Silver-catalyzed intramolecular hydroamination of alkynes in aqueous media: Efficient and regioselective synthesis for fused benzimidazoles

Article abstract of DOI:10.1039/c0gc00668h

A simple, convenient and green synthetic approach to diverse fused tricyclic benzimidazoles has been developed by Ag(i) complex catalyzed intramolecular hydroamination under the classic method or by microwave irradiation in water. This strategy presents a

Full text of DOI:10.1039/c0gc00668h

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PAPER
Silver-catalyzed intramolecular hydroamination of alkynes in aqueous
media: efficient and regioselective synthesis for fused benzimidazoles†
Xu Zhang,a,b Yu Zhou,b Hengshuai Wang,b Diliang Guo,a,b Deju Ye,b Yungen Xu,a Hualiang Jiangb and
Hong Liu*a,b
Received 11th October 2010, Accepted 1st December 2010
DOI: 10.1039/c0gc00668h
A simple, convenient and green synthetic approach to diverse fused tricyclic benzimidazoles has
been developed by Ag(I) complex catalyzed intramolecular hydroamination under the classic
method or by microwave irradiation in water. This strategy presents an operationally simple and
environmentally friendly transformation, in which various substituted benzimidazoles facilitated
efficient cyclization.
pyrroles, silyl ketene aminals, benzothiazines and other hetero-
Introduction
cycles in efficient and atom-economic ways.6,7 In particular, our
Fused benzimidazoles are important heterocyclic scaffolds in
group has made a contribution by the synthesis of isochromen-
drug discovery.1 Various substituted benzimidazoles have been
1-imines.8
suggested to be potential therapeutic agents involving antipro-
liferative, antitumor activity and for [1,2-a]-fused imidazoles,
Water, an environmentally friendly reaction medium, often
has an unpredictable effect on the rate and selectivity of organic
which have antiulcer, antidepressant and antimicrobial activity.2
reactions through hydrophobic interactions and the enrichment
Recently, oxygen- or nitrogen-containing fused benzimidazoles
of organic substrates in the local hydrophobic environment.9
have been successfully synthesized by C–H bond activation,3
Therefore, as a part of our ongoing efforts to develop new
rhodium-catalysed cyclization4 and radical cyclisation.5 How-
convenient and efficient strategies for the preparation of po-
ever, the described methods suffer from a relatively narrow scope
tential bioactive heterocycles with transition metal catalysts,8,10
of substrates. Thus, it is very important to develop novel and
we herein present our findings of the synthesis of fused
improved protocols for the synthesis of more abundant fused
benzimidazoles.
benzimidazoles by an Ag(I)-catalyzed chemo- and regioselective
intramolecular cyclization in aqueous media (Scheme 1).
Recently, transition metal-catalyzed transformations have
attracted considerable attention because of their remarkable
ability to activate p-systems, especially alkynes, towards inter- or
intramolecular hydroamination and inter- or intramolecular hy-
droarylation attacks to construct intriguing fused heterocycles.6
Among these transition metal catalysts, Ag(I) salts have gen-
erally been considered to have a low catalytic efficiency, and
only serve as either co-catalysts or Lewis acids. However, in
recent years, Ag(I) salts have been demonstrated to be impor-
tant and versatile catalysts for the synthesis of functionalized
heterocycles such as isoquinolines, (2H)-isoquinolines, (2H)-
1,2-oxaphosphorin 2-oxides, 5-substituted proline derivatives,
Scheme 1 Synthesis of fused tricyclic benzimidazoles.
aDepartment of Medicinal Chemistry, China Pharmaceutical University,
24 Tong jia Xiang, Nanjing, 210009, P. R. China
Results and discussion
bState Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai,
201203, China. E-mail: hliu@mail.shcnc.ac.cn; Fax: +86 21-50807042;
Tel: +86 21-50807042
The requisite cyclization precursors, benzimidazoles (A), are
readily synthesized from o-phenylene diamines through conden-
sation and cyclization reactions with acetic acid. Benzimidazoles
are readily synthesized according to the relevant literature.11
Initially, 2-(pent-4-ynyl)-1H-benzo[d]imidazole (A1) was cho-
sen as the model substrate for investigating the optimum
† Electronic supplementary information (ESI) available: Copies of
1H and 13C NMR spectra for the target compounds. See DOI:
10.1039/c0gc00668h
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Table 1 Optimization of the reaction conditionsa
product (Table 1, entry 17). Without a N2 atmosphere, the yield
of the target compound was drastically affected and decreased
to 75% (Table 1, entry 18). Meanwhile, a correlative Brønsted
acid was applied and no reaction took place (Table 1, entries
19 and 20). Briefly, the optimum results were achieved when A1
(0.40 mmol) was treated with 5 mol% of AgOTf in an aqueous
medium at 80 ◦C for 8 h under oil bath heating conditions
or at 150 ◦C for 15 min under microwave irradiation. Owing
to the same excellent yields being obtained under both above-
mentioned conditions, we chose both of them for subsequent
explorations.
Entry Catalyst (mmol%) Solvent Temp. (◦C) Time
Yield (%)
1
2
3
4
5
6
7
8
—
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
8 h
8 h
0
AgSbF6 (10)
AgNO3 (10)
AgI (10)
91
90
15
28
95
trace
60
94
65
87
93
95
95
Ag2CO3 (10)
AgOTf (10)
Ag2O (10)
AgOAc(10)
AgSO3CH3 (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
TfOH (10)
TfOH (10)
To evaluate the scope of the proposed catalytic methods,
we attempted to investigate the cyclization of a variety of
substituted benzimidazoles (A) under the above-mentioned
optimized conditions (Table 2). Firstly, we performed these
transformations under classic oil bath heating conditions,
and the results demonstrated that the protocol was tolerant
to substrates with different substituents R1, including H,
methyl and chloro groups (Table 2, entries 1–3). Furthermore,
introducing various substituents into the alkynyl groups of
various benzimidazoles was investigated (Table 2, entries 4–12).
When R2 was phenyl or several substituted phenyl groups,
this reaction was well implemented to form intriguing cyclized
products (Table 2, entries 4–7, 9, 11 and 12). However, no
products were observed in the cases of 2-(5-(2-(trifluoromethyl)-
phenyl)pent-4-ynyl)-1H-benzo[d]imidazole (A8) and 2-(5-
(4-(trifluoromethyl)phenyl)pent-4-ynyl)-1H-benzo[d]imidazole
(A10), presumably due to electronic effects (Table 2, entries
8 and 10). When we introduced a pyridine moiety as an R2
substituent, an excellent yield was also obtained. (Table 2, entry
12). Good yields could be obtained irrespective of electron-
donating methoxy, halide or heteroaromatic groups. (Table 2,
entries 7, 11 and 12). However, the substitution position and
type of the R1 and R2 substituents were found to be important
factors for influencing the yields of the products (Table 2, entries
1–12). Additionally, the replacement of the benzimidazole ring
with naphthoimidazole rings also led to good yields (Scheme 2,
A13 and A14). However, substitution of the benzimidazole ring
with perimidine or benzothiazole heterocycles led to a drastic
decrease of yield of the desired products under the optimized
reaction conditions (Scheme 2, A15 and A16).
Although some limitations were discovered in these inves-
tigations, when the cyclization transformation of substituted
benzimidazoles (A) was performed under microwave irradiation,
as shown in Table 2 and Scheme 2 (method B), better yields
were obtained in most cases, irrespective of the type or position
of the R1 and R2 substituents. Surprisingly, excellent yields were
observed in the cases of A8 and A10, respectively (Table 2, entries
8 and 10). However, when we interchanged the benzimidazole
ring with perimidine or benzothiazole heterocycles, no reactions
occurred under microwave irradiation conditions (Scheme 2,
A15 and A16).
Based on the above experimental results, we found that better
yields of the target compounds could be achieved under mi-
crowave irradiation. Therefore, more experiments were carried
out under the microwave-aided optimal reaction conditions,
and these further results indicated that the proposed reaction
could be extended to the synthesis of oxa-fused benzimidazoles
C17–C27 by using compounds A17–A27 as starting materials.
9
10
11
12
13
14
15
16
17
18
19
20
H2O
THF
EtOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
80
80
80
80
80
80
120
150
150
80
10 min 73b
10 min 87b
15 min 96b
15 min 75b,c
8 h
0
150
15 min 0b
a A1 (0.4 mmol), catalyst (5–10 mol %), solvent (3 mL), under N2 for
2–8 h. b The reaction was carried out under microwave irradiation in
H2O. c The reaction was carried out under air.
reaction conditions, including different catalysts, various sol-
vents, reaction temperatures and reaction times (Table 1). Under
catalyst-free conditions, no reaction took place and only starting
material A1 was recovered (Table 1, entry 1). Various Ag(I)
salts (10 mol%) were screened in toluene at 80 ◦C under an N2
atmosphere for 2 h. The results demonstrated that these Ag(I)
salts displayed distinct catalytic activities (Table 1, entries 2–9).
Among them, AgOTf was found to be the most effective cata-
lyst, and the desirable product 1-methylene-1,2,3,4-tetrahydro-
pyrido[1,2-a]benzimidazole (B1) was obtained in 95% yield
(Table 1, entry 6). Subsequently, we screened different solvents at
80 ◦C, and the results show that toluene is the most suitable for
this transformation (Table 1, entries 10–12). However, a similar
excellent result was also obtained when the transformation was
performed in an aqueous medium for a longer time (Table 1,
entry 13). Water was thus chosen for further investigations on the
basis of it being environmentally benign, abundant, cheap, and
often exhibiting a unique reactivity and selectivity that cannot be
obtained in conventional organic solvents.12 In addition, when
the AgOTf catalyst loading was decreased from 10 to 5 mol%, an
identical good yield of the target compound was also detected
(95% yield, Table 1, entry 14). Although microwave irradiation
was generally employed to facilitate this reaction, when we
treated A1 with 5 mol% AgOTf under microwave irradiation
in water at 80 ◦C for 10 min, the desired N-annelated product,
B1, was only formed in 73% yield and a small quantity of starting
material A1 was recovered (Table 1, entry 15). However, when the
reaction temperature increased to 120 ◦C, the yield of the desired
product was improved to 87% (Table 1, entry 16). Furthermore,
increasing the reaction temperature to 150 ◦C for 15 min under
an N2 atmosphere resulted in an excellent yield of the desired
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Table 2 Synthesis of piperidine[1,2-a]benzimidazoles in watera
Table 2 (Contd.)
Yield (%)
Yield (%)
Method A Method B
Entry R1
R2
H
Product
Method A Method B
Entry R1
R2
Product
1
2
3
H
94b
91b
92b
92
88
89
11
H
85
73
CH3
Cl
H
H
12
H
92
91
a Method A: 80 ◦C, 60 h, N2; Method B: MW, 150 ◦C, 15 min, N2.
b 80 ◦C, 8 h, N2.
4
5
6
H
Ph
84
35
43
81
86
87
CH3 Ph
Cl
Ph
7
8
H
H
62
0
86
84
Scheme 2
Method A: 80 ◦C, 60 h, N2; Method B: MW, 150 ◦C,
a)
9
H
H
87
85
87
15 min, N2; b) 80 ◦C, 8 h, N2.
As shown in Table 3, the tolerance of the catalytic system was
remarkable, and moderate to excellent yields of the desired
products were obtained (Table 3, entries 1–10). Excellent yields
were obtained when R2 was hydrogen and methyl group,
respectively, and only seven-membered heterocyclic frameworks,
formed via a 7-endo-dig ring-closing pathway, were generated
(Table 3, entries 1–6). However, introducing methyl groups make
the transformations require a longer time (50 min) to complete
substrate conversion. Hence, we found that the benzimidazoles
10
0
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Table 3 Synthesis of oxa-fused benzimidazoles under microwave irra-
of terminal alkynes and alkyl-replaced benzimidazoles have dis-
tinctive response characteristics for this cyclization, presumably
due to electronic effects and steric hindrance. When introducing
aryl groups into the R2 position, we surprisingly discovered
that two main products were formed, namely six-membered and
seven-membered ring-closing heterocyclic frameworks (Table 3,
entries 7–10), maybe owing to the electronic effects of the oxygen
atom and aryl groups. The p–p conjugative effect between the
acetylene bond and the aryl groups make the nitrogen atom
of benzimidazoles have a similar probability of attacking either
carbon of the acetylene bond, generating 6-exo-dig and 7-endo-
dig ring-closure products. In addition, a good yield was obtained
when we changed the benzimidazole ring of substrate A17 into
a naphthoimidazole ring, and only a seven-membered product
was formed via a 7-endo-dig ring-closing pathway (Scheme 2,
A27).
In principle, the cyclization of alkynes possessing a nucle-
ophilic group in proximity to the triple bond can construct
various heterocycles via different ring-closing pathways. As
shown in Scheme 3, there are two possible mechanisms for
this transformation to give two possible products: (a) a 6-
exo-dig cyclization process, leading to the formation of six-
membered product B1 and (b) a 7-endo-dig cyclization process,
leading the formation of seven-membered product C1. All the
fused benzimidazoles synthesized were characterized by their
1H NMR, 13C NMR and MS data. Additionally, the structures
of B11 and C17 were confirmed by X-ray diffraction (XRD)
studies (Fig. 1).
diation in watera
Product/yield (%)
Entry
1
R1
H
R2
H
B
C
—
2
3
4
5
6
CH3
Cl
H
—
—
—
—
—
H
H
CH3
CH3
CH3
CH3
Cl
7
8
H
H
Ph
Scheme 3 Two different pathways to fused benzimidazoles B1 and C1.
9
H
H
Fig. 1 The X-ray crystal structures of B11 and C17.
10
To gain insight into the mechanism of the reaction, we
performed labelling studies with deuterated starting materials
or solvents. The reactions of A2, A10, A19 and A23 in D2O
under the standard conditions afforded the deuterated products
[d]-B2, [d]-B10, [d]-B19, [d]-B23 and [d]-C23, respectively. The
reaction of deuterated alkyne [d]-A2 in H2O led to the formation
of non-deuterated product B2 (Scheme 4).
◦
a AgOTf, MW, H2O, 150 C, 15 min, N2. b AgOTf, MW, H2O, 150 ◦C,
50 min, N2.
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alkyne p-complex F in H2O. A subsequent attack of the nitrogen
atom at the electron-deficient triple bond leads to intermediates
D or E via a 6-exo-dig or 7-endo-dig ring-closing pathway,
respectively, which is followed by proton transfer to produce
the final products B or C.
In addition, the aforementioned labelling experiments indi-
cate that the vinyl protons of the products come from the solvent.
Key intermediate [d]-F could be formed by the treatment of
material A with D2O under the catalysis of the Ag salt, which is
consistent with the results reported in the literature.13 A further
electrophilic attack of the nitrogen atom towards the electron-
deficient triple bond results in the formation of intermediates
[d]-D or [d]-E by 6-exo-dig or 7-endo-dig ring-closing path-
ways, respectively. Subsequently, the resulting intermediates are
converted into the final products, [d]-B or [d]-C, by deuterium
transfer, respectively.
Conclusions
In summary, we have developed an efficient and convenient
method for the synthesis of fused tricyclic benzimidazoles via
Ag(I)-catalyzed intramolecular hydroamination in water. This
strategy presents an environmentally friendly transformation
that has a good functional group tolerance. Significantly, the
strategy affords the important motifs of both useful versatile
synthetic intermediates and potent biologically active com-
pounds. It is our expectation that these biologically intriguing
structures will be found broad applications in our related
medicinal chemistry program. These interesting transformations
have motivated us to further investigate their reaction pathway
as a part of future endeavours.
Scheme 4 Labelling studies with D2O or deuterated starting materials.
On the basis of our previous knowledge and the results
of the present studies, we postulate a plausible mechanism
for the construction of polycyclic molecular scaffold fused
benzimidazoles (Scheme 5).
Experimental section
General experimental procedures
The reagents were purchased from commercial sources and
used without further purification. Analytical thin layer chro-
matography (TLC) was HSGF 254 (0.15–0.2 mm thickness).
All of the microwave-assisted reactions were performed in an
Initiator TM EXP microwave system (Biotage, Inc.) at the
specified temperature using the standard mode of operation.
R
Column chromatography was performed with CombiFlashꢀ
Companion system (Teledyne Isco, Inc.). Proton and carbon
magnetic resonance spectra (1H NMR and 13C NMR) were
recorded in CDCl3 as a solvent with tetramethylsilane (TMS)
as internal standard (1H NMR: TMS at 0.00 ppm, CDCl3 at
7.24 ppm 13C NMR: CDCl3 at 77.0 ppm) or were recorded in
DMSO-d6 as a solvent with tetramethylsilane (TMS) as internal
standard (1H NMR: TMS at 0.00 ppm, DMSO at 2.50 ppm
13C NMR: DMSO at 40.0 ppm). Low and high-resolution mass
spectra (LR MS and HR MS) were measured on Finnigan MAT
95 spectrometer. using tetramethylsilane (TMS).
General procedure for the silver-catalyzed synthesis of diverse
substituted fused tricyclic benzimidazoles (compound B1, for
example)
Scheme 5 Possible mechanism for intramolecular cyclization.
Firstly, the carbon–carbon triple bonds of A are activated
Classic method using a thermostate oil bath (Method A).
by coordination with the transition metal salt to form Ag-
A mixture of A1 (0.40 mmol) and AgOTf (0.02 mmol) was
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stirred in water (3–5 mL) under N2. The vial was sealed and
the mixture stirred at 80 ◦C with oil bath heating for 8–60 h.
After the reaction, the vial was cooled to ambient temperature
and the crude reaction mixture extracted three times with ethyl
acetate (EA) (15 mL ¥ 3). The combined organic phase was
washed with a saturated NaHCO3 solution, brine, dried with
Na2SO4 and concentrated. The residue was purified by column
chromatography to provide desired product B1.
CDCl3): d 1.93 (s, 3H, CH3), 2.14–2.33 (m, 5H, CH2, CH3),
2.63 (t, 2H, CH2), 3.26 (t, 2H, CH2), 6.06 (s, 1H, CH), 6.25 (s,
1H, ArH), 6.98–7.01 (m, 2H, ArH), 7.13–7.15 (m, 3H, ArH),
7.38 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 19.9, 20.0,
21.5, 24.6, 33.2, 114.2, 114.4, 118.5, 126.8, 128.0, 128.7, 129.7,
130.2, 130.8, 133.2, 135.5, 141.7, 151.6; EI-MS m/z 288 [M]+;
HRMS (EI) calc. for C20H20N2 [M]+ 288.1626, found 288.1631.
7,8-Dichloro-1-[1-phenyl-meth-(Z)-ylidene]-1,2,3,4-tetrahy-
dropyrido[1,2-a]benzimidazole (B6). 1H NMR (300 MHz,
CDCl3): d 2.23–2.27 (m, 2H, CH2), 2.66 (t, 2H, CH2), 3.27 (t,
2H, CH2), 6.32 (s, 1H, CH), 6.36 (s, 1H, ArH), 6.94–6.97 (m,
2H, ArH), 7.17–7.19 (m, 3H, ArH), 7.68 (s, 1H, ArH); 13C NMR
(100 MHz, CDCl3): d 21.3, 24.7, 32.7, 115.1, 115.6, 119.6, 125.3,
126.1, 127.7, 128.4, 128.5, 130.0, 132.5, 134.6, 142.6, 154.2;
EI-MS m/z 328 [M]+; HRMS (EI) calc. for C18H14Cl2N2 [M]+
328.0534, found 328.0536.
Microwave method (Method B)
A mixture of A1 (0.40 mmol) and AgOTf (0.02 mmol) was
stirred in water (3–5 mL) under N2. The vial was sealed and
the mixture irradiated for 15 min at 150 ◦C. After the reaction,
the crude reaction mixture was cooled to ambient temperature
and extracted three times with EA (15 mL ¥ 3). The combined
organic phase was washed with saturated NaHCO3 solution,
brine, dried with Na2SO4 and concentrated. The residue was
purified by column chromatography on Combiflash to provide
desired product B1.
1-[1-(4-Methoxy-phenyl)-meth-(Z)-ylidene]-1,2,3,4-tetrhydro-
pyrido[1,2-a]benzimidazole (B7). 1H NMR (300 MHz, CDCl3):
d 2.28–2.32 (m, 2H, CH2), 2.67 (t, 2H, CH2), 3.51 (t, 2H, CH2),
3.74 (s, 3H, CH3), 6.35 (s, 1H, CH), 6.53–6.56 (d, J = 8.1 Hz,
1H, ArH), 6.67–6.70 (d, J = 8.7 Hz, 2H, ArH), 6.91–6.95 (m,
3H, ArH), 7.17–7.27 (t, 1H, ArH), 7.66–7.69 (d, J = 8.1 Hz, 1H,
ArH); 13C NMR (100 MHz, CDCl3): d 21.1, 24.7, 32.6, 55.2,
113.7, 114.2, 116.6, 117.9, 122.6, 123.2, 127.0, 130.1, 130.5,
130.6, 141.3, 154.3, 158.8; EI-MS m/z 290 [M]+; HRMS (EI)
calc. for C19H18N2O [M]+ 290.1419, found 290.1416.
The characterization data obtained were as follows: 1H NMR
d (300 MHz, CDCl3): 2.06 (m, 2H, CH2), 2.07 (t, J = 6.0 Hz,
2H, CH2), 2.67 (t, J = 6.3 Hz, 2H, CH2), 4.81 (d, J = 0.9 Hz,
1H, CH), 5.34 (d, J = 0.9 Hz 1H, CH), 7.26–7.29 (m, 2H, ArH),
7.68–7.72 (m, 2H, ArH); 13C NMR d (100 MHz, CDCl3): 21.3,
25.6, 31.6, 97.0, 112.4, 119.1, 122.8, 123.0, 132.2, 140.7, 143.0,
152.0; EI-MS m/z 184 [M]+; HRMS (EI) calc. for C12H12N2 [M]+
184.1000, found 184.0995.
1-[1-(2-Trifluoromethyl-phenyl)-meth-(Z)-ylidene]-1,2,3,4-tet-
rahydropyrido[1,2-a]benzimidazole (B8). 1H NMR (300 MHz,
CDCl3): d 2.24–2.33 (m, 2H, CH2), 2.75 (t, 2H, CH2), 3.31 (t,
2H, CH2), 6.28–6.31 (d, J = 8.4 Hz, 1H, ArH), 6.50 (s, 1H, CH),
6.72–6.76 (t, 2H, ArH), 6.97–7.02 (t, 1H, ArH), 7.04–7.09 (t,
1H, ArH), 7.18–7.23 (t, 1H, ArH), 7.59–7.62 (d, J = 8.1 Hz, 2H,
ArH), 7.70–7.72 (d, J = 8.4 Hz, 2H, ArH); 13C NMR (100 MHz,
CDCl3): d 21.6, 24.8, 33.2, 110.5, 112.5, 118.7, 121.8, 122.4,
124.4 (d, J = 270.0 Hz), 125.9 (d, J = 5.6 Hz), 127.1, 127.4 (J =
40 Hz), 130.6, 131.2, 131.4, 134.0, 135.3, 143.3, 152.3; EI-MS
m/z 328 [M]+; HRMS (EI) calc. for C19H15F3N2 [M]+ 328.1187,
found 328.1182.
Characterization data for other target compounds
7,8-Dimethyl-1-methylene-1,2,3,4-tetrahydropyrido[1,2-a]ben-
zimidazole (B2). 1H NMR (300 MHz, CDCl3): d 2.02–2.05 (m,
2H, CH2), 2.35 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.63 (t, 2H, CH2),
3.12 (t, 2H, CH2), 4.75 (s, 1H, CH), 5.29 (s, 1H, CH), 7.43 (s,
1H, ArH), 7.45 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3):
d 20.1, 20.6, 21.4, 25.7, 31.7, 96.0, 112.9, 119.4, 130.9, 131.5,
141.0, 142.0, 151.1; EI-MS m/z 212 [M]+; HRMS (EI) calc. for
C14H16N2 [M]+ 212.1313, found 212.1308.
7,8-Dichloro-1-methylene-1,2,3,4-tetrahydropyrido[1,2-a]ben-
zimidazole (B3). 1H NMR (300 MHz, CDCl3): d 2.05–2.08
(m, 2H, CH2), 2.63–2.66 (m, 2H, CH2), 3.11–3.15 (m, 2H, CH2),
4.84 (s, 1H, CH), 5.21 (s, 1H, CH), 7.71–7.74 (m, 2H, ArH);
13C NMR (100 MHz, CDCl3): d 21.0, 25.7, 31.4, 97.6, 113.7,
120.2, 126.5, 126.7, 131.4, 140.4, 142.9, 153.9; EI-MS m/z 252
[M]+; HRMS (EI) calc. for C12H10Cl2N2 [M]+ 252.0221, found
252.0218.
1-[1-(3-Trifluoromethyl-phenyl)-meth-(Z)-ylidene]-1,2,3,4-tet-
rahydropyrido[1,2-a]benzimidazole (B9). 1H NMR (300 MHz,
CDCl3): d 2.24–2.31 (m, 2H, CH2), 2.70 (t, 2H, CH2), 3.30 (t,
2H, CH2), 6.25 (s, 1H, CH), 6.28 (s, 1H, ArH), 6.78–6.83 (m, 1H,
ArH), 7.03–7.09 (t, 1H, ArH), 7.09–7.23 (m, 3H, ArH), 7.35–
7.38 (d, J = 7.8 Hz, 1H, ArH), 7.63–7.66 (d, J = 8.1 Hz, 1H,
ArH); 13C NMR (100 MHz, CDCl3): d 21.5, 24.6, 33.2, 113.2,
113.3, 119.0, 121.7, 122.5, 123.6 (d, J = 3.7 Hz), 125.5 (d, J =
3.7 Hz), 128.5, 130.5, 131.8, 134.6, 136.0, 143.6, 152.4; EI-MS
m/z 328 [M]+; HRMS (EI) calc. for C19H15F3N2 [M]+ 328.1187,
found 328.1173.
1-[1-Phenyl-meth-(Z)-ylidene]-1,2,3,4-tetrahydropyrido [1,2-
a]benzimidazole (B4). 1H NMR (300 MHz, CDCl3): d 2.27
(br, 2H, CH2), 2.68 (t, 2H, CH2), 3.39 (br, 2H, CH2), 6.35 (s,
1H, CH), 6.40–6.43 (d, J = 8.1 Hz, 1H, ArH), 6.83 (t, 1H,
ArH), 6.97–6.98 (br, 2H, ArH), 7.12–7.14 (m, 4H, ArH), 7.67–
7.69 (br, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 21.3, 24.4,
32.9, 113.7, 115.8, 118.3, 121.9, 122.7, 127.3, 128.3, 128.7, 132.5,
134.9, 140.6, 150.3; EI-MS m/z 260 [M]+; HRMS (EI) calc. for
C18H16N2 [M]+ 260.1313, found 260.1304.
1-[1-(4-Trifluoromethyl-phenyl)-meth-(Z)-ylidene]-1,2,3,4-tet-
rahydropyrido[1,2-a]benzimidazole (B10). 1H NMR (300 MHz,
CDCl3): d 2.25–2.32 (m, 2H, CH2), 2.71 (t, 2H, CH2), 3.31 (t, 2H,
CH2), 6.27–6.30 (m, 2H, CH, ArH), 6.81–6.86 (td, 1H, ArH),
7.05–7.08 (d, J = 7.8 Hz 2H, ArH), 7.11–7,17 (m, 1H, ArH),
7.36–7.39 (d, J = 7.8 Hz, 2H, ArH), 7.65–7.68 (d, J = 8.1 Hz,
1H, ArH); 13C NMR (100 MHz, CDCl3): d 20.7, 25.1, 32.5,
7,8-Dimethyl-1-[1-phenyl-meth-(Z)-ylidene]-1,2,3,4-tetrahy-
dropyrido[1,2-a]benzimidazole (B5). 1H NMR (300 MHz,
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113.8, 116.0, 118.0, 123.2, 123.8 (d, J = 270.6 Hz), 124.0, 125.2,
129.0, 129.3 (d, J = 32.3 Hz), 129.8, 133.9, 138.1, 140.8, 155.3;
EI-MS m/z 328 [M]+; HRMS (EI) calc. for C19H15F3N2 [M]+
328.1187, found 328.1178.
EI-MS m/z 214 [M]+; HRMS (EI) calc. for C13H14N2O [M]+
214.1106, found 214.1108.
2,3-Dichloro-7H,9H-8-oxa-4b,10-diazabenz[a]azulene (C19).
1H NMR (300 MHz, CDCl3): d 4.61–4.62 (m, 2H, CH2), 4.95
(s, 2H, CH2), 5.45–5.50 (m, 1H, CH), 6.78–6.83 (m, 1H, CH),
7.48 (s, 1H, ArH), 7.79 (s, 1H, ArH); 13C NMR (100 MHz,
CDCl3): d 67.9, 71.6, 110.8, 116.9, 119.0, 121.3, 127.0, 127.7,
133.4, 141.5, 155.4; ESI-MS m/z 255 [M + H]+; HRMS (ESI)
calc. for C11H9Cl2N2O [M + H]+ 255.0092, found 255.0089.
1-[1-(4-Chloro-phenyl)-meth-(Z)-ylidene]-1,2,3,4-tetrahydro-
pyrido[1,2-a]benzimidazole (B11). 1H NMR (300 MHz,
CDCl3): d 2.23–2.30 (m, 2H, CH2), 2.66 (t, 2H, CH2), 3.29 (t,
2H, CH2), 6.22 (s, 1H, CH), 6.37–6.40 (d, J = 8.1 Hz, 1H, ArH),
6.85–6.91 (m, 3H, ArH), 7.08–7.17 (m, 3H, ArH), 7.64–7.67 (d,
J = 8.1 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 21.3,
24.4, 33.1, 113.6, 114.0, 118.7, 121.9, 122.6, 128.4, 130.0, 130.8,
132.8, 133.4, 133.6, 143.0, 152.6; EI-MS m/z 294 [M]+; HRMS
(EI) calc. for C18H15ClN2 [M]+ 294.0924, found 294.0922.
5-Methyl-7H,9H-8-oxa-4b,10-diazabenz[a]azulene
(C20).
1H NMR (300 MHz, CDCl3): d 2.52 (s, 3H, CH3), 4.07-4.09
(d, J = 6.3 Hz, 2H, CH2), 4.81 (s, 2H, CH2), 5.81–5.86 (m,
1H, CH), 7.31–7.34 (m, 2H, ArH), 7.54–7.57 (m, 1H, ArH),
7.80–7.83 (m, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 20.1,
62.9, 63.3, 112.2, 116.7, 120.7, 123.0, 123.5, 133.6, 138.5, 143.2,
152.1; EI-MS m/z 200 [M]+; HRMS (EI) calc. for C12H12N2O
[M]+ 200.0950, found 200.0956.
1-[1-Pyridin-3-yl-meth-(Z)-ylidene]-1,2,3,4-tetrahydropyrido-
[1,2-a]benzimidazole (B12). 1H NMR (300 MHz, CDCl3): d
2.17–2.26 (m, 2H, CH2), 2.66 (t, 2H, CH2), 3.27 (t, 2H, CH2),
6.21 (s, 1H, CH), 6.29–6.32 (d, J = 8.4 Hz, 1H, ArH), 6.78–
6.83 (t, 1H, ArH), 6.91–6.95 (m, 1H, ArH), 7.02–7.11 (m, 2H,
ArH), 7.61–7.64 (d, J = 8.1 Hz, 1H, ArH), 8.34 (br, 2H, ArH);
13C NMR (100 MHz, CDCl3): d 21.1, 24.2, 32.9, 110.8, 113.2,
118.8, 121.7, 122.4, 122.7, 130.3, 131.0, 135.0, 135.2, 143.2,
147.7, 149.5, 152.4; EI-MS m/z 261 [M]+; HRMS (EI) calc.
for C17H15N3 [M]+ 261.1266, found 261.1251.
2,3,5-Trimethyl-7H,9H -8-oxa-4b,10-diazabenz[a]azulene
(C21). 1H NMR (300 MHz, CDCl3): d 2.37 (s, 3H, CH3), 2.39
(s, 3H, CH3), 2.48 (s, 3H, CH3), 4.01–4.03 (d, J = 6.9 Hz, 2H,
CH2), 4.76 (s, 2H, CH2), 5.76–5.78 (t, 1H, CH), 7.30 (s, 1H,
ArH), 7.55 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 20.0,
20.1, 20.6, 62.8, 63.0, 112.3, 116.0, 120.5, 131.8, 132.1, 132.6,
138.7, 141.7, 151.3; EI-MS m/z 228 [M]+; HRMS (EI) calc. for
C14H16N2O [M]+ 228.1263, found 228.1258.
1-Methylene-1,2,3,4-tetrahydronaphth[2¢,3¢:4,5]imidazo[1,2-
a]pyridine (B13). 1H NMR (300 MHz, CDCl3): d 2.07–2.10
(m, 2H, CH2), 2.69 (t, 2H, CH2), 3.21 (t, 2H, CH2), 4.85 (s,
1H, CH), 5.47 (s, 1H, CH), 7.41–7.43 (m, 2H, ArH), 7.91–7.98
(m, 2H, ArH), 8.08 (s, 1H, ArH), 8.13 (s, 1H, ArH); 13C NMR
(100 MHz, CDCl3): d 21.0, 26.2, 31.7, 96.2, 109.1, 115.9, 124.0,
124.4, 127.9, 128.1, 130.4, 130.4, 132.9, 140.8, 143.3, 155.7; EI-
MS m/z 234 [M]+; HRMS (EI) calc. for C16H14N2 [M]+ 234.1157,
found 234.1150.
2,3-Dichloro-5-methyl-7H,9H-8-oxa-4b,10-diazabenz[a]azul-
ene (C22). 1H NMR (300 MHz, CDCl3): d 2.46 (s, 3H, CH3),
4.08–4.10 (d, J = 6.0 Hz, 2H, CH2), 4.75 (s, 2H, CH2), 5.77–5.81
(t, 1H, CH), 7.63 (s, 1H, ArH), 7.83 (s, 1H, ArH); 13C NMR
(100 MHz, CDCl3): d 20.3, 62.9, 63.9, 113.5, 117.5, 121.5, 127.0,
127.4, 132.6, 136.9, 142.4, 154.1; EI-MS m/z 268 [M]+; HRMS
(EI) calc. for C12H10Cl2N2O [M]+ 268.0170, found 268.0179.
1-[1-Phenyl-meth-(Z)-ylidene]-1,2,3,4-tetrahydronaphth-
[2¢,3¢:4,5]imidazo[1,2-a]pyridine (B14). 1H NMR (300 MHz,
CDCl3): d 2.25–2.33 (m, 2H, CH2), 2.72 (t, 2H, CH2), 3.37 (t,
2H, CH2), 6.36 (s, 1H, CH), 6.66 (s, 1H, ArH), 7.01–7.04 (m,
2H, ArH), 7.09–7.11 (m, 3H, ArH), 7.23–7.25 (m, 1H, ArH),
7.27–7.40 (m, 2H, ArH), 7.90–7.93 (d, J = 7.8 Hz, 1H, ArH),
8.09 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 21.3, 25.1,
33.2, 110.7, 114.6, 115.2, 123.6, 123.9, 127.1, 127.9, 127.9, 128.1,
128.5, 128.8, 129.6, 130.0, 132.9, 135.4, 143.3, 156.8; EI-MS m/z
310 [M]+; HRMS (EI) calc. for C22H18N2 [M]+ 310.1470, found
310.1470.
4-[1-Phenyl-meth-(Z)-ylidene]-3,4-dihydro-1H-2-oxa-4a,9-
diazafluorene (B23). 1H NMR (300 MHz, CDCl3): d 4.46 (s,
2H, CH2), 5.24 (s, 2H, CH2), 6.21–6.24 (d, J = 8.4 Hz, 1H, ArH),
6.38 (s, 1H, CH), 6.80–6.86 (t, 1H, ArH), 7.10–7.23 (m, 6H,
ArH), 7.66–7.69 (d, J = 8.1 Hz, 1H, ArH); 13C NMR (100 MHz,
CDCl3): d 65.3, 70.4, 114.1, 116.2, 119.3, 122.1, 122.9, 128.0,
128.4, 128.5, 129.2, 131.0, 134.4, 143.5, 148.3; EI-MS m/z 262
[M]+; HRMS (EI) calc. for C17H14N2O [M]+ 262.1106, found
262.1097.
5-Phenyl-7H,9H-8-oxa-4b,10-diazabenz[a]azulene
(C23).
1H NMR (300 MHz, CDCl3): d 4.18–4.20 (d, J = 6.9 Hz, 2H,
CH2), 4.94 (s, 2H, CH2), 6.24 (t, 1H, CH), 6.50–6.53 (d, J =
8.1 Hz, 1H, ArH), 7.02–7.07 (t, 1H, ArH), 7.23–7.28 (t, 1H,
ArH), 7.34–7.47 (m, 5H, ArH), 7.80–7.83 (d, J = 8.1 Hz, 1H,
ArH); 13C NMR (100 MHz, CDCl3): d 62.7, 63.0, 112.9, 117.3,
120.5, 123.3, 127.4, 128.9, 130.1, 133.75, 133.84, 142.2, 143.0,
152.8; EI-MS m/z 262 [M]+; HRMS (EI) calc. for C17H14N2O
[M]+ 262.1106, found 262.1104.
7H,9H-8-Oxa-4b,10-diaza-benz[a]azulene (C17). 1H NMR
(300 MHz, CDCl3): d 4.61–4.63 (m, 2H, CH2), 4.99 (s, 2H, CH2),
5.39–5.44 (m, 1H, CH), 6.94–6.98 (d, J = 9.9 Hz, 1H, CH),
7.29–7.41 (m, 3H, ArH), 7.72–7.75 (m, 1H, ArH); 13C NMR
(100 MHz, CDCl3): d 68.2, 71.6, 109.1, 115.5, 119.6, 120.1,
122.9, 123.6, 134.3, 142.2, 153.5; EI-MS m/z 186 [M]+; HRMS
(EI) calc. for C11H10N2O [M]+ 186.0793, found 186.0791.
2,3-Dimethyl-7H,9H-8-oxa-4b,10-diazabenz[a]azulene (C18).
1H NMR (300 MHz, CDCl3): d 2.37 (s, 3H, CH3), 2.39 (s, 3H,
CH3), 4.60–4.62 (m, 2H, CH), 4.96 (s, 2H, CH2), 5.33–5.39 (m,
1H, CH), 6.88–6.93 (m, 1H, CH), 7.15 (s, 1H, ArH), 7.48 (s,
1H, ArH); 13C NMR (100 MHz, CDCl3): d 20.2, 20.6, 68.3,
71.6, 109.4, 114.8, 119.8, 120.1, 131.7, 132.7, 132.9, 140.7, 152.6;
4-[1-(2-Trifluoromethyl-phenyl)-meth-(Z)-ylidene]-3,4-dihy-
dro-1H-2-oxa-4a,9-diazafluorene (B24). 1H NMR (300 MHz,
CDCl3): d 4.53 (s, 2H, CH2), 5.24 (s, 2H, CH2), 6.06–6.09 (d,
J = 8.4 Hz, 1H, ArH), 6.57 (s, 1H, CH), 6.75–6.80 (t, 1H, ArH),
6.97–7.10 (d, J = 7.8 Hz, 1H, ArH), 7.10–7.18 (m, 2H, ArH),
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7.31–7.36 (t, 1H, ArH), 7.64–7.66 (d, J = 8.4 Hz 1H, ArH), 7.77–
7.79 (d, J = 8.1 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3):
d 65.3, 70.3, 111.7, 112.9, 119.3, 122.3, 123.0, 124.1 (d, J =
271.9 Hz), 126.1 (d, J = 5.0 Hz), 127.9, 128.0 (d, J = 29.6 Hz),
130.5, 130.9, 131.2, 131.7, 133.0, 143.3, 148.5; EI-MS m/z 330
[M]+; HRMS (EI) calc. for C18H13F3N2O [M]+ 330.0980, found
330.0977.
8H,10H-9-Oxa-5b,11-diazanaphth[2,3-a]azulene (C27). 1H
NMR (300 MHz, CDCl3): d 4.66–4.67 (m, 2H, CH2), 5.05 (s, 2H,
CH2), 5.41–5.47 (m, 1H, CH), 7.05–7.10 (m, 1H, CH), 7.41–7.50
(m, 2H, ArH), 7.79 (s, 1H, ArH), 7.94–8.02 (m, 2H, ArH), 8.20
(s, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 68.5, 71.9, 105.2,
114.7, 117.3, 119.7, 124.0, 124.9, 127.5, 128.6, 130.5, 130.8; ESI-
MS m/z 237 [M + H]+; HRMS (ESI) calc. for C15H13N2O [M +
H]+ 237.1028, found 237.1022.
5-(2-tert-Butyl-phenyl)-7H,9H-8-oxa-4b,10-diazabenz[a]azul-
ene (C24). 1H NMR (300 MHz, CDCl3): d 4.42–4.44 (d, J =
5.4 Hz, 2H, CH2), 5.00 (s, 2H, CH2), 5.91 (t, 1H, CH), 6.15–6.18
(d, J = 8.4 Hz, 1H, ArH), 6.92–6.98 (t, 1H, ArH), 7.17–7.22 (t,
1H, ArH), 7.47–7.50 (m, 1H, ArH), 7.62–7.66 (m, 2H, ArH),
7.73–7.77 (m, 1H, ArH), 7.79–7.82 (m, 1H, ArH); 13C NMR
(100 MHz, CDCl3): d 64.2, 65.9, 111.7, 120.4, 120.9, 122.8,
123.46, 123.5 (d, J = 272.3 Hz), 127.2 (d, J = 5.0 Hz), 129.0
(d, J = 30.6 Hz), 129.9, 131.9, 132.3, 134.1, 134.3, 136.7, 142.8,
152.9; EI-MS m/z 330 [M]+; HRMS (EI) calc. for C18H13F3N2O
[M]+ 330.0980, found 330.0975.
Acknowledgements
We gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China (Grants 20721003,
81025017 and 20872153) and National S&T Major Projects
(2009ZX09301-001, 2009ZX09501-001 and 2009ZX09501-
010).
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CDCl3): d 4.50 (s, 2H, CH2), 5.24 (s, 2H, CH2), 6.17–6.19 (m, 1H,
ArH), 6.40 (s, 1H, CH), 6.85–6.90 (t, 1H, ArH), 7.18–7.23 (m,
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ArH); 13C NMR (100 MHz, CDCl3): d 65.3, 70.3, 113.8, 114.4,
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5-(4-Trifluoromethyl-phenyl)-7H,9H -8-oxa-4b,10-diaza-
benz[a]azulene (C25). 1H NMR (300 MHz, CDCl3): d 4.25 (d,
J = 6.6 Hz, 2H, CH2), 4.96 (s, 2H, CH2), 6.31 (t, 1H, CH), 6.46–
6.48 (d, J = 7.8 Hz, 1H, ArH), 7.06–7.12 (t, 1H, ArH), 7.29–7.32
(m, 1H, ArH), 7.48–7.51 (d, J = 8.4 Hz, 2H, ArH), 7.68–7.71
(d, J = 8.1 Hz, 2H, ArH), 7.83–7.85 (d, J = 8.1 Hz, 1H, ArH);
13C NMR (100 MHz, CDCl3): d 63.0, 63.3, 112.6, 119.6, 120.7,
123.3, 123.6, 126.0 (d, J = 3.7 Hz), 127.7, 137.4, 140.5, 143.1,
152.7; EI-MS m/z 330 [M]+; HRMS (EI) calc. for C18H13F3N2O
[M]+ 330.0980, found 330.0979.
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4-[1-(4-Chloro-phenyl)-meth-(Z)-ylidene]-3,4-dihydro-1H-2-
oxa-4a,9-diazafluorene (B26). 1H NMR (300 MHz, CDCl3): d
4.46 (s, 2H, CH2), 5.24 (s, 2H, CH2), 6.26–6.28 (d, J = 8.1 Hz,
1H, ArH), 6.32 (s, 1H, CH), 6.90–6.95 (t, 1H, ArH), 7.03–7.06
(d, J = 8.4 Hz, 2H, ArH), 7.18–7.23 (m, 3H, ArH), 7.70–7.72
(d, J = 7.8 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 65.3,
70.3, 114.0, 114.9, 119.5, 122.3, 123.1, 128.6, 128.9, 130.5, 132.7,
133.8; EI-MS m/z 296 [M]+; HRMS (EI) calc. for C17H13ClN2O
[M]+ 296.0716, found 296.0718.
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5-(4-Chloro-phenyl)-7H,9H-8-oxa-4b,10-diazabenz[a]azulene
(C26). 1H NMR (300 MHz, CDCl3): d 4.19–4.21 (d, J = 7.2 Hz,
2H, CH2), 4.94 (s, 2H, CH2), 6.24 (t, 1H, CH), 6.53–6.55 (d, J =
8.1 Hz, 1H, ArH), 7.06–7.11 (t, 1H, ArH), 7.27–7.33 (m, 3H,
ArH), 7.38–7.42 (m, 2H, ArH), 7.82–7.85 (d, J = 8.4 Hz, 1H,
ArH); 13 C NMR (100 MHz, CDCl3): d 62.75, 63.0, 112.8, 117.8,
120.6, 123.2, 123.5, 128.7, 129.3, 132.3, 136.1, 141.0, 143.0; EI-
MS m/z 296 [M]+; HRMS (EI) calc. for C17H13ClN2O [M]+
296.0716, found 296.0718.
404 | Green Chem., 2011, 13, 397–405
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