-yl]-
1
hexanoate (5f) Red liquid; H NMR (CDCl3, 300 MHz)
δ: 7.44—7.01 (m, 3H), 4.11 (q, J＝7.2 Hz, 2H), 2.91 (t,
J＝7.5 Hz, 2H), 2.44 (s, 3H), 2.26 (t, J＝7.2 Hz, 2H),
1.89—1.79 (m, 2H), 1.67—1.57 (m, 2H), 1.43—1.33 (m,
2H), 1.23 (t, J＝7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ: 173.6, 155.0, 138.4, 137.0, 131.4, 123.2, 114.2, 113.7,
60.1, 33.8, 30.7, 28.8, 28.4, 27.8, 24.2, 21.4, 14.0; HRMS
calcd for C16H22N2O2 274.1681, found 274.1682.
Ethyl 6-(1H-perimidin-2-yl)hexanoate (7m) Light
1
grey solid, m.p. 139—140 ℃; H NMR (CDCl3, 400
MHz) δ: 7.14—6.30 (m, 6H), 4.12 (q, J＝7.2 Hz, 2H),
2.35—2.30 (m, 4H), 1.78—1.72 (m, 2H), 1.70—1.63 (m,
2H), 1.48—1.40 (m, 2H), 1.24 (t, J＝7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ: 174.0, 156.9, 135.3, 128.2,
121.7, 119.3, 60.4, 35.4, 33.8, 28.3, 26.9, 24.0, 14.2;
HRMS calcd for C19H22N2O2 310.1681, found 310.1682.
Ethyl 3-[2-(1H-perimidin-2-yl)ethoxy]propanoate
Ethyl 6-(6-nitro-1H-benzo[d]imidazol-2-yl)-hex-
anoate (5g) Red liquid; 1H NMR (CDCl3, 300 MHz) δ:
8.48 (s, 1H), 8.18—8.14 (m, 1H), 7.60—7.58 (m, 1H),
4.15 (q, J＝7.2 Hz, 2H), 3.02 (t, J＝7.2 Hz, 2H), 2.36 (t,
J＝7.2 Hz, 2H), 1.96—1.86 (m, 2H), 1.75—1.65 (m,
2H), 1.50—1.40 (m, 2H), 1.26 (t, J＝7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ: 173.7, 155.0, 138.2, 136.8,
131.6, 123.2, 114.3, 113.9, 60.2, 33.8, 28.7, 28.4, 27.8,
24.2, 21.4, 14.0; HRMS calcd for C15H19N3O4 305.1376,
found 305.1377.
1
(7n) Pale yellow solid, m.p. 75—76 ℃; H NMR
(DMSO-d6, 400 MHz) δ: 7.09—6.29 (m, 6H), 4.00 (q,
J＝7.2 Hz, 2H), 3.73 (t, J＝6.8 Hz, 2H), 3.67 (t, J＝6.4
Hz, 2H), 2.53 (t, J＝6.4 Hz, 2H), 2.49 (t, J＝6.8 Hz,
2H), 1.12 (t, J＝7.2 Hz, 3H); 13C NMR (DMSO-d6, 100
MHz) δ: 171.0, 155.1, 145.2, 138.3, 135.0, 128.7, 127.9,
121.4, 118.4, 117.5, 112.9, 101.6, 67.3, 65.7, 59.8, 34.9,
34.5, 13.9; HRMS calcd for C18H20N2O3 312.1474,
found 312.1475.
5-(1H-Benzo[d]imidazol-2-yl)pentanenitrile
(5h)
Pale yellow solid, m.p. 166 — 167 ℃ ; 1H NMR
(DMSO-d6, 300 MHz) δ: 7.46—7.09 (m, 4H), 2.84 (t, J＝
7.5 Hz, 2H), 2.55 (t, J＝7.2 Hz, 2H), 1.91—1.81 (m, 2H),
1.69—1.59 (m, 2H); 13C NMR (DMSO-d6, 75 MHz) δ:
154.4, 138.3, 121.0, 120.4, 114.6, 27.5, 26.4, 24.2, 15.8;
HRMS calcd for C12H13N3 199.1109, found 199.1109.
Diethyl [4-(1H-benzo[d]imidazol-2-yl)butyl]-
Ethyl 4-[2-(1H-perimidin-2-yl)phenyl]butanoate
1
(7o) Green solid; H NMR (CDCl3, 400 MHz) δ:
7.89—6.23 (m, 10H), 3.87 (q, J＝7.2 Hz, 2H), 2.91 (t,
J＝7.2 Hz, 2H), 2.33 (t, J＝7.2 Hz, 2H), 2.07—2.00 (m,
2H), 1.11 (t, J＝7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ: 174.0, 154.6, 139.2, 135.3, 134.8, 129.9, 129.7, 128.3,
127.9, 126.3, 121.7, 119.5, 60.4, 33.7, 31.9, 25.8, 13.9;
HRMS calcd for C23H22N2O2 358.1681, found 358.1683.
5-(1H-Perimidin-2-yl)pentanenitrile (7p) Yellow
green solid, m.p. 118—119 ℃; 1H NMR (DMSO-d6, 400
1
phosphonate (5i) White solid, m.p. 78—79 ℃; H
NMR (CDCl3, 400 MHz) δ: 7.54—7.18 (m, 4H), 4.12—
4.04 (m, 4H), 2.95 (t, J＝7.2 Hz, 2H), 2.03—1.96 (m,
2H), 1.84—1.67 (m, 4H), 1.30 (t, J＝7.2 Hz, 6H); 13C
Chin. J. Chem. 2011, 29, 1880— 1886
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Cai et al.
FULL PAPER
MHz) δ: 7.11—6.26 (m, 6H), 2.55 (t, J＝6.8 Hz, 2H),
2.28 (t, J＝7.2 Hz, 2H), 1.77—1.70 (m, 2H), 1.67—1.60
(m, 2H); 13C NMR (DMSO-d6, 75 MHz) δ: 156.7, 135.0,
128.4, 128.2, 128.1, 121.3, 120.5, 117.9, 33.6, 25.4, 24.3,
15.9; HRMS calcd for C16H15N3 249.1266, found
249.1268.
Table
1
Condition screening for the condensation of
o-phenylenediamine and ethyl benzoylacetatea
2-(4-Tosylbutyl)-1H-perimidine (7q) Green solid,
m.p. 169—170 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.67
(d, J＝7.6 Hz, 2H), 7.22 (d, J＝8.0 Hz, 2H), 7.06—6.38
(m, 6H), 3.07 (t, J＝6.8 Hz, 2H), 2.33 (s, 3H), 2.25 (t,
J＝6.8 Hz, 2H), 1.86—1.71 (m, 4H); 13C NMR (CDCl3,
100 MHz) δ: 165.0, 156.3, 144.9, 135.5, 135.3, 129.9,
128.2, 127.8, 123.0, 121.7, 119.4, 55.5, 34.7, 25.6, 22.1,
21.5; HRMS calcd for C22H22N2O2S 378.1402, found
378.1394.
2-Tosyl-1',3'-dihydrospiro[cyclohexane-1,2'-peri-
midine] (8) White solid, m.p. 195—196 ℃; 1H NMR
(CDCl3, 400 MHz) δ: 7.52 (d, J＝8.0 Hz, 2H), 7.19—
7.10 (m, 6H), 6.42—6.32 (m, 2H), 5.08 (brs, 1H), 4.81
(brs, 1H), 3.53—3.52 (m, 1H), 2.51—2.42 (m, 1H), 2.34
(s, 3H), 2.01—1.96 (m, 2H), 1.84—1.76 (m, 1H), 1.69—
1.47 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ: 144.3,
138.4, 137.8, 134.3, 130.4, 129.7, 129.6, 128.0, 127.2,
126.6, 118.2, 117.2, 107.4, 107.0, 66.8, 65.2, 35.1, 29.7,
23.4, 21.5, 21.2; HRMS calcd for C23H24N2O2S
392.1558, found 392.1542.
Entry
1
Catalyst
—
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
i-PrOH
Benzene
THF
Yield/%
0
2
LaCl3
SmCl3
GdCl3
YbCl3
AlCl3
ZnCl2
FeCl3
YbCl3
YbCl3
YbCl3
YbCl3
YbCl3
65 (43)b
69
71
85
0
3
4
5
6
7
0
8
20
72
68
34
72
11
9
10
11
12
13
H2O
a
Reaction conditions: o-phenylenediamine (1 mmol), ethyl ben-
zoylacetate (1 mmol), catalyst (5 mol%), solvent (0.5 mL), 50 ℃,
24 h. b Room temperature.
With the optimum reaction conditions in hand, we
performed an exploration of substrate scope with struc-
tural varied linear β-ketoesters and o-phenylenediamines.
As can be seen from Table 2, all the reactions proceeded
smoothly affording the expected benzimidazoles in
moderate to excellent yields. An obvious difference in
the activity between β-alkyl-substituted ketoesters and
β-aryl-substituted ones was observed. The former reacted
well at room temperature leading to the corresponding
products in high yields, whereas the latter requires ele-
vated temperature to produce the comparable yields.
Besides, β-aryl-substituted ketoesters with an electron-
withdrawing group attached on the aromatic ring were
more reactive than those with an electron-donating
group (Entries 6—9), while o-phenylenediamine with an
electron-donating group on the benzene ring showed
higher activity compared to that with an elec-
tron-withdrawing group (Entries 10, 11). These differ-
ences in reactivity may be attributed to the electronic
effects.
Anyway, the condensation described above does not
meet the requirements of atom-economic chemistry.
Thus a range of cyclic β-ketoesters were employed to
make a better use of this YbCl3-catalyzed C—C bond
cleavage reaction. As described in Table 3, the rings of
cyclic ketones were opened and the expected benzimi-
dazoles were obtained in moderate to good yields. The
activity of 2-carbethoxy cyclohexanone (4a) was higher
than that of 2-carbethoxy cyclopentanone (4b) (Entries 1,
2). However, an apparently increased yield was obtained
when the reaction of the latter was carried out in reflux-
Results and discussion
The condensation reaction of o-phenylenediamine
(1a) with ethyl acetoacetate (2a) in the presence of 5
mol% of ytterbium chloride (YbCl3) was carried out at
room temperature for 24 h at first. After workup, a
compound was isolated in 85% yield, which was identi-
fied as 2-methyl-1H-benzo[d]imidazole (3a). To our
knowledge, this was the best result for this reaction un-
der such mild conditions. However, when ethyl benzoy-
lacetate 2e was used instead of ethyl acetoacetate, a
lower yield was given. Then the reaction conditions,
including temperature, solvent, and catalyst, were opti-
mized using the condensation of o-phenylenediamine
and ethyl benzoylacetate as the model reaction. The re-
sults are listed in Table 1. It was found that raising the
reaction temperature from room temperature to 50 ℃
brought about a considerable increase in yield (Entry 2),
while the condensation could not proceed at 50 ℃ in
the absence of catalyst (Entry 1). A series of metal chlo-
rides were used as Lewis acids to assess the influence of
central metal on the activity. Inferior results were ob-
tained when traditional Lewis acids such as AlCl3,
ZnCl2, and FeCl3 were used, whereas all of the lantha-
nide chlorides screened were effective in catalyzing the
reaction. The activity order was Yb＞Gd＞Sm＞La, re-
verse to the order of their ionic radii. Thus YbCl3 was
chosen for carrying out the following investigation on
solvents, which revealed that ethanol was the best choice
(Entry 5).
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Chin. J. Chem. 2011, 29, 1880— 1886

Efficient Synthesis of Functionalized Benzimidazoles and Perimidines
Table 2 YbCl3-catalyzed condensation of o-phenylenediamine
and β-ketoestersa
ing EtOH. 3-Carbethoxy-4-pyrone (4d) also exhibited a
good activity (Entry 4). As we predicted, the reaction of
2-carbethoxy-3,4-dihydronaphthalen-1(2H)-one (4e) ge-
nerated the corresponding product in a lower yield (En-
try 5) due to the stability of the carbonyl adjacent to a
benzene ring. In order to introduce more diversity into
the 2-subsitituent of benzimidazoles, some cyclic ke-
tones bearing coordination groups such as CN, SO2Ar
and P(O)(OEt)2 at 2-position were utilized and the de-
sired functionalized benzimidazoles were successfully
obtained. It was noteworthy that the excellent results
were obtained with 2-sulfonyl-substituted cyclic ketones,
which were transformed quantitatively into the corre-
sponding products (Entries 10, 11).
In order to demonstrate that the C—C bond cleavage
catalyzed by YbCl3 has a broader synthetic utility,
1,8-naphthalenediamine was examined in addition to
o-phenylenediamines. Perimidine compounds were
produced and the results are summarized in Table 4. In
most cases, the reactions were carried out in refluxing
EtOH, and 1.5 equiv. of 1,8-naphthalenediamine was
necessary to afford the corresponding products in desired
yields. It is noteworthy that the ring size of cyclic ketones
played a crucial role for the reaction. 2-Carbethoxy
cyclopentanone 4b gave product 7l in a 94% yield while
2-carbethoxy cyclohexanone 4a afforded product 7m
Entry
1
R1
H
R2
Product
3a
Yield/%
97
CH3
2
H
CH3CH2
n-Amyl
i-Butyl
3b
3c
91
3
H
86
4
H
3d
3e
78
5b
6b
7b
8b
9b
10
11b
H
C6H5
85
H
4-CH3OC6H4
4-CH3C6H4
4-FC6H4
4-BrC6H4
CH3
3f
57
H
3g
71
H
3h
3i
87
H
84
CH3
3j
98
NO2
CH3
3k
82
a Reaction conditions: o-phenylenediamine (1 mmol), β-ketoester
(1 mmol), YbCl3 (5 mol%), EtOH (0.5 mL), room temperature,
24 h. b 50 ℃.
Table 3 YbCl3-catalyzed condensation of o-phenylenediamine and 2-substituted cyclic ketonesa
Entry
1
R1
Cyclic ketone
Product
Yield/%
86
H
H
4a
4b
5a
2
3
4
52 (85b)
5b
H
H
74
4c
5c
71
4d
5d
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Cai et al.
FULL PAPER
Continued
Entry
R1
Cyclic ketone
Product
Yield/%
5
H
47b,c
4e
4a
5e
6
7
CH3
NO2
H
80
5f
4a
40
5g
8
68b
71b
98
4h
4i
5h
9
H
5i
10
H
4j
5j
11
H
98
4k
5k
a Reaction conditions: o-phenylenediamine (1 mmol), cyclic ketone (1 mmol), YbCl3 (5 mol%), EtOH (0.5 mL), room temperature, 24 h.
b Reaction was carried out in refluxing EtOH. c Catalyst loading 10 mol%.
only in a 50% yield (Entries 1, 2), which is contrary to
the cases of synthesizing benzimidazoles. In addition,
2-sulfonyl cyclopantanone 4j smoothly provided the
desired product 7q in a 98% yield at room temperature
(Entry 6), while 2-sulfonyl cyclohexanone 4k produced
compound 8 almost quantitatively rather than the
ring-opened product (Scheme 1). In view of these re-
sults, it can tentatively be concluded that the difference
in cyclic tension between cyclopantanone and cyclo-
hexanone and that between benzimidazole and pe-
rimidine are determinative factors to affect the reaction
activity and pathway.
β-ketoester to the lanthanide center, (ii) nucleophilic
attack of one amino group of the diamine on the more
electrophilic carbonyl group of β-ketoester, (iii) C—C
bond cleavage in a retro-Claisen-type reaction leading to
an ester and an amide, followed by (iv) condensation of
carbonyl with another amino group to generate the tar-
get benzimidazole and regenerate the lanthanide catalyst.
In this process, the formation of six-membered cyclic
complex A is presumably a key step which not only ac-
tivates the carbonyl group but also favors the electron
migration leading to the dissociation of β-ketoester. To
confirm this hypothesis, a control experiment was tried
using tetronic acid as a β-ketoester (Scheme 3). As we
predicted, enamine 109 was isolated as a major product,
and no benzimidazole was obtained. The result should
A plausible reaction mechanism is given in Scheme
2. It was considered that benzimidazole could be formed
via a four-step sequence involving (i) coordination of
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Efficient Synthesis of Functionalized Benzimidazoles and Perimidines
Table 4 YbCl3-catalyzed condensation of 1,8-naphthalene-
diamine and 2-substituted cyclic ketonesa
Scheme 1
Entry Cyclic ketone
Product
Yield/%
94
Scheme 2
1
2
3
4b
4a
4d
7l
50
7m
91b
7n
4
5
6
4e
4h
4j
34
Scheme 3
7o
7p
97c
be attributed to the difficulty in forming six-membered
cyclic complex, because the coordination of the two
carbonyl groups of tetronic acid to a lanthanide center is
sterically impossible.
98c,d
Conclusion
In conclusion, we have described here a novel and
facile route for the synthesis of functionalized benzimi-
dazoles and perimidines by the condensation of diamines
and β-carbonyl compounds via the C—C bond cleavage
catalyzed by YbCl3. The reaction can be carried out un-
der mild conditions without use of oxidants, strong
7q
a Reaction conditions: 1,8-naphthalenediamine (1.5 mmol), cyclic
ketone (1 mmol), YbCl3 (5 mol%), refluxing EtOH (1 mL), 24 h.
50 ℃. 1,8-Naphthalenediamine (1.1 mmol). Room tempera-
b
c
d
ture.
Chin. J. Chem. 2011, 29, 1880— 1886
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1885

Cai et al.
FULL PAPER
Bronsted acids, or microwave irradiation. Further stud-
ies on the application of this lanthanide catalyzed C—
C bond cleavage reaction in synthesis are currently un-
der investigation.
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Chin. J. Chem. 2011, 29, 1880— 1886