Copper-catalyzed cascade synthesis of alkyl 6-aminobenzimidazo[2,1-a] isoquinoline-5-carboxylates

Article abstract of DOI:10.1021/jo200508q

A convenient and efficient copper-catalyzed cascade method has been developed for synthesis of benzimidazoisoquinoline derivatives via reactions of readily available substituted 2-(2-halophenyl)benzoimidazoles with alkyl cyanoacetates under mild condition

Full text of DOI:10.1021/jo200508q

ARTICLE
pubs.acs.org/joc
Copper-Catalyzed Cascade Synthesis of Alkyl
6-Aminobenzimidazo[2,1-a]isoquinoline-5-carboxylates
Juyou Lu and Hua Fu*
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. China
S Supporting Information
b
ABSTRACT:
A convenient and efficient copper-catalyzed cascade method has been developed for synthesis of benzimidazoisoquinoline
derivatives via reactions of readily available substituted 2-(2-halophenyl)benzoimidazoles with alkyl cyanoacetates under mild
condition, and the corresponding alkyl 6-aminobenzimidazo[2,1-a]isoquinoline-5-carboxylates were obtained in good to excellent
yields. The novel method provides diverse and useful poly N-heterocyclic compounds for combinatorial chemistry and medicinal
chemistry.
’ INTRODUCTION
N-Heterocycles widely occur in natural products and biologically
active molecules and play important roles in the pharmaceutical and
agrochemical industries.1 The benzimidazole derivatives have at-
tracted much attention for their wide applications as the enzyme
inhibitors,2 drugs,3 dyes,4 and polymers.5 The isoquinoline deriva-
tives are an important class of alkaloids commonly found in natural
Figure 1. Benzimidazoisoquinoline as hybrid structure of isoquinoline
products6 and are often used as building blocks in pharmaceutical
and benzoimidazole.
compounds.7 For example, they were applied as potential PET
radioligands for imaging peripheral benzodiazepine receptor8a and
Recently, there has been a great progress in copper-catalyzed
cross-coupling reactions.11,12 Their application to the construc-
as orally bioavailable Kv1.5 antagonists for the treatment of atrial
fibrillation.8b The hybrid structures of benzimidazole and isoquino-
line frameworks, benzimidazoisoquinoline derivatives (Figure 1),
show important biological activities, such as anti-HIV-1, anticancer,
antimicrobial, and antifungal properties.9 However, few syntheses of
benzimidazoisoquinolines have been reported to date.10 Dyker and
co-workers have developed reactions of 2-alkynylbenzaldehydes
with o-phenylenediamine in nitrobenzene at 150 °C for 2 d to lead
to benzimidazoisoquinoline derivatives.10a Yanada et al. reported a
palladium-catalyzed approach under microwave irradiation.10b The
methods have harsh reaction conditions and limited substrate
scopes that greatly restrict screening and discovery of potent
biologically active molecules. Very recently, an efficient copper-
catalyzed benzimidazoisoquinolines has been developed via reac-
tions of various 2-ethynylbenzaldehydes and benzenediamines in
the presence of NBS or I2.10c We realize that the benzimidazoiso-
quinolines containing amino and carboxylate groups can be useful
biologically active molecules and intermediates. However, there is
not an efficient method for their synthesis thus far.
tion of N-heterocycles has been reported by us13 and other
research groups.14 Herein, we report a convenient and efficient
copper-catalyzed cascade synthesis of alkyl 6-aminobenzimi-
dazo[2,1-a]isoquinoline-5-carboxylates through reactions of
substituted 2-(2-halophenyl)benzoimidazoles with alkyl cyanoa-
cetates under mild condition.
’ RESULTS AND DISCUSSION
As shown in Table 1, 2-(2-bromophenyl)benzoimidazole (1a)
and ethyl 2-cyanoacetate (2b) were chosen as the model sub-
strates to optimize reaction conditions including catalysts,
ligands, bases, solvents, and temperature under nitrogen atmo-
sphere. First, copper catalysts (0.1 equiv) were investigated
by using 0.2 equiv of pipecolinic acid as the ligand, 2 equiv
of Cs2CO3 as the base, and DMSO as the solvent at 60 °C
Received: March 8, 2011
Published: April 26, 2011
r
2011 American Chemical Society
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Table 1. Copper-catalyzed Cascade Synthesis of Ethyl 6-Aminobenzimidazo[2,1-a]isoquinoline-5-carboxylate (3b) via Reaction
of 2-(2-Bromophenyl)-1H-benzo[d]imidazole (1a) with Ethyl 2-Cyanoacetate (2b): Optimization of Conditionsa
entry
catalyst
CuI
ligand
base
solvent
temp (°C)
yield (%)b
1
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
C
D
E
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KHCO3
Na2CO3
Li2CO3
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
50
80
60
56
46
45
45
12
41
8
2
CuBr
3
CuCl
4
Cu2O
5
Cu(OAc)2
CuCl2
CuO
6
7
8
CuSO4
5
9
0
10
11
12
13
14
16
17
18
19
20
21
22
23
24
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
50
22
81
27
14
20
50
25
10
5
DMA
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
trace
56
63
70c
A
A
A
a Reaction conditions: under nitrogen atmosphere, 2-(2-bromophenyl)-1H-benzo[d]imidazole (1a) (0.5 mmol), ethyl 2-cyanoacetate (2b) (1 mmol),
catalyst (0.05 mmol), ligand (0.1 mmol), base (1.0 mmol), solvent (2 mL), reaction time 12 h. b Isolated yield. c CuI (0.025 mmol).
(entries 1ꢀ8). CuI provided the highest yield (entry 1), and no
target product was observed in the absence of copper catalyst
(entry 9). DMF and DMA were also attempted as the solvents
(entries 10 and 11), and DMSO was best (compare entries 1, 10,
and 11). Several bases were assayed (entries 12ꢀ17), and K2CO3
provided the highest yield (entry 12). Other ligands were
screened (entries 18ꢀ21), and pipecolinic acid showed the
highest activity (compare entries 12, 18ꢀ21). We investigated
different reaction temperature (compare entries 12, 22, and 23),
and 60 °C was suitable (entry 12). When 5 mol % CuI was used
as the catalyst, a 70% yield was provided (entry 24).
The scope of copper-catalyzed cascade synthesis of benzimi-
dazoisoquinoline derivatives from reactions of substituted 2-(2-
halophenyl)benzoimidazoles with alkyl 2-cyanoacetates was in-
vestigated under the optimized conditions (0.1 equiv of CuI as
the catalyst, 0.2 equiv of pipecolinic acid as the ligand, 2 equiv of
K2CO3 as the base in DMSO under nitrogen atmosphere). As
shown in Table 2, the tested substrates afforded good to excellent
yields. The reactions provided benzimidazoisoquinolines with
amino and carboxylate groups, and the functional groups are
favor for further modification. In addition, the copper-catalyzed
cascade reactions above could tolerate functional groups such as
CꢀCl bond (entries 10ꢀ17), ether (entries 7ꢀ9, 17), and ester
groups (entries 1ꢀ17). We attempted scale-up reaction of 2-(2-
bromophenyl)benzoimidazole (1a) with ethyl 2-cyanoacetate
(2b), and a 76% yield was afforded (Scheme 1).
A possible mechanism for synthesis of benzimidazoisoquino-
line derivatives was proposed in Scheme 2. First, coordination of
pipecolinic acid with CuI provides complex CuL in the presence
of base (K2CO3). Treatment of substituted 2-(2-halophenyl)-
benzoimidazole (1) with CuL gives I, and oxidative addition of I
leads to II. Reaction of II with alkyl cyanoacetate provides C-
arylation intermediate III, and the intramolecular nucleophilic
attack of NH of benzoimidazole to CN in III affords the target
product (3).
We also attempted copper-catalyzed reaction of 2-(2-
bromophenyl)-1H-benzo[d]imidazole (1a) with phenylacety-
lene in DMF under similar conditions, and the cascade coupling
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Table 2. Copper-Catalyzed Cascade Synthesis of Benzimidazoisoquinolines with Amino and Carboxylate Groupsa
a Reaction conditions: under nitrogen atmosphere, 1 (0.5 mmol), 2 (1.0 mmol), CuI (0.05 mmol), pipecolinic acid (0.1 mmol), K2CO3 (1.0 mmol),
DMSO (2 mL), reaction time 12 h, reaction temperature 80 °C for entries 10ꢀ12; 60 °C for others. b Isolated yield.
provided product 4 in 65% yield (Scheme 3). Therefore, sub-
stituted 2-(2-halophenyl)benzoimidazoles (1) are good building
blocks for synthesis of poly N-heterocycles under copper catalysis.
(from reactions of substituted benzene-1,2-diamines with 2-ha-
loobenzoic acids in acid medium15), and alkyl cyanoacetates as
the starting materials. The copper-catalyzed reactions of substi-
tuted 2-(2-bromophenyl)benzoimidazoles with alkyl cyanoace-
tates proceeded very well under mild conditions, and the
corresponding benzimidazoisoquinolines with amino and carbox-
ylate groups were obtained in good to excellent yields. The novel
method provides diverse and useful poly N-heterocyclic com-
pounds for combinatorial chemistry and medicinal chemistry.
’ CONCLUSION
We have developed a convenient and efficient copper-cata-
lyzed cascade method for the synthesis of benzimidazoisoquino-
line derivatives. The protocol uses inexpensive CuI as the catalyst,
readily available substituted 2-(2-halophenyl)benzoimidazoles
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Scheme 1. Scale-up Reaction of 2-(2-Bromophenyl)benzoimidazole (1a) and Ethyl 2-Cyanoacetate (2b)
Scheme 2. Possible Copper-Catalyzed Mechanism for Synthesis of Benzimidazoisoquinoline Derivatives
Scheme 3. Copper-Catalyzed Reaction of 2-(2-
Bromophenyl)-1H-benzo[d]imidazole (1a) with
Phenylacetylene
’ EXPERIMENTAL SECTION
General Procedure for Synthesis of Compounds 3aꢀq.
Substituted 2-(2-halophenyl)benzoimidazole (1) (0.5 mmol), alkyl
cyanoacetate (2) (1 mmol), CuI (0.05 mmol, 10 mg), pipecolinic acid
(0.1 mmol, 13 mg), and K2CO3 (1.0 mmol, 138 mg) were added to a
10 mL two-neck round-bottom flask charged with a magnetic stirrer.
The flask was evacuated and backfilled with nitrogen, and then DMSO
(2.0 mL) was added to the flask under a stream of nitrogen. The mixture
was stirred at 60 or 80 °C under nitrogen atmosphere for 12 h. After
completion of the reaction, the resulting solution was cooled to room
temperature. The solvent was removed with the aid of a rotary
evaporator, and the residue was purified by column chromatography
on silica gel to provide the desired product (3aꢀq).
149.4, 148.2, 144.6, 131.0, 130.4, 129.9, 125.2, 125.1, 125.0, 124.1, 122.2,
120.1, 118.1, 113.2, 88.7, 61.0, 14.5. HR-MS [M þ H]þ m/z calcd for
C18H16N3O2 306.1243, found 306.1234.
3a. Eluent: petroleum ether/ethyl acetate (10:1). Yield 75% (109
mg). Yellow solid, mp 194ꢀ195 °C. 1H NMR (CDCl3, 300 MHz, ppm)
δ 8.70 (d, 1H, J = 6.8 Hz), 8.46 (d, 1H, J = 8.6 Hz), 7.99 (s, 1H), 7.96 (s,
1H), 7.61ꢀ7.33 (m, 6H), 4.00 (s, 3H). 13C NMR (CDCl3, 75 MHz,
ppm) δ 168.8, 148.5, 147.3, 143.8, 129.9, 129.6, 128.9, 124.3, 124.2,
124.1, 123.3, 121.4, 119.3, 117.2, 112.1, 87.6, 50.7. HR-MS [M þ H]þ
m/z calcd for C17H14N3O2 292.1086, found 292.1085.
3b. Eluent: petroleum ether/ethyl acetate (10:1). Yield 81% (124
mg). Yellow solid, mp 154ꢀ156 °C. 1H NMR (CDCl3, 300 MHz, ppm)
δ 8.52 (d, 1H, J = 7.6 Hz), 8.32 (d, 1H, J = 8.6 Hz), 7.80 (d, 1H, J = 8.2
Hz), 7.72 (d, 1H, J = 8.2 Hz), 7.45ꢀ7.09 (m, 6H), 4.33 (q, 2H, J = 7.2
Hz), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz, ppm) δ 169.2,
3c. Eluent: petroleum ether/ethyl acetate (10:1). Yield 78% (130 mg).
1
Yellow solid, mp 148ꢀ150 °C. H NMR (CDCl3, 300 MHz, ppm)
δ 8.60 (d, 1H, J = 7.9 Hz), 8.40 (d, 1H, J = 8.6 Hz), 7.87 (d, 1H, J = 8.2
Hz), 7.83 (d, 1H, J = 8.6 Hz), 7.52ꢀ7.18 (m, 6H), 4.33 (t, 2H, J = 6.8
Hz), 1.82ꢀ1.75 (m, 2H), 1.54ꢀ1.46 (m, 2H), 1.00 (t, 3H, J = 7.2 Hz).
13C NMR (CDCl3, 75 MHz, ppm) δ 169.4, 149.5, 148.3, 144.8, 131.2,
130.5, 129.9, 125.3, 125.2, 125.1, 124.3, 122.2, 120.2, 118.2, 113.2, 88.9,
66.1, 30.8, 19.6, 14.0. HR-MS [M þ H]þ m/z calcd for C20H20N3O2
334.1556, found 334.1553.
3d. Eluent: petroleum ether/ethyl acetate (10:1). Yield 80% (122 mg).
1
Yellow solid, mp 216ꢀ218 °C. H NMR (CDCl3, 300 MHz, ppm)
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δ 8.42 (s, 1H), 8.27 (d, 1H, J = 8.6 Hz), 7.93ꢀ7.89 (m, 2H), 7.46 (t, 1H,
J = 7.9 Hz), 7.34ꢀ7.26 (m, 4H), 3.94 (s, 3H), 2.43 (s, 3H). 13C NMR
(CDCl3, 75 MHz, ppm) δ 169.8, 149.2, 148.4, 144.8, 134.2, 132.2, 130.0,
128.5, 125.3, 125.2, 124.8, 122.3, 120.3, 118.2, 113.3, 88.9, 51.7, 20.9. HR-
MS [M þ H]þ m/z calcd for C18H16N3O2 306.1243, found 306.1245.
3e. Eluent: petroleum ether/ethyl acetate (10:1). Yield 88% (140
mg). Yellow solid, mp 143ꢀ145 °C. 1H NMR (CDCl3, 300 MHz, ppm)
δ 8.38 (s, 1H), 8.30 (d, 1H, J = 8.6 Hz), 7.88 (t, 2H, J = 8.2 Hz), 7.42
(t, 1H, J = 7.6 Hz), 7.32ꢀ7.24 (m, 4H), 4.39 (q, 2H, J = 7.2 Hz), 2.41
(s, 3H), 1.45 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz, ppm)
δ 169.4, 149.1, 148.3, 144.8, 134.1, 132.1, 130.0, 128.7, 125.3, 125.2,
124.7, 122.2, 120.2, 118.2, 113.3, 89.0, 61.0, 20.9, 14.5. HR-MS
[M þ H]þ m/z calcd for C19H18N3O2 320.1399, found 320.1402.
3f. Eluent: petroleum ether/ethyl acetate (10:1). Yield 71% (123 mg).
3l. Eluent: petroleum ether/ethyl acetate (10:1). Yield 95% (174
mg). Yellow solid, mp 208ꢀ210 °C. 1H NMR (CDCl3, 300 MHz, ppm)
δ 8.66 (d, 1H, J = 2.4 Hz), 8.45 (d, 1H, J = 9.2 Hz), 7.97 (dd, 2H, J = 8.2
Hz, 2.4 Hz), 7.56ꢀ7.39 (m, 5H), 4.42 (t, 2H, J = 6.5 Hz), 1.86ꢀ1.81 (m,
2H), 1.56ꢀ1.51 (m, 2H), 1.02 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75
MHz, ppm) δ 169.3, 149.6, 147.3, 144.9, 130.8, 130.1, 130.0, 129.6,
127.1, 125.7, 124.4, 122.9, 120.7, 119.5, 113.2, 88.5, 65.2, 30.9, 19.6, 13.9.
HR-MS [M þ H]þ m/z calcd for C20H19ClN3O2 368.1166, found
368.1169.
3m. Eluent: petroleum ether/ethyl acetate (10:1). Yield 82% (147
1
mg). Yellow solid, mp 263ꢀ265 °C. H NMR (DMSO-d6, 600 MHz,
ppm) δ 8.64 (s, 1H), 8.52 (d, 1H, J = 7.6 Hz), 8.36 (d, 1H, J = 8.2 Hz),
8.08 (s, 1H), 7.89 (s, br, 2H), 7.63 (t, 1H, J = 7.6 Hz), 7.41 (t, 1H, J = 7.6
Hz), 3.97 (s, 3H). 13C NMR (DMSO-d6, 150 MHz, ppm) δ 169.0,
150.1, 148.9, 144.5, 131.9, 131.6, 129.8, 128.4, 125.3, 124.7, 124.6, 120.5,
117.7, 117.2, 89.8, 52.3. HR-MS [M þ H]þ m/z calcd for
C17H12Cl2N3O2 360.0307, found 360.0310.
1
Yellow solid, mp 176ꢀ178 °C. H NMR (CDCl3, 300 MHz, ppm)
δ 8.41 (s, 1H), 8.31 (d, 1H, J = 8.6 Hz), 7.92ꢀ7.88 (m, 2H), 7.44 (t, 1H,
J = 7.6 Hz), 7.34ꢀ7.23 (m, 4H), 4.35 (t, 2H, J = 6.5 Hz), 2.43 (s, 3H),
1.83ꢀ1.78 (m, 2H), 1.55ꢀ1.47 (m, 2H), 1.01 (t, 3H, J = 7.2 Hz). 13C
NMR (CDCl3, 75 MHz, ppm) δ 169.5, 149.1, 148.3, 144.8, 134.1, 132.1,
130.1, 128.7, 125.3, 124.7, 122.2, 120.2, 118.2, 113.3, 89.1, 65.0, 30.8,
20.9, 19.6, 13.9. HR-MS [M þ H]þ m/z calcd for C21H22N3O2
348.1712, found 348.1715.
3n. Eluent: petroleum ether/ethyl acetate (10:1). Yield 80% (149 mg).
1
Yellow solid, mp 258ꢀ259 °C. H NMR (CDCl3, 300 MHz, ppm) δ
8.63 (d, 1H, J = 8.2 Hz), 8.51 (d, 1H, J = 8.6 Hz), 8.13 (s, 1H), 8.00
(s, 1H), 7.60 (t, 1H, J = 8.2 Hz), 7.44 (t, 1H, J = 7.2 Hz), 7.17 (s, br, 2H),
4.52 (q, 2H, J = 7.2 Hz), 1.51 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75
MHz, ppm) δ 169.1, 150.0, 148.5, 144.4, 131.3, 129.8, 129.1, 126.0,
125.6, 125.5, 124.9, 121.2, 118.2, 114.8, 90.6, 61.4, 14.5. HR-MS
[M þ H]þ m/z calcd for C18H14Cl2N3O2 374.0463, found 374.0467.
3o. Eluent: petroleum ether/ethyl acetate (10:1). Yield 75% (150 mg).
3g. Eluent: petroleum ether/ethyl acetate (10:1). Yield 81% (130 mg).
1
Yellow solid, mp 206ꢀ208 °C. H NMR (CDCl3, 300 MHz, ppm)
δ 8.42 (d, 1H, J = 9.2 Hz), 8.11ꢀ8.00 (m, 3H), 7.55 (t, 1H, J = 7.9 Hz),
7.40 (t, 1H, J = 7.9 Hz), 7.33 (s, br, 2H), 7.22 (dd, 1H, J = 9.2 Hz, 2.7
Hz), 4.01 (s, 3H), 3.99 (s, 3H). 13C NMR (CDCl3, 75 MHz, ppm) δ
169.9, 156.7, 148.4, 148.3, 144.8, 130.3, 127.3, 125.5, 124.9, 122.5, 121.1,
120.5, 119.5, 113.5, 105.4, 89.3, 55.8, 51.9. HR-MS [M þ H]þ m/z calcd
for C18H16N3O3 322.1192, found 322.1191.
1
Yellow solid, mp 251ꢀ252 °C. H NMR (CDCl3, 300 MHz, ppm) δ
8.51 (d, 1H, J = 7.2 Hz), 8.41 (d, 1H, J = 8.6 Hz), 7.99 (s, 1H), 7.88
(s, 1H), 7.56 (t, 1H, J = 7.2 Hz), 7.36 (t, 1H, J = 7.2 Hz), 7.08 (s, br, 2H),
4.42 (t, 2H, J = 6.5 Hz), 1.88ꢀ1.83 (m, 2H), 1.56ꢀ1.51 (m, 2H), 1.03
(t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz, ppm) δ 169.1, 149.7,
148.5, 144.2, 131.2, 129.6, 128.9, 125.8, 125.5, 125.2, 124.8, 120.9, 117.9,
114.7, 90.6, 65.4, 30.8, 19.6, 13.9. HR-MS [M þ H]þ m/z calcd for
C20H18Cl2N3O2 402.0776, found 402.0772.
3h. Eluent: petroleum ether/ethyl acetate (10:1). Yield 86% (144 mg).
1
Yellow solid, mp 189ꢀ191 °C. H NMR (CDCl3, 300 MHz, ppm) δ
8.40 (d, 1H, J = 9.6 Hz), 8.03 (d, 1H, J = 2.7 Hz), 7.97 (t, 2H, J = 7.9 Hz),
7.49 (t, 1H, J = 7.6 Hz), 7.33 (t, 1H, J = 7.9 Hz), 7.21 (s, br, 2H), 7.17
(dd, 1H, J = 9.2 Hz, 2.7 Hz), 4.45 (q, 2H, J = 7.2 Hz), 3.95 (s, 3H), 1.47
(t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz, ppm) δ 169.4, 156.5,
148.2, 148.1, 144.8, 130.2, 127.1, 125.4, 125.0, 122.4, 120.9, 120.3, 119.5,
113.5, 105.2, 89.3, 61.1, 55.7, 14.5. HR-MS [M þ H]þ m/z calcd for
C19H18N3O3 336.1348, found 336.1342.
3p. Eluent: petroleum ether/ethyl acetate (10:1). Yield 86% (178 mg).
Yellow solid, mp 268ꢀ270 °C. 1H NMR (DMSO-d6, 600 MHz, ppm) δ
8.59 (s, 1H), 8.24 (d, 2H, J = 8.9 Hz), 8.00 (s, 1H), 7.80 (s, br, 2H), 7.40
(d, 2H, J = 8.2 Hz), 4.38 (t, 2H, J = 6.2 Hz), 2.42 (s, 3H), 1.79ꢀ1.77
(m, 2H), 1.49ꢀ1.47 (m, 2H), 0.98 (t, 3H, J = 7.6 Hz). 13C NMR
(DMSO-d6, 150 MHz, ppm) δ 168.7, 149.9, 148.5, 144.5, 134.0, 132.9,
129.8, 129.6, 128.2, 125.3, 124.8, 124.5, 120.3, 117.7, 117.1, 89.8, 65.0,
30.8, 20.9, 19.6, 14.0. HR-MS [M þ H]þ m/z calcd for C21H20Cl2N3O2
416.0933, found 416.0935.
3q. Eluent: petroleum ether/ethyl acetate (10:1). Yield 88% (177 mg).
Yellow solid, mp 255ꢀ256 °C. 1H NMR (DMSO-d6, 600 MHz, ppm) δ
8.60 (s, 1H), 8.32 (d, 1H, J = 8.9 Hz), 8.04 (s, 1H), 7.88 (d, 1H, J = 2.7
Hz), 7.68 (s, br, 2H), 7.24 (dd, 1H, J = 9.6 Hz, 2.7 Hz), 4.44 (q, 2H,
J = 7.6 Hz), 3.90 (s, 3H), 1.42 (t, 3H, J = 7.6 Hz). 13C NMR (DMSO-d6,
150 MHz, ppm) δ 168.5, 156.5, 149.5, 147.7, 144.4, 129.9, 128.3, 127.3,
125.7, 124.5, 121.1, 120.3, 118.8, 117.2, 106.2, 90.1, 61.2, 55.9, 14.7. HR-
MS [M þ H]þ m/z calcd for C19H16Cl2N3O3 404.0569, found
404.0571.
Synthesis of Compound 4. 2-(2-Bromophenyl)benzoimidazole
(1a) (0.5 mmol, 137 mg), phenylacetylene (1 mmol, 102 mg), CuI (0.05
mmol, 10 mg), pipecolinic acid (0.1 mmol, 13 mg), and K2CO3 (1.0
mmol, 138 mg) were added to a 10 mL two-neck round-bottom flask
charged with a magnetic stirrer. The flask was evacuated and backfilled
with nitrogen, and then DMF (2.0 mL) was added to the flask under a
stream of nitrogen. The mixture was stirred at 100 °C under nitrogen
atmosphere for 12 h. After completion of the reaction, the resulting
solution was cooled to room temperature. The solvent was removed
with the aid of a rotary evaporator, and the residue was purified by
column chromatography on silica gel to provide the desired product 4.
Eluent: petroleum ether/ethyl acetate (10:1). Yield 65% (96 mg).
3i. Eluent: petroleum ether/ethyl acetate (10:1). Yield 85% (154 mg).
1
Yellow solid, mp 165ꢀ166 °C. H NMR (CDCl3, 300 MHz, ppm) δ
8.47 (d, 1H, J = 9.2 Hz), 8.12 (d, 1H, J = 3.1 Hz), 8.09 (d, 1H, J = 8.2 Hz),
8.02 (d, 1H, J = 8.2 Hz), 7.55 (t, 1H, J = 7.6 Hz), 7.42 (t, 1H, J = 7.6 Hz),
7.32 (s, br, 2H), 7.22 (dd, 1H, J = 9.2 Hz, 2.7 Hz), 4.45 (t, 2H, J = 6.5
Hz), 3.99 (s, 3H), 1.88ꢀ1.88 (m, 2H), 1.57ꢀ1.50 (m, 2H), 1.01 (t, 3H,
J = 7.6 Hz). 13C NMR (CDCl3, 75 MHz, ppm) δ 169.6, 156.6, 148.3,
144.9, 130.3, 127.3, 125.5, 125.1, 122.5, 121.0, 120.4, 119.6, 113.5, 105.4,
89.6, 65.1, 55.8, 30.9, 19.6, 13.9. HR-MS [M þ H]þ m/z calcd for
C21H22N3O3 364.1661, found 364.1662.
3j. Eluent: petroleum ether/ethyl acetate (10:1). Yield 89% (145 mg).
1
Yellow solid, mp 246ꢀ248 °C. H NMR (CDCl3, 300 MHz, ppm) δ
8.67 (d, 1H, J = 2.0 Hz), 8.43 (d, 1H, J = 9.2 Hz), 7.99 (d, 2H, J = 8.2 Hz),
7.56ꢀ7.41 (m, 5H), 4.01 (s, 3H). 13C NMR (CDCl3, 75 MHz, ppm) δ
169.7, 149.8, 147.4, 130.9, 130.2, 130.1, 129.5, 127.2, 125.8, 124.5, 123.0,
120.8, 119.5, 113.2, 88.3, 52.0. HR-MS [M þ H]þ m/z calcd for
C17H13ClN3O2 326.0696, found 326.0698.
3k. Eluent: petroleum ether/ethyl acetate (10:1). Yield 93% (158 mg).
1
Yellow solid, mp 212ꢀ214 °C. H NMR (CDCl3, 300 MHz, ppm) δ
8.54 (d, 1H, J = 1.7 Hz), 8.37 (d, 1H, J = 9.2 Hz), 7.89 (t, 2H, J = 7.9 Hz),
7.51ꢀ7.32 (m, 5H), 4.44 (q, 2H, J = 7.2 Hz), 1.47 (t, 3H, J = 7.2 Hz). 13C
NMR (CDCl3, 75 MHz, ppm) δ 169.0, 149.6, 147.1, 144.8, 130.7, 130.0,
129.9, 129.5, 126.9, 125.6, 124.2, 122.8, 120.6, 119.3, 113.2, 88.3, 61.2,
14.5. ESI-MS [M þ H]þ m/z 340.2. HR-MS [M þ H]þ m/z calcd for
C18H15ClN3O2 340.0853, found 340.0852.
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dx.doi.org/10.1021/jo200508q |J. Org. Chem. 2011, 76, 4600–4605

The Journal of Organic Chemistry
ARTICLE
1
Yellow solid, mp 198ꢀ200 °C. H NMR (CDCl3, 300 MHz, ppm) δ
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8.89 (d, 1H, J = 8.6 Hz), 7.99 (d, 1H, J = 7.9 Hz), 7.71ꢀ7.59 (m, 8H),
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’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dures, characterization data, and 1H, 13C NMR spectra of these
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: fuhua@mail.tsinghua.edu.cn.
’ ACKNOWLEDGMENT
The authors wish to thank the National Natural Science
Foundation of China (Grant No. 20972083), and the Ministry
of Science and Technology of China (2009ZX09501-004) for
financial support.
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