Copper-catalyzed domino addition/double cyclization: An approach to polycyclic benzimidazole derivatives

Article abstract of DOI:10.1021/jo402742k

An efficient and versatile method for the assembly of novel polycyclic benzimidazole derivatives has been developed by Cu-catalyzed domino addition/double cyclization reactions. A wide variety of polycyclic benzimidazole derivatives, which might be used as synthetic medicines and functional materials, were successfully assembled from bis-(o-haloaryl) carbodiimides. Unexpected N-methylated benzo[4,5]imidazo[1,2-a]indoles can also be selectively assembled. Multibonds and polycyclic moieties were conveniently formed in one pot during these domino processes.

Full text of DOI:10.1021/jo402742k

Article
pubs.acs.org/joc
Copper-Catalyzed Domino Addition/Double Cyclization: An
Approach to Polycyclic Benzimidazole Derivatives
Guodong Yuan, Haiquan Liu, Jilong Gao, Kangjian Yang, Qingsheng Niu, Hui Mao, Xiaoxia Wang,
and Xin Lv*
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang Normal
University, Jinhua 321004, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient and versatile method for the
assembly of novel polycyclic benzimidazole derivatives has
been developed by Cu-catalyzed domino addition/double
cyclization reactions. A wide variety of polycyclic benzimida-
zole derivatives, which might be used as synthetic medicines
and functional materials, were successfully assembled from bis-
(o-haloaryl)carbodiimides. Unexpected N-methylated benzo-
[4,5]imidazo[1,2-a]indoles can also be selectively assembled.
Multibonds and polycyclic moieties were conveniently formed
in one pot during these domino processes.
employed as antibiotics and antiviral agents.8 Although these
fused benzimidazoles play important roles in medicinal
chemistry and material science, efficient and concise approaches
to these molecules have been rarely documented. The limited
INTRODUCTION
■
N-Heterocylic moieties widely exist in natural products,
pharmaceutical agents, and synthetic materials. Development
for efficient synthesis of diverse N-heterocylic derivatives is of
great interest in the field of organic chemistry.1 Among the N-
methods for the assembly of benzo[4,5]imidazo[1,2-a]imidazo-
[1,2-c]quinazolines (I) and benzo[4,5]imidazo[1,2-a]indoles
heterocyles, benzimidazoles are important because of their broad
(III)9 may suffer from the tedious steps, low efficiency, and/or
the narrow scopes, and there is no report about synthesis of
benzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazolines (II).
spectrum of biological activities2 and interesting material
applications.3 The synthesis of polycyclic benzimidazole
derivatives has attracted much attention, as is concluded from
their applications in the fields of medicinal chemistry4 and
organic material science.5
Catalytic domino reaction is an efficient and facile strategy for
one-step construction of molecular complexity.10 Because of
their high efficiency, low cost, and convenience, Cu-catalyzed
domino reactions have emerged as attractive protocols for
generating structurally diversified molecules.11 On the other
hand, Cu-mediated C−H functionalization12 and cross-cou-
pling13 have been applied as powerful tools for the assembly of
heterocycles via domino processes.11b,c,13a Notably, although
great achievements have been accomplished in the C−H
functionalization using transition-metal catalysis, only limited
domino approaches to N-heterocyles through Cu-catalyzed
intramolecular direct sp2 C−H arylation of azoles have been
developed thus far.14 And to the best of our knowledge, there is
no report about the one-pot multibond-forming elaboration of
benzo[4,5]imidazo[1,2-a]indoles and azole-fused benzo[4,5]-
imidazo[1,2-a]quinazolines. As part of our ongoing efforts to
assemble N-heterocycles using Cu-mediated domino proto-
cols,15 we report on a novel Cu-catalyzed domino synthesis of the
The combination of benzimidazole, quinazoline, and azole
moieties leads to the azole-fused benzimidazoquinazolines
(Figure 1, I and II). Such heterocycles have aroused considerable
interest in the field of organic light-emitting devices (OLEDs).6
Imidazo[1,2-c]quinazoline derivatives are also useful in
pharmaceutical areas for their antimicrobial, antitumor, and
antipsychotic activities.7 Benzo[4,5]imidazo[1,2-a]indoles (III),
which incorporate imidazole and indole frameworks, might be
Received: December 11, 2013
Published: February 3, 2014
Figure 1. Structures of the target polycyclic benzimidazole derivatives.
© 2014 American Chemical Society
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polycyclic benzimidazole derivatives from bis-(o-haloaryl)-
carbodiimides.16
(4.0 equiv) as base in dioxane at 110 °C. However, no desired
product was detected under these conditions (Table 1, entry 1).
K3PO4 also failed to show any improvement (entry 2). In light of
the previous methods developed for the intermolecular sp2 C−H
arylation of azoles,17 we also attempted to utilize strong bases to
facilitate the present domino transformation. To our delight,
when the base was replaced by t-BuOLi, the desired product
3a6a,18 was obtained in 21% yield (entry 3). Other bases such as t-
BuOK and mix bases are unsuitable (entries 4 and 5). A higher
yield was achieved when DMF was used as the solvent (entry 6).
Raising the temperature to 125 °C provided 3a in 75% yield
(entry 7). However, no obvious improvement was observed
when heated to 140 °C (entry 8). We examined different Cu
catalysts (entries 7, 9, and 10), and CuI proved to be the most
efficient. No desired product was observed in a control
experiment without the addition of Cu catalyst (entry 11).
Other ligands (BtOH, L-proline and 2,2′-bipy) were also
screened (entries 12−14), and 1,10-phen showed the best effect
(entry 7). We also investigated different organic solvent (entries
3, 7, 15, and 16) and identified DMF as the optimal solvent.19
After the optimized conditions had been established, the scope
of the domino synthesis was studied using a series of bis-(o-
halophenyl)carbodiimides and azoles. As shown in Table 2, a
variety of azoles smoothly reacted with bis-(o-iodophenyl)-
carbodiimides to afford the desired benzo[4,5]imidazo[1,2-
a]quinazolines in moderate to good yields. Azoles such as
imidazole, benzimidazoles, pyrazole, and indoles are compatible
with the reaction (entries 1−7).20,21 Benzimidazoles showed
higher efficiency in comparison with other azoles tested (entries
2 and 3). It is noticeable that indoles can also successfully deliver
corresponding benzo[4,5]imidazo[1,2-a]indolo-[1,2-c]-
quinazolines via addition/coupling/direct C2-arylation process
(entries 5−7). The bis-(o-iodophenyl)carbodiimides bearing
electron-donating group (p-Me) or electron-withdrawing group
(p-F) on the aryl rings seemed less reactive and gave moderate
yields (entries 8 and 10). Bis-(o-iodophenyl)carbodiimides 1c
with branched alkyl groups on the phenyl rings reacted smoothly
with benzimidazole 2b (entry 9). The use of substituted 2-
bromo-2′-iodo-diphenylcarbodiimide 1e successfully delivered
the desired product (entry 11), indicating that the intramolecular
sp2 C−H arylation of imidazole with aryl bromide also proceeded
smoothly under these conditions.
Having developed a novel domino method for the assembly of
benzo[4,5]imidazo[1,2-a]quinazolines, we then sought to
synthesize benzo[4,5]imidazo[1,2-a]indole derivatives by using
active methylene compounds as the nucleophiles. Initially, bis-(o-
iodophenyl)carbodiimide 1a and diethyl malonate 6a were used
as the starting materials, and the reaction was carried out under
the above optimized conditions (at 100 °C). However, no
desired product was observed. Shifting the base to K3PO4 and
replacing the ligand with 8-hydroquinoline gave the desired
product 7a in 21% yield. Other Cu catalysts such as CuCl and
CuBr showed less effective. Gratifyingly, with DMSO as the
solvent instead of DMF, the yield was remarkably improved
(88% yield).
The scope of this domino reaction was then explored under
the above modified conditions. As shown in Table 3, a range of
bis-(o-iodophenyl)carbodiimides and active methylene com-
pounds underwent the domino cyclization smoothly and deliver
the desired products 7 in moderate to good yields.22 Various
nucleophiles such as diethyl malonate, dimethyl malonate, ethyl
acetoacetate and ethyl cyanoacetate performed well in these
domino reactions (Table 3, entries 1−4). Notably, β-keto ester
We envisaged that the reaction of bis-(o-haloaryl)-
carbodiimide 1 with azole 2 might proceed through a
nucleophilic addition, an intramolecular C−N coupling, and an
intramolecular sp2 C−H arylation under proper Cu catalysis
(Scheme 1). We anticipate that the hypothetic process would be
a good vehicle for the direct assembly of benzo[4,5]imidazo[1,2-
a]quinazoline 3.
Scheme 1. Proposed Domino Synthesis of
Benzo[4,5]imidazo[1,2-a]quinazolines
RESULTS AND DISCUSSION
■
With this hypothesis in mind, we commenced our investigation
with the model reaction between bis-(o-iodophenyl)-
carbodiimide 1a and imidazole 2a under Cu(I) catalysis (Table
1, entry 1). The reaction was initially promoted by CuI (5 mol %)
and 1,10-phenanthroline (1,10-phen, 10 mol %) with K2CO3
a
Table 1. Optimization of the Reaction Conditions
b
temp
(°C)
yield
(%)
entry
cat
ligand
base
solvent
c
1
2
3
4
5
CuI
CuI
CuI
CuI
CuI
1,10-phen K2CO3
1,10-phen K3PO4
1,10-phen t-BuOLi
1,10-phen t-BuOK
dioxane
dioxane
dioxane
dioxane
dioxane
110
110
110
110
110
nd
nd
21
trace
17
1,10-phen K3PO4/
d
t-BuOLi
6
CuI
CuI
CuI
CuBr
CuCl
−
CuI
CuI
CuI
CuI
CuI
1,10-phen t-BuOLi
1,10-phen t-BuOLi
1,10-phen t-BuOLi
1,10-phen t-BuOLi
1,10-phen t-BuOLi
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMAc
110
125
140
125
125
125
125
125
125
125
125
28
7
75
8
76
9
trace
64
10
11
12
13
14
15
16
1,10-phen t-BuOLi
nd
e
BtOH
t-BuOLi
t-BuOLi
t-BuOLi
trace
nd
L-proline
f
2,2′-bipy
12
1,10-phen t-BuOLi
69
1,10-phen t-BuOLi
72
a
Reaction conditions: bis-(o-iodophenyl)carbodiimide 1a 0.5 mmol (1
equiv), imidazole 2a 0.55 mmol (1.1 equiv), Cu catalyst 0.05 mmol
(10 mol %), ligand 0.10 mmol (20 mol %), and base 2 mmol (4
b
c
equiv), in solvent (3 mL), under N2, 24 h. Isolated yield. nd = not
d
e
detected. Mole ratio = 1:1. BtOH = 1H-benzotriazole-1-methanol.
f
2,2′-bipy = 2,2′-bipyridine.
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a
Table 2. Domino Reactions of Bis-(o-haloaryl)carbodiimides and Azoles
a
Reaction conditions: bis-(o-haloaryl)carbodiimide 0.5 mmol (1 equiv), azole 0.55 mmol (1.1 equiv), CuI 0.05 mmol (10 mol %), 1,10-phen 0.10
b
c
d
mmol (20 mol %), and t-BuOLi 2 mmol (4 equiv), in DMF (3 mL), under N2, at 125 °C for 24 h. Isolated yield. At 140 °C. t-BuOLi 2.5 mmol (5
equiv) was used as the base.
exclusively delivered the deacylation product (entries 3 and 6).
An inseparable mixture was obtained when acetylacetone 6e was
utilized, probably because of the special activity of the β-diketone
and the instability of the product (entry 5). The steric hindrance
on the nucleophile might also affect its reactivity. Ethyl 3-oxo-3-
phenylpropanoate 6f afforded the desired product in low yield
(entry 6, with small amount of unexpected byproduct 5a23). On
the basis of entries 1−3, 5, and 6, it could be concluded that the
reactions with malonic diesters gave the decarboxylation
products, β-keto esters selectively delivered the deacylation
products, and the diketones were incompatible with the reaction
conditions and afforded a mixture of inseparable components.
Both electron-donating and electron-withdrawing groups on the
phenyl rings of bis-(o-haloaryl)carbodiimides were well tolerated
(entries 7−10 and 12−13). The 2-bromo-2′-iodo-diphenylcar-
bodiimides also efficiently reacted with malonates (entries 11−
13). Asymmetric diiodide 1f gave a mixture of two regioisomers
(entry 9), because of the two different cyclization directions of
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a
Table 3. Domino Reactions of Bis-(o-haloaryl)carbodiimides and Active Methylene Compounds
a
Reaction conditions: bis-(o-haloaryl)carbodiimide 0.5 mmol (1 equiv), active methylene compound 0.55 mmol (1.1 equiv), CuI 0.05 mmol (10 mol
%), 8-hydroxyquinoline 0.10 mmol (20 mol %), and K3PO4 2 mmol (4 equiv), in DMSO (3 mL), under N2, prestirred at 50 °C for 3 h, and then
b
c
d
stirred at 100 °C for 24 h. Isolated yield. An inseparable complex mixture was obtained. Small amount of unexpected byproduct 5a was also
e
isolated (its yield is given in parentheses). A mixture of two isomers was obtained (the isomeric ratio in parentheses was approximately determined
f
1
by H NMR). At 110 °C.
the adduct. It is worth noting that sole desired product was
isolated when substituted 2-bromo-2′-iodo-diphenylcarbodii-
mide was used (entries 12 and 13).
To our surprise, when we reduced the amount of base to 3
equiv and raised the temperature to 120 °C for the reaction with
dimethyl malonate, an unexpected N-methylated product 8a was
isolated in company with the formation of 7b (Scheme 2, eq 1).
The structure of 8a was ascertained unambigously by the X-ray
crystal diffraction analysis (for details, see the Supporting
Information). Amazingly, other active methylene species such
as 6a and 6c did not afford similar N-alkylated derivatives, and
only 7a was obtained. The result that 7b did not react with 6b to
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Scheme 2. Initial Attempts to Obtain N-Methylated Benzo[4,5]imidazo[1,2-a]indoles
generate 8a even at 140 °C (Scheme 2, eq 2) indicates that the
methylated product should be formed intramolecularly.
Scheme 3. Cu-Catalyzed One-Pot Selective Synthesis of
Products 7 and 8
Reducing the amount of K3PO4 to 2 equiv did not afford any
double-cyclized product 8a. And only a moderate yield of
unmethylated product 7b was isolated (Scheme 2, eq 3),
indicating that both adequate amount of base and appropriate
temperature might be indispensable for the formation of the
methylated product. We also found that when 2 equiv of base was
used and the mixture was heated to 140 °C, a complex mixture
was obtained (Scheme 2, eq 4; 16% yield of 7b and 37% yield of
8a, companied by small amount of other byproducts24).
Interestingly, when another equivalent of K3PO4 was added
and the temperature was raised up to 140 °C, 8a was isolated as
the major product (65% yield) accompanied with a small amount
of 7b (11% yield) (Scheme 2, eq 5), indicating that the
methylated and unmethylated products might be selectively
obtained just by tuning the conditions. Further investigation
found that heating process also significantly affected the results.
When the mixture was preheated at 50 °C and then stirred at 100
°C, product 7b was exclusively generated, whereas N-methylated
derivative 8a was obtained as almost the sole product when
prestirred at rt and then immediately heated to 140 °C. In order
to extend the application scope of the method, we carried out
representative experiments for tandem synthesis of methylated
benzo[4,5]imidazo[1,2-a]indoles (Scheme 3). Substrates 1b and
1c bearing either electron-donating or electron-withdrawing
groups on the phenyl rings also successfully provided the desired
N-methylated products. Therefore, the selective one-pot
assembly of methylated or unalkylated benzo[4,5]imidazo[1,2-
a]indoles can be facilely and tunably achieved.
CONCLUSIONS
■
In summary, we have developed a versatile and efficient approach
to various benzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazolines,
benzo[4,5]imidazo[1,2-a]-indolo[1,2-c]quinazolines, and
benzo[4,5]imidazo[1,2-a]indoles by Cu-catalyzed domino
addition/coupling/sp2 C−H arylation, addition/double cou-
pling/deacylation and addition/decarboxylative methylation/
double coupling reactions. Using bis-(o-haloaryl)carbodiimides
and azoles/active methylene compounds as the substrates, the
corresponding polycyclic benzimidazoles could be conveniently
assembled in moderate to good yields. Notably, multibonds and
polycyclic moieties were conveniently formed in one pot.
Furthermore, N-methylated and unalkylated benzo[4,5]imidazo-
[1,2-a]indole derivatives were selectively synthesized. The
domino synthesis may be useful for the assembly of various
polycyclic N-heterocycles of pharmaceutical and material
interests.
Preliminary investigation found that Cu catalyst was
indispensable to the domino reaction.25 In view of above
observations and the previous reports,16,26 possible mechanisms
for the domino synthesis of compound 7b and 8a was proposed
(Scheme 4). The addition of 6b to carbodiimide 1a initiates the
reaction and gives intermediate I, which might proceed through
two different routes: (A) an C−N coupling, a C−C coupling, a
decarboxylation, and an isomerization, or (B) an intramolecular
decarboxylative methylation, a C−C coupling, an isomerization,
and a C−N coupling; thus, corresponding products 7b and 8a
formed, respectively.
EXPERIMENTAL SECTION
■
General Information. All one-pot reactions were carried out in an
overdried Schlenk tube equipped with a magnetic stir bar under N2
atmosphere. 1,4-Dioxane, DMF, DMAc, and DMSO were distilled from
CaH2. Bis-(o-haloaryl)carbodiimides 1 were prepared according to the
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Scheme 4. Possible Mechanisms for the Synthesis of 7b and 8a
known literatures.27 All other reagents were obtained from commercial
sources and used as received, if not stated otherwise. All melting points
are uncorrected. The NMR spectra were recorded in CDCl3 or DMSO-
d6 on a 400 or 600 MHz instrument with TMS as internal standard.
Chemical shifts (δ) were reported in ppm with respect to TMS. Data are
represented as follows: chemical shift, mutiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, b = broad), coupling
constant (J, Hz) and integration. TLC was carried out with 0.2 mm thick
silica gel plates (GF254). Visualization was accomplished by UV light.
The columns were hand packed with silica gel 60 (160−200 mesh). Key
products were additionally confirmed by high-resolution mass spectra
(HRMS) (excepting for the isomeric mixture 7g + 7g′). HRMS analyses
were carried out using a TOF-MS instrument with an ESI source.
Typical Procedure for the Synthesis of Compound 3. An oven-
dried Schlenk tube was charged with imidazole 2 (0.55 mmol, 1.1 equiv),
CuI (0.05 mmol), 1,10-phen (0.1 mmol), and t-BuOLi (2 mmol). The
Schlenk tube was capped and then evacuated and backfilled with N2 (3
times). Under a positive pressure of N2, DMF (1.5 mL) was added via
syringe, and the mixture was stirred at rt for 10 min. Then a solution of
bis-(o-iodophenyl)carbodiimide 1 (0.5 mmol, 1.0 equiv) in DMF (1.5
mL) was added dropwise via syringe. The Schlenk tube was sealed and
allowed to prestir at rt for 2 h. Then the mixture was stirred at 125 °C for
24 h. After being cooled to rt, 30 mL of EtOAc was added. The mixture
was washed with brine (15 mL × 3). The organic phase was dried over
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel using petroleum ether/EtOAc (3:1, v:v)
as eluent to afford product 3.
114.8, 114.7, 112.6, 20.7, 20.6; HRMS (ESI) m/z calcd for C22H17N4 [M
+ H]+ 337.1448, found 337.1451.
Benzo[4,5]imidazo[1,2-a]pyrazolo[1,5-c]quinazoline (3d).6b Yel-
low solid, 93 mg, 72% yield: Rf = 0.2 (petroleum ether:EtOAc = 1:1, v:v);
1
mp 178−180 °C (recrystallized from EtOAc); H NMR (600 MHz,
CDCl3) δ 8.38 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.14 (d, J =
1.8 Hz, 1H), 8.05−8.07 (m, 1H), 7.97−7.99 (m, 1H), 7.69−7.72 (m,
1H), 7.48−7.51 (m, 2H), 7.45−7.46 (m, 1H), 7.02 (d, J = 1.8 Hz, 1H);
13C NMR (150 MHz, CDCl3) δ 144.4, 137.2, 132.1, 130.9, 130.3, 125.4,
125.2, 124.5, 123.2, 120.7, 115.3, 115.2, 112.9, 110.2, 101.1; HRMS
(ESI) m/z calcd for C16H11N4 [M + H]+ 259.0978, found 259.0972.
Benzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3e). Yellow
solid, 108 mg, 70% yield: Rf = 0.4 (petroleum ether:EtOAc = 3:1,
v:v); mp 237−239 °C (recrystallized from petroleum ether/EtOAc); 1H
NMR (600 MHz, CDCl3) δ 9.08 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.4 Hz,
1H), 8.07−8.09 (m, 2H), 7.91 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz,
1H), 7.52−7.56 (m, 2H), 7.42−7.46 (m, 2H), 7.37−7.40 (m, 2H), 7.19
(s, 1H); 13C NMR (150 MHz, CDCl3) δ 142.9, 131.7, 129.5, 129.1,
125.0, 124.7, 123.8, 123.7, 123.4, 122.4, 120.4, 119.5, 117.2, 115.8, 115.0,
112.4, 98.6; HRMS (ESI) m/z calcd for C21H14N3 [M + H]+ 308.1182,
found 308.1189.
13-Fluorobenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3f).
Yellow solid, 107 mg, 66% yield: Rf = 0.3 (petroleum ether:EtOAc =
3:1, v:v); mp 235−237 °C (recrystallized from petroleum ether/
EtOAc); 1H NMR (600 MHz, CDCl3) δ 8.83 (d, J = 9.6 Hz, 1H), 8.30
(d, J = 7.8 Hz, 1H), 8.10−8.13 (m, 2H), 7.93 (d, J = 7.2 Hz, 1H), 7.70−
7.73 (m, 1H), 7.59−7.62 (m, 1H), 7.42−7.48 (m, 3H), 7.20 (s, 2H); 13C
NMR (150 MHz, CDCl3) δ 142.9, 131.7, 129.2, 125.1, 124.6, 123.9,
122.6, 119.7, 115.2, 112.5, 112.3, 112.2, 102.9, 102.7, 98.3; HRMS (ESI)
m/z calcd for C21H13FN3 [M + H]+ 326.1088, found 326.1093.
12-Methoxybenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline
(3g). Yellow solid, 105 mg, 62% yield: Rf = 0.2 (petroleum ether:EtOAc
= 3:1, v:v); mp 229−231 °C (recrystallized from petroleum ether/
EtOAc); 1H NMR (600 MHz, CDCl3) δ 8.97 (d, J = 9.0 Hz, 1H), 8.32
(d, J = 8.4 Hz, 1H), 8.12−8.15 (m, 2H), 7.92 (d, J = 7.8 Hz, 1H), 7.59−
7.63 (m, 1H), 7.39−7.47 (m, 3H), 7.23 (d, J = 2.4 Hz, 1H), 7.15−7.18
(m, 2H), 3.96 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 143.4, 143.1,
131.8, 131.7, 130.5, 130.4, 129.0, 125.0, 124.7, 123.8, 122.3, 119.5, 116.6,
115.1, 113.5, 112.5, 102.1, 98.3, 55.7; HRMS (ESI) m/z calcd for
C22H16N3O [M + H]+ 338.1288, found 338.1297.
Benzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline (3a).6b Yel-
low solid, 97 mg, 75% yield: Rf = 0.2 (petroleum ether:EtOAc = 1:1,
1
v:v); mp 155−157 °C (recrystallized from EtOAc); H NMR (400
MHz, CDCl3) δ 8.63 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.22−
8.24 (m, 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.91−7.94 (m, 1H), 7.75−7.80
(m, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.47−7.54 (m,
2H); 13C NMR (150 MHz, CDCl3) δ 141.3, 141.2, 132.8, 132.7, 130.6,
125.6, 125.2, 124.6, 123.4, 120.1, 118.8, 115.1, 113.8, 113.2, 100.0;
HRMS (ESI) m/z calcd for C16H11N4 [M + H]+ 259.0978, found
259.0983.
Benzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[1,2-c]quinazoline
(3b).6b Yellow solid, 133 mg, 86% yield: Rf = 0.6 (petroleum
ether:EtOAc = 1:1, v:v); mp 231−233 °C (recrystallized from
1
petroleum ether/EtOAc); H NMR (600 MHz, CDCl3) δ 8.70−8.73
5,10-Dimethylbenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]-
quinazoline (3h). Yellow solid, 82 mg, 57% yield: Rf = 0.2 (petroleum
ether:EtOAc = 1:1, v:v); mp 195−197 °C (recrystallized from EtOAc);
1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H),
8.14 (s, 1H), 7.97 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.55 (d,
J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 2.65 (s, 3H), 2.57 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 141.2, 135.5, 133.3, 132.5, 131.5, 131.0,
130.7, 125.8, 125.1, 120.9, 119.4, 116.7, 114.9 (d, J = 6.0 Hz), 113.7,
113.2, 100.0, 22.2, 21.0; HRMS (ESI) m/z calcd for C18H15N4 [M + H]+
287.1291, found 287.1309.
(m, 1H), 8.65−8.67 (m, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.0
Hz, 1H), 7.93−7.96 (m, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.68−7.71 (m,
1H), 7.52−7.55 (m, 2H), 7.46−7.47 (m, 1H), 7.37−7.39 (m, 1H),
7.32−7.35 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 144.5, 143.8, 142.5,
141.6, 134.1, 132.0, 130.3, 130.0, 126.6, 125.3, 124.4, 124.2, 123.1, 120.0,
119.6, 115.0, 114.9, 114.5, 112.6; HRMS (ESI) m/z calcd for C20H13N4
[M + H]+ 309.1135, found 309.1122.
2,3-Dimethylbenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[1,2-c]-
quinazoline (3c). White solid, 146 mg, 87% yield: Rf = 0.5 (petroleum
ether:EtOAc = 1:1, v:v); mp 239−241 °C (recrystallized from
7,12-Diisopropylbenzo[4,5]imidazo[1,2-a]benzo[4,5]imidazo[1,2-
c]quinazoline (3i). White solid, 139 mg, 71% yield: Rf = 0.4 (petroleum
ether:EtOAc = 3:1, v:v); mp 207−209 °C (recrystallized from
1
petroleum ether/EtOAc); H NMR (600 MHz, CDCl3) δ 8.63−8.65
(m, 1H), 8.42 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H),
7.86 (d, J = 8.0 Hz, 1H), 7.69−7.73 (m, 1H), 7.64 (s, 1H), 7.49 (t, J = 7.5
Hz, 1H), 7.39−7.42 (m, 1H), 7.36−7.38 (m, 1H), 2.50 (s, 3H), 2.44 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 143.8, 142.6, 142.3, 141.8, 134.5,
134.0, 133.9, 131.5, 128.7, 126.4, 125.2, 124.1, 122.9, 119.9, 119.6, 114.9,
1
petroleum ether/EtOAc); H NMR (600 MHz, CDCl3) δ 8.79−8.81
(m, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.97−7.98
(m, 2 H), 7.84 (d, J = 8.4 Hz, 1H). 7.69−7.72 (dd, J1 = 1.8 Hz, J2 = 8.4
Hz, 1H), 7.53−7.56 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 3.12−3.21 (m,
1754
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Article
2H), 1.40−1.43 (m, 12H); 13C NMR (150 MHz, CDCl3) δ 146.3, 145.0,
144.4, 143.9, 141.6, 140.9, 132.6, 130.7, 130.5, 125.3, 124.3, 124.2, 119.7,
119.6, 115.1, 115.0, 114.5, 110.4, 34.9, 33.9, 24.7, 23.9; HRMS (ESI) m/
z calcd for C26H25N4 [M + H]+ 393.2074, found 393.2058.
5,10-Difluorobenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline
(3j). Yellow solid, 94 mg, 64% yield: Rf = 0.4 (petroleum ether:EtOAc =
1:1, v:v); mp 202−204 °C (recrystallized from EtOAc); 1H NMR (600
MHz, CDCl3) δ 8.27−8.30 (m, 1H), 8.20−8.23 (m, 1H), 8.14 (d, J = 0.8
Hz, 1H), 7.83−7.87 (m, 2H), 7.64 (d, J = 0.8 Hz, 1H), 7.46−7.50 (m,
1H), 7.26−7.28 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 140.2, 138.2,
133.4, 133.1, 128.7, 120.8 (d, J = 10.2 Hz), 118.2, 118.0, 116.6 (d, J = 8.2
Hz), 114.3, 112.8, 112.7, 111.6, 111.4, 100.5, 100.3; HRMS (ESI) m/z
calcd for C16H9F2N4 [M + H]+ 295.0790, found 295.0797.
10-Fluorobenzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazoline
(3k). White solid, 75 mg, 54% yield: Rf = 0.3 (petroleum ether:EtOAc =
3:1, v:v); mp 193−195 °C (recrystallized from petroleum ether/
EtOAc); 1H NMR (600 MHz, CDCl3) δ 8.61 (d, J = 7.2 Hz, 1H), 8.22
(d, J = 8.0 Hz, 1H), 8.12−8.16 (m, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.82−
7.84 (m, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.63 (m, 1H), 7.58 (t, J = 6.8 Hz,
1H), 7.25−7.27 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 141.0, 138.3,
132.8, 132.2, 130.7, 125.9, 125.3, 120.64, 120.57, 114.7, 113.8, 112.7,
112.5, 100.8, 100.7; HRMS (ESI) m/z calcd for C16H10FN4 [M + H]+
277.0884, found 277.0895.
2-(1H-Imidazol-1-yl)-1-(2-iodophenyl)-1H-benzo[d]imidazole (In-
termediate 4a). White solid, 131 mg, 68% yield (reaction at 75 °C): Rf =
0.4 (petroleum ether:EtOAc = 4:1, v:v); 1H NMR (400 MHz, CDCl3) δ
8.05−8.08 (m, 1H), 7.82−7.86 (m, 2H), 7.57−7.62 (m, 1H), 7.38−7.46
(m, 2H), 7.28−7.35 (m, 2H), 7.20 (s, 1H), 7.07 (s, 1H), 7.01 (d, J = 8.0
Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 142.6, 140.9, 140.5, 137.5,
135.3, 132.0, 130.3, 129.6, 124.1, 123.9, 119.8, 118.5, 110.7, 98.4; HRMS
(ESI) calcd for C16H12IN4 [M + H]+ 387.0101, found 387.0129.
5-Phenyl-5H-benzo[d]benzo[4,5]imidazo[1,2-a]imidazole (By-
product 5a). White solid: Rf = 0.3 (petroleum ether:EtOAc = 3:1,
v:v); mp 142−144 °C (recrystallized from petroleum ether/EtOAc); 1H
NMR (600 MHz, CDCl3) δ 7.86−7.89 (m, 4H), 7.81 (d, J = 8.0 Hz,
1H), 7.66 (t, J = 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.5 Hz,
1H), 7.32−7.42 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 152.4, 147.1,
135.22, 135.16, 130.1, 127.6, 124.7, 123.3, 123.2, 122.1, 120.3, 119.0,
110.9, 110.8, 110.2; HRMS (ESI) calcd for C19H14N3 [M + H]+
284.1182, found 284.1191.
General Procedure for the Synthesis of Compound 7. An oven-
dried Schlenk tube was charged with CuI (0.05 mmol), 1,10-phen (0.1
mmol), and K3PO4 (2 mmol). The Schlenk tube was capped and then
evacuated and backfilled with N2 (3 times). Under a positive pressure of
N2, a solution of active methylene compound 6 (0.55 mmol, 1.1 equiv)
in DMSO (1.5 mL) was added via syringe, and the mixture was stirred at
rt for 10 min. Then a solution of bis-(o-iodophenyl)carbodiimide 1 (0.5
mmol, 1.0 equiv) in DMSO (1.5 mL) was added dropwise via syringe.
The Schlenk tube was sealed and allowed to prestir at 50 °C for 3 h.
Then the mixture was stirred at 100 °C for 24 h. After being cooled to rt,
30 mL of EtOAc was added. The mixture was washed with brine (15 mL
× 3). The organic phase was dried over Na2SO4 and concentrated. The
residue was purified by column chromatography on silica gel using
petroleum ether/EtOAc (10:1, v:v) as eluent to afford product 7.
Ethyl 10H-benzo[4,5]imidazo[1,2-a]indole-11-carboxylate (7a).
White solid, 122 mg, 88% yield (Table 3, entry 1): Rf = 0.6 (petroleum
ether:EtOAc = 1:1, v:v); mp 222−224 °C (recrystallized from EtOAc);
1H NMR (600 MHz, DMSO-d6) δ 12.10 (b, 1H), 8.22 (d, J = 7.8 Hz,
Hz, J2 = 14.4 Hz, 2H), 7.22 −7.25 (m, 1H), 3.87 (s, 3H); 13C NMR (150
MHz, DMSO-d6) δ 164.4, 147.2, 136.3, 136.1, 130.8, 127.3, 126.4 (d, J =
3.6 Hz), 124.1, 123.3, 121.9 (d, J = 1.8 Hz), 120.3 (d, J = 1.2 Hz), 120.1,
112.44, 112.40, 111.8 (d, J = 5.6 Hz), 50.7; HRMS (ESI) m/z calcd for
C16H13N2O2 [M + H]+ 265.0972, found 265.0967.
10H-Benzo[4,5]imidazo[1,2-a]indole-11-carbonitrile (7c). White
solid, 84 mg, 73% yield: Rf = 0.5 (petroleum ether:EtOAc = 1:1, v:v);
1
mp 197−199 °C (recrystallized from petroleum ether/EtOAc); H
NMR (600 MHz, DMSO-d6) δ 12.84 (b, 1H), 8.23 (d, J = 7.8 Hz, 1H),
8.19 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.8 Hz,
1H), 7.39 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.2 Hz,
1H), 7.27−7.30 (m, 1H); 13C NMR (150 MHz, DMSO-d6) δ 147.7,
136.1, 131.9, 126.6, 126.2, 124.4, 123.5, 122.0, 120.9, 118.2, 112.3, 112.2,
111.9; HRMS (ESI) m/z calcd for C15H10N3 [M + H]+ 232.0869, found
232.0875.
Ethyl 2,7-dimethyl-10H-benzo[4,5]imidazo[1,2-a]indole-11-car-
boxylate (7d). White solid, 132 mg, 86% yield: Rf = 0.5 (petroleum
ether:EtOAc = 1:1, v:v); mp 213-215 °C (recrystallized from EtOAc);
1H NMR (600 MHz, DMSO-d6) δ 11.91 (b, 1H), 8.03 (s, 1H), 8.00 (d, J
= 8.1 Hz, 1H), 7.79 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.1 Hz,
1H), 7.04 (d, J = 8.2 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H)
(overlapped with the signal of DMSO-d6), 2.47 (s, 3H), 1.39 (t, J = 7.1
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 164.2, 145.4, 134.1, 132.1,
131.5, 126.6, 125.5, 124.6, 121.2, 120.3, 112.0, 111.9, 111.4, 100.0, 58.8,
22.0, 21.5, 15.4; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+
307.1441, found 307.1453.
Ethyl 2,7-diisopropyl-10H-benzo[4,5]imidazo[1,2-a]indole-11-
carboxylate (7e). White solid, 138 mg, 76% yield: Rf = 0.3 (petroleum
ether:EtOAc = 3:1, v:v); mp 215−217 °C (recrystallized from
1
petroleum ether/EtOAc); H NMR (400 MHz, DMSO-d6) δ 11.89
(b, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.45 (d, J =
8.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.10 (dd, J1 = 1.2 Hz, J2 = 8.2 Hz,
1H), 4.36 (q, J = 7.1 Hz, 2H), 3.03−3.13 (m, 2H), 1.41 (t, J = 7.1 Hz,
3H), 1.30−1.35 (m, 12 H); 13C NMR (100 MHz, DMSO-d6) δ 164.2,
147.6, 143.5, 142.9, 134.4, 131.0, 126.7, 125.7, 121.9, 118.7, 117.5, 112.1,
111.6, 109.4, 58.8, 34.3, 34.2, 25.0, 24.9, 15.4; HRMS (ESI) m/z calcd
for C23H27N2O2[M + H]+ 363.2067, found 363.2101.
Ethyl 2,7-dichloro-10H-benzo[4,5]imidazo[1,2-a]indole-11-car-
boxylate (7f). Yellow solid, 122 mg, 70% yield: Rf = 0.5 (petroleum
ether:EtOAc = 1:1, v:v); mp 231−233 °C (recrystallized from EtOAc);
1H NMR (400 MHz, DMSO-d6) δ 11.88 (b, 1H), 8.00 (s, 1H), 7.98 (d, J
= 8.2 Hz, 1H), 7.78 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.2 Hz,
1H), 7.03 (d, J = 8.2 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, DMSO-d6) δ 164.5, 147.7, 138.5, 131.5,
128.8, 128.7, 125.9, 125.5, 124.9, 121.2, 120.8, 111.8, 109.7, 100.0, 59.0,
22.0; HRMS (ESI) m/z calcd for C17H13Cl2N2O2 [M + H]+ 347.0349,
found 347.0356.
Ethyl 7-fluoro-10H-benzo[4,5]imidazo[1,2-a]indole-11-carboxy-
late (7g) and Ethyl 2-fluoro-10H-benzo[4,5]imidazo[1,2-a]indole-
11-carboxylate (7g′). Mole ratio = 69:31 (approximately determined
by 1H NMR). Yellow solid, 105 mg, 71% yield (total): Rf = 0.6
(petroleum ether:EtOAc = 1:1, v:v). Major (approximate attributions):
1H NMR (400 MHz, DMSO-d6) δ 12.1 (b, 1H), 8.18−8.21 (m, 2H),
7.99 (t, J = 6.8 Hz, 1H), 7.52−7.56 (m, 1H), 7.30−7.40 (m, 2H), 7.22 (t,
J = 7.8 Hz, 1H), 4.35 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H); 13
C
NMR (100 MHz, DMSO-d6) δ 164.2, 136.2, 136.1, 127.2, 126.4, 124.2,
123.6, 122.1, 120.3, 118.6, 112.8, 112.4, 111.8, 107.2, 100.0, 58.9, 15.4.
Minor (approximate attributions): 1H NMR (400 MHz, DMSO-d6) δ
12.2 (b, 1H), 8.10−8.15 (m, 2H), 7.62−7.65 (m, 1H), 7.48−7.52 (m,
1H), 7.30−7.40 (m, 2H), 7.00−7.05 (m, 1H), 4.35 (q, J = 7.0 Hz, 2H),
1.40 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.2,
136.6, 135.9, 127.4, 126.2, 124.1, 123.3, 121.9, 120.2, 118.4, 112.8, 112.6,
111.7, 107.4, 100.9, 59.2, 15.3.
1H), 8.14 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8
Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.34 (dd, J1 = 8.0 Hz, J2 = 16.2 Hz, 2H),
7.23 (t, J = 7.5 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H);
13C NMR (150 MHz, DMSO-d6) δ 164.2, 138.4, 136.3, 127.2, 126.4,
124.1, 123.3, 121.9, 120.3, 112.5, 111.8, 100.0, 59.0, 15.4; HRMS (ESI)
m/z calcd for C17H15N2O2 [M + H]+ 279.1128, found 279.1121.
Methyl 10H-benzo[4,5]imidazo[1,2-a]indole-11-carboxylate (7b).
White solid, 106 mg, 80% yield (Table 3, entry 2): Rf = 0.2 (petroleum
ether:EtOAc = 3:1, v:v); mp 214−216 °C (recrystallized from
Methyl 7-methyl-10H-benzo[4,5]imidazo[1,2-a]indole-11-carbox-
ylate (7h). Yellow solid, 104 mg, 75% yield: Rf = 0.5 (petroleum
ether:EtOAc = 1:1, v:v); mp 209−211 °C (recrystallized from
1
petroleum ether/EtOAc); H NMR (600 MHz, DMSO-d6) δ 12.00
1
petroleum ether/EtOAc); H NMR (600 MHz, DMSO-d6) δ 12.21
(b, 1H), 7.99−8.02 (m, 2H), 7.68−7.84 (m, 2H), 7.40 (d, J = 7.2 Hz,
1H), 7.17 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 3.85 (s, 3H), 2.47
(s, 3H); 13C NMR(150 MHz, DMSO-d6) δ 160.4, 134.1, 132.2, 131.5,
(b, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.2
Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37−7.40 (m, 1H), 7.33 (dd, J1 = 7.2
1755
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Article
126.6, 125.5, 124.6, 121.2, 120.1, 112.0, 111.9, 111.4, 50.6, 22.0; HRMS
(ESI) m/z calcd for C17H15N2O2 [M + H]+ 279.1128, found 279.1120.
Ethyl 7-fluoro-10H-benzo[4,5]imidazo[1,2-a]indole-11-carboxy-
late (7i). Yellow solid, 114 mg, 77% yield: Rf = 0.6 (petroleum
ether:EtOAc = 1:1, v:v); mp 201−203 °C (recrystallized from
°C): Rf = 0.6 (petroleum ether:EtOAc = 3:1, v:v); mp 160−162 °C
1
(recrystallized from EtOAc/EtOH); H NMR (600 MHz, CDCl3) δ
11.25 (b, 2H), 7.57−7.58 (m, 2H), 6.99−7.04 (m, 4H), 6.56−6.59 (m,
2H), 3.85 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 171.2, 158.7, 139.3,
138.8, 128.2, 126.2, 123.8, 93.6, 80.4, 51.8; HRMS (ESI) calcd for
C18H17I2N2O4 [M + H]+ 578.9272, found 578.9293.
1
petroleum ether/EtOAc); H NMR (600 MHz, DMSO-d6) δ 12.11
(b, 1H), 8.13−8.29 (m, 2H), 7.93−8.00 (m, 1H), 7.49−7.56 (m, 1H),
7.29−7.40 (m, 2H), 7.21−7.25 (m, 1H), 4.35 (q, J = 6.9 Hz, 2H), 1.40
(t, J = 6.9 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 164.9, 133.5,
132.8, 127.0, 123.6, 121.9, 120.3, 112.0, 111.8, 111.0, 110.8, 100.0 (d, J =
7.0 Hz), 59.0, 15.4; HRMS (ESI) m/z calcd for C17H14FN2O2 [M + H]+
297.1034, found 297.1043.
Procedure for the N-Methylation of 7b Using MeI. Compound
7b (0.3 mmol, 1.0 equiv), K2CO3 (0.6 mmol, 2.0 equiv), and a solution
of methyl iodide (0.45 mmol, 1.5 equiv) in DMF (20 mL) were
successively added to a flask under an N2 atmosphere. The mixture was
heated to 50 °C for 12 h. After being cooled to rt and quenced by aq. sat.
Na2SO3 (5 mL), 30 mL of EtOAc was added. The organic phase was
separated, washed by water (15 mL × 3), and dried over Na2SO4. The
solvent was removed in vacuo, and the resulting residue was purified by
column chromatography on silica gel using petroleum ether/EtOAc
(10:1, v:v) as eluent to afford the product as a yellow solid (75 mg, 90%
yield). Its spectral data (1H NMR and 13C NMR) are in good accordance
with those of product 8a.
General Procedure for the Synthesis of Compound 8. An oven-
dried Schlenk tube was charged with CuI (0.05 mmol), 1,10-phen (0.1
mmol), and K3PO4 (1 mmol). The Schlenk tube was capped and then
evacuated and backfilled with N2 (3 times). Under a positive pressure of
N2, a solution of active methylene compound 6 (0.55 mmol, 1.1 equiv)
in DMSO (1.5 mL) was added via syringe, and the mixture was stirred at
rt for 10 min. Then a solution of bis-(o-iodophenyl)carbodiimide 1 (0.5
mmol, 1.0 equiv) in DMSO (1.5 mL) was added dropwise via syringe.
The Schlenk tube was allowed to prestir at rt for about 2 h. Then the
mixture was immediately stirred at 140 °C for about 3 h. After being
cooled, additional equivalent of K3PO4 (0.5 mmol) was added under a
positive pressure of N2. The Schlenk tube was sealed and allowed to
continue stir at 140 °C for 21 h. After being cooled to rt, 30 mL of EtOAc
was added. The mixture was washed with brine (15 mL × 3). The
organic phase was dried over Na2SO4 and concentrated. The residue was
purified by column chromatography on silica gel using petroleum ether/
EtOAc (10:1, v:v) as eluent to afford product 8.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for the products, X-ray crystal structure
of 8a, and X-ray data for 8a (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lvxin@zjnu.cn.
■
Methyl 10-methyl-10H-benzo[4,5]imidazo[1,2-a]indole-11-car-
boxylate (8a). Yellow solid, 100 mg, 72% yield (Scheme 3, entry 1):
Rf = 0.4 (petroleum ether:EtOAc = 1:1, v:v); mp 204−206 °C
Notes
The authors declare no competing financial interest.
1
(recrystallized from petroleum ether/EtOAc); H NMR (600 MHz,
ACKNOWLEDGMENTS
DMSO-d6) δ 8.22 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.07 (d, J
= 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.39 (t, J
= 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 4.23 (s,
3H), 3.86 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 164.7, 137.8,
131.7, 131.2, 126.7, 125.9, 124.1, 123.4, 122.4, 121.2, 120.7, 111.6, 111.4,
110.9, 100.0, 50.9, 32.4; HRMS (ESI) m/z calcd for C17H15N2O2 [M +
H]+ 279.1128, found 279.1131.
■
This work was financially supported by the National Natural
Science Foundation of China (No. 21202152) and the Zhejiang
Provincial Natural Science Foundation (No. Y4110044). We also
thank Prof. Weiliang Bao for his suggestions on the experiments
and helping provide characterization of several compounds.
Important Crystal Data for 8a. C17H14N2O2, M = 278.30,
monoclinic, space group P21/n, a = 11.3450(7) Å, b = 8.1717(6) Å, c
= 14.9978(9) Å, V = 1344.91(15) Å3, Z = 4, T = 170(2) K, 5419
reflections collected, 2451 independent reflections, Final R = 0.0533, wR
= 0.0978, GoF = 1.057 for 2451 reflections with I > 2σ(I) and 192
parameters. Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre: deposition no. CCDC-
975905.
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Methyl 2,7,10-trimethyl-10H-benzo[4,5]imidazo[1,2-a]indole-11-
carboxylate (8b). Yellow solid, 95 mg, 62% yield: Rf = 0.6 (petroleum
ether:EtOAc = 1:1, v:v); mp 195−197 °C (recrystallized from
1
petroleum ether/EtOAc); H NMR (600 MHz, CDCl3) δ 7.99 (s,
1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.18
(d, J = 8.1 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.29 (s, 3H), 3.98 (s, 3H),
2.58 (s, 3H), 2.55 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 164.6, 135.7,
132.6, 131.7, 125.2, 123.9, 121.5, 121.2, 111.2, 110.0, 109.1, 50.6, 32.1,
21.9, 21.6; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+ 307.1441,
found 307.1447.
Methyl 2,7-difluoro-10-methyl-10H-benzo[4,5]imidazo[1,2-a]-
indole-11-carboxylate (8c). Yellow solid, 101 mg, 64% yield: Rf = 0.6
(petroleum ether:EtOAc = 1:1, v:v); mp 174−176 °C (recrystallized
1
from petroleum ether/EtOAc); H NMR (600 MHz, DMSO-d6) δ
8.23−8.26 (m, 1H), 8.18−8.20 (m, 1H), 7.69−7.71 (m, 1H), 7.65−7.66
(m, 1H), 7.28−7.32 (m, 1H), 7.01−7.05 (m, 1H), 4.20 (s, 3H), 3.86 (s,
3H); 13C NMR (150 MHz, DMSO-d6) δ 164.8, 133.5, 132.8, 127.0,
124.1, 123.6, 123.3, 122.5, 121.9, 120.3, 112.5, 112.0, 111.8, 111.0, 100.0,
59.0, 31.2; HRMS (ESI) calcd for C17H13F2N2O2 [M + H]+ 315.0940,
found 315.0948.
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Dimethyl 2-(bis((2-iodophenyl)amino)methylene)malonate (In-
termediate 9a). Yellow solid, 275 mg, 95% yield (reaction at 100
1756
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The Journal of Organic Chemistry
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(20) There are rare reports about the Cu-catalyzed domino
transformations with intramolecular sp2 C−H arylation of azoles as
the key step; see: ref 14b, c.
(21) We have also attempted to use other azoles such as pyrrole and
theophylline as the reagents. Unfortunately, in both cases, no desired
double-cyclized product was observed, and moderate yields of
unexpected byproduct 5a were isolated. The pathway to the unexpected
byproduct is uncertain, and the mechanism study is currently underway.
(9) Up to now, only one patent describes the multistep synthesis of
benzo[4,5]imidazo[1,2-a]imidazo[1,2-c]quinazolines; see ref 6b. And
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using MeI, and the derivative (8a) was ascertained by the X-ray crystal
diffraction analysis. For details, see the Experimental Section.
(23) The pathway to the unexpected byproduct is uncertain, and the
mechanism study is currently underway.
(24) These byproducts were unstable and could not be separated.
(25) The control experiment indicated that without the addition of Cu
catalyst, only addition intermediate 9a was generated and no cyclized
product formed:
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(17) We found that better results could be obtained when the reaction
was carried out under the conditions similar to those developed by
Daugulis et al., which were successfully applied for the intermolecular sp2
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(18) The spectral data of compound 3a are in good accordance with
those in a previous report (ref 6b).
(19) During the preliminary study, we found that monocyclized
product 4a was isolated as the sole product when the reaction was
performed at 75 °C, indicating that a higher temperature was necessary
for the second cyclization process:
1757
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