Copper-catalyzed domino intramolecular cyclization: A facile and efficient approach to polycyclic indole derivatives

Article abstract of DOI:10.1039/c1ob06488f

A mild and efficient Cu₂O-catalyzed domino intramolecular C-N coupling/C-Y (Y = O, S, N) bond formation was successfully achieved. Thus oxazino[3,2-a]indole, thiazino[3,2-a]indole and indolo[2,1-b]quinazoline derivatives were facilely assembled

Full text of DOI:10.1039/c1ob06488f

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PAPER
Copper-catalyzed domino intramolecular cyclization: a facile and efficient
approach to polycyclic indole derivatives†
Ziming Xia, Kuo Wang, Jiening Zheng, Zheyong Ma, Zhanguo Jiang, Xiaoxia Wang* and Xin Lv*
Received 30th August 2011, Accepted 16th November 2011
DOI: 10.1039/c1ob06488f
A mild and efficient Cu2O-catalyzed domino intramolecular C–N coupling/C–Y (Y = O, S, N) bond
formation was successfully achieved. Thus oxazino[3,2-a]indole, thiazino[3,2-a]indole and indolo[2,1-b]
quinazoline derivatives were facilely assembled from readily accessible gem-dibromovinyl systems. The
protocol is general and practical, affording a variety of the indole-incorporated products in good to
excellent yields even under air atmosphere.
The readily available gem-dihalovinyl systems have been
Introduction
employed for the one-pot synthesis of various 2-substituted
indole heterocycles.13,14 For example, Lautens and co-workers
Indole moiety is a privileged structural motif in many biologi-
cally active and medicinally valuable molecules.1 The indole-
developed a Cu-catalyzed intramolecular double amidation to
form imidazoindolones using gem-dibromovinyl systems.13j
incorporated oxazino[3,2-a]indole and indolo[2,1-b]quinazoline
derivatives have been known as important heterocycles in
pharmaceutical areas (Fig. 1). For example, SB-207266 and its
metabolites (A) exhibit 5-HT4 receptor antagonist activity and
are used to control cardiovascular or gastrointestinal disorders;2
indo[2,1-b][1,3]benzoxazines (B) are potent drugs for the treat-
ment of atrial arrhythmia and CNS disorders;3 tryptanthrins and
their analogues (C), which possess various biological activities,4
have aroused great interest as antibacterial,5 antifungal,6 and
anticancer4b,7 agents; several indolo[2,1-b]quinazoline-12-ones
(D) show remarkable antileishmanial activity.8
Although oxazino[3,2-a]indole and indolo[2,1-b]quinazoline
derivatives play important roles in biological and medicinal
areas, few approaches to these compounds have been developed
to date. These molecules could be elaborated via multiple steps
from indole or its derivatives,2a,2d,4b but the methods may suffer
from tedious procedures, poor precursor scopes, and/or low
efficiency.
Recently, it was reported that certain novel polycyclic indole
derivatives were assembled from gem-dihalovinyl systems via
Pd-catalyzed Suzuki–Miyaura coupling/direct arylation,13d Pd-
catalyzed amination/direct arylation,13f Cu-catalyzed coupling/
Pd-catalyzed C–H activatioon,14b and nucleophilic addition/Cu-
catalyzed N-arylation/Pd-catalyzed arylation processes.14c These
strategies provided efficient and facile access to the novel poly-
cyclic indole derivatives.
However, to the best of our knowledge, there is no report for
the one-pot synthesis of oxazino[3,2-a]indole and indolo[2,1-b]
quinazoline derivatives, which are of potentially biological and
medicinal value. And as far as we know, copper-catalyzed
cascade intramolecular C–N coupling/C–Y (Y = O, S) bond for-
mation has not been explored. In addition, although Cu-cata-
lyzed tandem intramolecular amidation/amidation has been
reported,13j there is no report about Cu-catalyzed domino intra-
molecular amidation/amination.
In the last decade, copper-mediated coupling strategies have
drawn much attention for their low cost and high efficiency.9
And recently, Cu-catalyzed carbon-heteroatom coupling has
become a powerful tool for the assembly of various useful
heterocyclic compounds via one-pot protocols.10–12
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. E-mail: lvxin@zjnu.cn,
wangxiaoxia@zjnu.cn
†Electronic supplementary information (ESI) available: characterization
data for the substrates, intermediates and by-product, X-ray crystallo-
graphic information of product 2a, and spectra for the compounds.
CCDC reference number 832179. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1ob06488f
Fig. 1 Several biologically and medicinally valuable oxazino[3,2-a]
indol-12-ones and indolo[2,1-b]quinazolin-12-ones.
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Table 1 Optimization of the reaction conditions
Scheme 1 Retrosynthesis of benzoxazino[3,2-a]indol-12-ones.
Yield
Entry [Cu]
L
Solvent
T/°C Time (h) (%)a,b
Scheme 2 The first approach to 2a.
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
L1 Toluene
L1 Toluene
L1 Toluene
L2 Toluene
L3 Toluene
L4 Toluene
L5 Toluene
L6 Toluene
L7 Toluene
L8 Toluene
75
70
50
70
70
70
70
70
70
70
70
70
3
3
24
3
1
24
24
24
24
24
24
1
87
87
47
86
95
32
38
15
6
19
20
49
92
46
61
95
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
—
Toluene
L3 DMF
L3 Dioxane 70
L3 CH3CN
L3 DME
L3 Toluene
L3 Toluene
L3 Toluene
1
70
70
70
70
70
70
70
70
70
70
70
15
15
3
1
1
5
30
1
1
1
Fig. 2 The X-ray crystal structure of 2a.
95
96
87
Cu(OAc)2·H2O L3 Toluene
—
Cu2O
Cu2O
Cu2O
Cu2O
In the context of developing a domino coupling for the assem-
bly of oxazino[3,2-a]indole and indolo[2,1-b]quinazoline deriva-
tives using readily available gem-dibromovinyl substrates, we
conceived that benzoxazino[3,2-a]indol-12-one 2 might be
synthesized from o-gem-dibromovinyl salicylanilide 1 via Cu-
catalyzed domino intramolecular C–N coupling/C–O bond form-
ation process (Scheme 1).
L3 Toluene
L3 Toluene
L3 Toluene
L3 Toluene
L3 Toluene
n.d.c
96d
96d,e
90d,f
91d,e,g
1
a Reaction conditions: substrate 1a (0.5 mmol), copper-catalyst
(0.05 mmol, 10 mol%), ligand (0.10 mmol, 20 mol%), K2CO3 (4
equiv), in solvent (3 mL), under N2. b Isolated yield. c n.d. = not
detected. d Cu2O (5 mol%) as the catalyst and DMEDA (10 mol%) as
the ligand. e K2CO3 (3 equiv) was used as the base. f K2CO3 (2 equiv)
was used as the base. g Under common conditions: in commercial
toluene under air atmosphere.
Results and discussion
The first approach
During our initial studies, o-gem-dibromovinyl salicylanilide 1a,
which could be conveniently synthesized from o-gem-dibromo-
vinylaniline and salicylic acid,15 was employed as the substrate.
The first attempt was carried out using 1a in the presence of CuI
(10 mol%), 1,10-phenanthroline (1,10-Phen, 20 mol%), and
K2CO3 (4 equiv) in dry toluene under nitrogen atmosphere at
75 °C (Scheme 2). Fortunately, the desired polycyclic product 2a
was successfully isolated after 3 h. The colourless single crystals
of 2a were obtained by recrystallization in ethyl acetate/pet-
roleum ether (1 : 10, v:v) at room temperature. And the structure
of 2a was ascertained unambiguously by the X-ray crystal dif-
fraction analysis (Fig. 2).
from 75 °C to 70 °C did not bring about obvious change in the
efficiency (Entry 2), but a further decrease in the temperature to
50 °C caused drastic drop in the yield (47%) and longer reaction
time (>24 h) (Entry 3). Considering that the ligand type may
influence the domino transformation, a range of ligands were
therefore screened (Entries 2 and 4–10, L1–L8). 1,10-Phenanthro-
line and 2,2′-bipyridine gave good results, but DMEDA was the
optimal ligand (Entry 5 vs. Entries 2 and 4). DMEDA gave the
cleanest reaction, affording 2a in excellent yield within 1 h
(Entry 5, 95% yield). It should be noted that in the absence of
ligand, the desired product was obtained only in 20% yield
(Entry 11). The influence of solvents was also investigated
(Entries 5 and 12–15). DMF, CH3CN and 1,2-dimethoxyethane
(DME) afforded lower yields. Both dioxane and toluene gave
satisfactory yields, and toluene was slightly superior to dioxane
(Entry 5 vs. Entry 13). Therefore, toluene was chosen as the best
solvent. It was found that a Cu-catalyst was essential for the
Optimization of the reaction
The optimization of the reaction conditions was performed and
the results were listed in Table 1. Initially, the reaction tempera-
ture was investigated (Entries 1–3). Lowering the temperature
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Table 2 Domino intramolecular C–N/C–O bond formation reactions
Entry
1
Substrate
Product
Time, yielda,b
Entry
9
Substrate
Product
Time, yielda,b
6 h, 93%
1 h, 96%
1 h, 91%c
2
3
1 h, 94%
3 h, 91%c
10
11
1 h, 96%
6 h, 94%
6 h, 81%
3 h, 90%
0.5 h, 58%d
4
5
6
6 h, 91%
6 h, 88%c
12
13
14
2 h, 96%
1 h, 94%
1 h, 93%c
—
24 h, trace
1 h, 96%
6 h, 76%
7
8
5 h, 97%
6 h, 90%c
15
6 h, 85%
a Reaction conditions: substrate 1 (0.5 mmol), Cu2O (0.025 mmol, 5 mol%), DMEDA (0.05 mmol, 10 mol%), K2CO3 (3 equiv), in toluene (3 mL),
under N2, at 70 °C. b Isolated yield. c Under common conditions: in commercial toluene under air atmosphere. d The intermediate (2-bromo-1H-indol-
1-yl)(2-hydroxy-6-methylphenyl)methanone 3a was also isolated (in 33% yield).
tandem cyclization (Entry 20). Different copper sources were
also examined. Among the tested Cu-catalysts such as CuI,
CuCl, CuBr, Cu(OAc)2·H2O and Cu2O (Entries 5 and 16–19),
Cu2O performed the best and gave 2a in 96% yield (Entry 18).
Reducing the amount of the Cu-catalyst and ligand to 5 mol%
and 10 mol%, respectively, did not affect the efficiency (Entry
21). We also examined the influence of the base. Different bases
including K2CO3, K3PO4, Na2CO3 and Cs2CO3 were evaluated
during the preliminary investigation. The results showed that
K3PO4 and Na2CO3 were less effective. Both K2CO3 and
Cs2CO3 were equally efficient. With respect to the lower cost,
K2CO3 was chosen as the optimal base for the reaction. Three
equivalents of the base seemed to be suitable for the reaction
(Entries 21–23). An additional experiment showed that the reac-
tion could also proceed smoothly under the common conditions
(in commercial toluene under air atmosphere, Entry 24).
Scope of the reaction
Domino intramolecular C–N coupling/C–O bond formation
reactions. After the optimized conditions were established, we
then investigated the generality of this Cu-catalyzed domino
reaction by using a variety of the substrates (Table 2). Most of
the substituted o-gem-dibromovinyl substrates reacted smoothly
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and afforded the desired polycyclic products in excellent yields
within 6 h. As shown in Table 2, both electron-donating groups
(Entries 2–3 and 12–14) and electron-withdrawing groups
(Entries 4–5, 7–11 and 15) on the indolyl or phenyl ring were
well tolerated. However, the o-gem-dibromovinyl salicylanilide
bearing two strongly electron-withdrawing groups on the phenyl
ring gave the desired tetracyclic product only in trace amount
(Entry 6), due probably to the weakening of the nucleophilicity
of both the NH and OH groups. It was noteworthy that the
domino reactions seemed insensitive to the ortho-steric hin-
drance on the aryl ring. 4-Methyl-12H-benzo[5,6]-[1,3]oxazino
[3,2-a]indol-12-one 2c could be smoothly assembled from the
corresponding substrate 1c (Entry 3). And interestingly, both the
o-gem-dibromovinyl systems bearing 3-hydroxy-2-naphthoyl
and 2-hydroxy-1-naphthoyl could efficiently afford the penta-
cyclic products within 1 h (Entries 13 and 14). The method was
also viable for the synthesis of 6-substituted benzoxazino[3,2-a]
indol-12-one derivatives (Entry 15).
Scheme 3 The reaction of 4a under different conditions.
temperature and changing the solvent did not improve the result.
Interestingly, when K2CO3 was replaced by Cs2CO3, the desired
polycyclic product 5a could be obtained in excellent yield
within 1 h (Scheme 3). In addition to the stronger basicity of
Cs2CO3, its good solubility in toluene may play the major role in
this case.9a
Further investigation proved that Cu2O was the best catalyst
and DMEDAwas the optimal ligand for this domino process. On
the basis of these results, the optimal conditions for the reactions
of indolo-[2,1-b]quinazolin-12-ones were established as the fol-
lowing: in toluene under N2 at 70 °C with Cu2O (5 mol%) as
catalyst along with DMEDA (10 mol%) as additive and Cs2CO3
(3 equiv) as base.
Intermediates 3 could also be isolated from the reaction mix-
tures, indicating that the reaction might occur in the desired
manner. For example, reducing the reaction time of 1c to 0.5 h
gave a mixture of the desired product 2c and the intermediate 3a
(in 58% and 33% yield, respectively) (Table 2, Entry 3).
Under the above modified conditions, a series of 2-amino-N-
(2-(2,2-dibromovinyl)phenyl)-benzamides 416 were utilized to
examine the scope of the reaction (Table 3, entries 1–5). Gener-
ally, the electron-rich and electron-deficient groups (such as Me,
Ph, and Cl) on the aryl was well tolerated (Entries 1–4). However,
the double cyclization required longer reaction time and/or higher
temperature due to the impact of the steric hindrance (Entries 2
and 4). An N-acetyl substrate was also investigated, but an in-
separable mixture was obtained because of the instability of the
desired product (Entry 5). Under the common conditions, the
reactions also proceeded successfully (Entries 1 and 4).
Domino intramolecular C–N coupling/C–N (or C–S) bond for-
mation reactions. Having developed an efficient protocol for the
synthesis of benzoxazino[3,2-a]indol-12-ones, we then sought to
extend the protocol to assemble indolo-[2,1-b]quinazolin-12-
ones. Initially, compound 4a was used as the starting material.
The first attempt was also carried out under the above optimized
conditions. However, no desired double cyclized product 5a was
observed, and the intermediate N-anthraniloyl 2-bromoindole 6a
was isolated in 97% yield, indicating that the second cyclization
might be more difficult than the first. Increasing the reaction
Table 3 Domino intramolecular C–N/C–N (or C–S) bond formation reactions
Entry
1
Substrate
Product
Time, yielda,b
Entry
4
Substrate
Product
Time, yielda,b
1 h, 96%
6 h, 86%c
1 h, 90%d
6 h, 82%c,d
e
2
3
5 h, 81%
2 h, 94%
5
6
—
24 h, 95%f
18 h, 80%g
a Reaction conditions: substrate 4 (0.5 mmol), Cu2O (0.025 mmol, 5 mol%), DMEDA (0.05 mmol, 10 mol%), Cs2CO3 (3 equiv), in toluene (3 mL),
f
at 70 °C. b Isolated yield. c At 100 °C. d Under common conditions. e An inseparable mixture was obtained. Conversion. g Using K2CO3 as the base,
at 70 °C; the intermediate (2-bromo-1H-indol-1-yl) (2-mercaptophenyl)methanone 6e was also isolated (in 17% yield).
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Scheme 4 Selective synthesis of monocyclized and double cyclized
products.
In order to further extend our method for the preparation of S-
containing polycyclic products, the domino reaction of N-(2-
(2,2-dibromovinyl)phenyl)-2-mercaptobenzamide 4f was also
investigated. To our delight, the protocol was also viable for the
assembly of 12H-benzo[5,6][1,3]thiazino[3,2-a]indol-12-one
(Table 3, Entry 6). Thus the cascade C–N coupling/C–S bond
formation could also be successfully achieved under the similar
reaction conditions (using K2CO3 as the base).
Scheme 6 Synthesis of double cyclized products on large scale.
reactions proceeded equally well on 10 mmol scale and gave the
corresponding double cyclized products in good to excellent
yields despite the requirement of more amount of promoters and
longer reaction times (Scheme 6).17
Mechanism
Tunable synthesis of different cyclized products
Preliminary investigation found that the copper catalyst was
indispensable to the first cyclization.18 In order to elucidate
whether the second step was promoted by copper catalyst or
simply by base, control experiments were carried out addition-
ally. As shown in Scheme 7, without a copper catalyst, the
double cyclized product (2c or 5a) could be obtained only in
poor yield even in longer reaction time. Based on the above
experiments, we propose that the second cyclization should also
proceed mainly via copper-catalyzed intramolecular coupling
reaction.
The reactions could proceed at either stage of the cyclization by
utilizing different bases. With K2CO3 as the base, monocyclized
product anthraniloyl 2-bromoindoles 6 were solely obtained in
satisfactory yields; while Cs2CO3 afforded double cyclized pro-
ducts 5 in good to excellent yields (Scheme 4).
One-pot synthesis of an imidazoindolone derivative
Our catalytic system was also applied successfully to the assem-
bly of an imidazoindolone 8, which had been synthesized using
the tandem intramolecular amidation facilitated by CuI/trans-
1,2-cyclohexyldiamine (Scheme 5).13j Surprisingly, compared
with the reported method (at 120 °C), the present protocol could
smoothly give the desired product at room temperature. It would
be of potential value for the assembly of the chiral indole deriva-
tives owing to its particularly mild conditions.
In view of the above observations and the previous reports,13
a possible mechanism for the copper(I)-catalyzed domino intra-
molecular cyclization was proposed (Scheme 8). The o-gem-
dibromovinyl substrate I, which might act as a N,Y-bidentate
ligand,9d,19 chelates with low valent Cu to form complex II. Oxi-
dative addition of II leads to III (the NH on amide may still
chelate with Cu). The intramolecular N-vinylation gives the
monocyclized intermediate V (via complex IV). Finally, the
intramolecular C–Y bond formation affords the double cyclized
product VIII (via intermediate VI and complex VII).
Synthesis on large scale
Large-scale reactions of several representative substrates (1a, 1b,
1d, 1g and 4a) using the simplified procedures were also investi-
gated (for details, see Experimental section). These domino
Conclusions
In summary, we have developed a mild and efficient Cu2O-cata-
lyzed domino intramolecular C–N coupling/C–Y (Y = O, S, N)
bond formation process, which has been applied in the assembly
of novel fused heterocyclic indole derivatives. Benzo[5,6][1,3]
oxazino[3,2-a]indol-12-ones, thiazino[3,2-a]indol-12-one and
indolo[2,1-b]quinazolin-12-ones were facilely and rapidly
obtained in good to excellent yields from gem-dibromovinyl
Scheme 5 One-pot synthesis of an imidazoindolone derivative.
Scheme 7 The reactions of monocyclized products 3a and 6a under different conditions.
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Scheme 8 Proposed mechanism for the copper-catalyzed double cyclization process.
systems. The method is particularly practical since the high
efficiency was maintained even under air atmosphere. The proto-
col also enables the facile and efficient synthesis of these poly-
cyclic products in large scale. Additionally, its potential to
assemble imidazoindolones under particularly mild conditions
opens an attractive entrance toward this valuable molecule class.
Therefore, the domino approach may be practical and useful for
the synthesis of the polyaromatic indole derivatives in the field
of biology and medicine science. Further investigations concern-
ing more synthetic applications of the copper-catalyzed domino
coupling strategy are underway.
ortho-hydroxy/phenylamino/mercapto benzoic acid (10 mmol),
and dry toluene (50 mL) in an oven-dried two-necked flask was
stirred at reflux. PCl3 (0.4 mL) was added dropwise via a
syringe. The reaction mixture was stirred at reflux until the reac-
tion completed (monitored by TLC). After being cooled to room
temperature, the reaction mixture was diluted by EtOAc/THF
(4 : 1, v:v), washed subsequently with aq. HCl, and sat.
NaHCO3. The organic phase was dried over Na2SO4, and con-
centrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (300–400 mesh) using petrol/
EtOAc (15 : 1 → 8 : 1, v:v) as eluent to afford the corresponding
substrate.
Experimental
General procedure for the synthesis of substrates 4a–c16.
SOCl2 (8 mL) was added dropwise to a stirred solution of o-ami-
nobenzoic acid (10 mmol) in dry CHCl3 (50 mL) at 0 °C, and
the mixture was stirred for another 15 min. The reaction mixture
was allowed to stir at room temperature for 30 min, and then stir
at reflux for 12 h. After removing the solvent and the excess
SOCl2 under reduced pressure, the corresponding o-aminoben-
zoyl chloride could be obtained (could be used directly without
further purification).
To a stirred solution of o-gem-dibromovinylaniline (10 mmol)
in dry CHCl3 (50 mL), was added dropwise a solution of the
corresponding o-aminobenzoyl chloride (10 mmol) in dry
CHCl3 (10 mL) at 0 °C, and the mixture was stirred for another
15 min. The reaction mixture was allowed to stir at room temp-
erature for 30 min, and then stirred at reflux until the reaction
completed (monitored by TLC). After being cooled to room
temperature, the reaction mixture was diluted by EtOAc/THF
(4 : 1, v:v), washed subsequently with sat. NaHCO3 and brine.
The organic phase was dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash chrom-
atography on silica gel (300–400 mesh) using petrol/EtOAc
(15 : 1 → 8 : 1, v:v) as eluent to afford the corresponding
substrate.
General information
Toluene was distilled from sodium/benzophenone. Phosphorus
trichloride (PCl3) was re-distilled before use. o-gem-Dibromo-
vinylaniline13e,13h and substrate 713j were prepared according to
the known literatures. All other reagents were obtained from
commercial sources and used without further purification, if not
stated otherwise. Petrol ether (60–90 °C) was used. All melting
points are uncorrected. The IR spectra were recorded on a FT-IR
spectrophotometer. The NMR spectra were recorded in CDCl3 or
d6-DMSO on a 400 MHz instrument with TMS as internal stan-
dard. Recorded shifts are reported in parts per million (δ)
downfield from TMS. Data are represented as follows: Chemical
shift, multiplicity (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
(300–400 mesh) or basic alumina (200–300 mesh). Unless other-
wise noted, all one-pot reactions were carried out in an oven-
dried Schlenk tube equipped with a magnetic stir bar under N2
atmosphere. Unknown compounds including the typical sub-
strates and all the key products were additionally confirmed by
HRMS. Mass spectra were obtained using ESI ionization.
General procedure for the synthesis of substrates 4e. A
mixture of substrate 4a (1 mmol), TEA (5 mmol), and dry THF
(10 mL) in an oven-dried flask was stirred at 0 °C. Acetylchlor-
ide (3.0 mmol) was added dropwise via a syringe. The reaction
mixture was stirred at 0 °C for 10 min, then allowed to stir at
room temperature until the reaction completed (monitored by
TLC). The reaction mixture was diluted by EtOAc, and washed
with sat. NaHCO3 and brine. The organic phase was dried over
General procedure
General procedure for the synthesis of the substrates (Com-
pounds 1 and 4)
General procedure for the synthesis of substrates 1a–o, 4d
and 4f15. A mixture of o-gem-dibromovinylaniline (10 mmol),
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Na2SO4, and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel
(300–400 mesh) using petrol/EtOAc (15 : 1, v:v) as eluent to
afford the corresponding substrate 4e.
and K2CO3 (1.5 mmol, 3 equiv). The Schlenk tube was capped,
and then evacuated and backfilled with N2 (3 times). Under a
positive pressure of N2, DMEDA (0.05 mmol, 10 mol%) and
toluene (3 mL) was added via syringe. The Schlenk tube was
sealed and allowed to stir at room temperature (monitored by
TLC). An additional 30 mL of EtOAc was added. The mixture
was subsequently washed with sat. Na2CO3 and brine. The
organic phase was dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromato-
graphy on silica gel (300–400 mesh) using petrol/EtOAc (15 : 1
→ 8 : 1, v:v) as eluent to give the corresponding product 8.
General procedure for the synthesis of the products (double
cyclized and monocyclized products)20
General procedure for the synthesis of the double cyclized
products 2. An oven-dried Schlenk tube was charged with a
magnetic stir bar, substrate 1 (0.5 mmol, 1 equiv), Cu2O
(0.025 mmol, 5 mol%), and K2CO3 (1.5 mmol, 3 equiv). The
Schlenk tube was capped, and then evacuated and backfilled
with N2 (3 times). Under a positive pressure of N2, DMEDA
(0.05 mmol, 10 mol%) and toluene (3 mL) was added via
syringe. The Schlenk tube was sealed and allowed to stir at
70 °C (monitored by TLC). After being cooled to room tempera-
ture, an additional 30 mL of EtOAc was added. The mixture was
subsequently washed with sat. Na2CO3 and brine. The organic
phase was dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
on basic alumina (200–300 mesh) using petrol/EtOAc (15 : 1 →
8 : 1, v:v) as eluent to give the corresponding product 2.
General procedure for the one-pot reactions under common
conditions. A Schlenk tube was charged with a magnetic stir
bar, gem-dibromovinyl substrate (0.5 mmol, 1 equiv), Cu2O
(0.025 mmol, 5 mol%), and K2CO3 (1.5 mmol, 3 equiv). Then
DMEDA (0.05 mmol, 10 mol%) and commercial toluene (3 mL)
was added via syringe under air atmosphere. The Schlenk tube
was sealed and allowed to stir at the indicated temperature (mon-
itored by TLC). After being cooled to room temperature, an
additional 30 mL of EtOAc was added. The mixture was sub-
sequently washed with sat. Na2CO3 and brine. The organic
phase was dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
on basic alumina (200–300 mesh) using petrol/EtOAc (15 : 1 →
8 : 1, v:v) as eluent to give the corresponding product.
General procedure for the synthesis of the double cyclized
products 5. An oven-dried Schlenk tube was charged with a
magnetic stir bar, substrate 4 (0.5 mmol, 1 equiv), Cu2O
(0.025 mmol, 5 mol%), and Cs2CO3 (K2CO3 for the synthesis of
5e) (1.5 mmol, 3 equiv). The Schlenk tube was capped, and then
evacuated and backfilled with N2 (3 times). Under a positive
pressure of N2, DMEDA (0.05 mmol, 10 mol%) and toluene
(3 mL) was added via syringe. The Schlenk tube was sealed and
allowed to stir at 70–100 °C (monitored by TLC). After being
cooled to room temperature, an additional 30 mL of EtOAc was
added. The mixture was subsequently washed with sat. Na2CO3
and brine. The organic phase was dried over Na2SO4, and con-
centrated under reduced pressure. The residue was purified by
column chromatography on basic alumina (200–300 mesh) using
petrol/EtOAc (15 : 1 → 8 : 1, v:v) as eluent to give the corre-
sponding product 5.
Procedure for the one-pot synthesis on a large scale
General procedure for the one-pot synthesis of 2 on 10 mmol
scale. An oven-dried two-necked 100 mL flask was charged
with a magnetic stir bar, substrate 1 (10 mmol), Cu2O
(1.0 mmol, 10 mol%), and K2CO3 (30 mmol, 3 equiv). The flask
was capped, and then evacuated and backfilled with N2 (3
times). Under a positive pressure of N2, DMEDA (2 mmol,
20 mol%) and toluene (60 mL) was added immediately via
syringe. The flask was stirred at 70 °C under N2 until the sub-
strate was consumed completely (monitored by TLC). After
being cooled to room temperature, an additional 500 mL of
EtOAc was added. The mixture was subsequently washed with
sat. Na2CO3 (3 × 100 mL) and brine (3 × 100 mL). The organic
phase was dried over Na2SO4, then flashed through a plug of
basic alumina (200–300 mesh), and the plug was washed with
additional EtOAc (3 × 50 mL). The combined filtrate was con-
centrated in vacuo to give the corresponding product 2. The
product could be further purified by recrystallization in petrol/
THF.
General procedure for the synthesis of the monocyclized pro-
ducts 6. An oven-dried Schlenk tube was charged with a mag-
netic stir bar, substrate
4 (0.5 mmol, 1 equiv), Cu2O
(0.025 mmol, 5 mol%), and K2CO3 (1.5 mmol, 3 equiv). The
Schlenk tube was capped, and then evacuated and backfilled
with N2 (3 times). Under a positive pressure of N2, DMEDA
(0.05 mmol, 10 mol%) and toluene (3 mL) was added via
syringe. The Schlenk tube was sealed and allowed to stir at
70 °C (monitored by TLC). After being cooled to room tempera-
ture, an additional 30 mL of EtOAc was added. The mixture was
subsequently washed with sat. Na2CO3 and brine. The organic
phase was dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
on basic alumina (200–300 mesh) using petrol/EtOAc (15 : 1 →
8 : 1, v:v) as eluent to give the corresponding product 6.
General procedure for the one-pot synthesis of 5 on 10 mmol
scale. An oven-dried two-necked 100 mL flask was charged
with a magnetic stir bar, substrate 4 (10 mmol), Cu2O
(1.0 mmol, 10 mol%), and Cs2CO3 (30 mmol, 3 equiv). The
flask was capped, and then evacuated and backfilled with N2 (3
times). Under a positive pressure of N2, DMEDA (2 mmol,
20 mol%) and toluene (60 mL) was added immediately via
syringe. The flask was stirred at 70 °C under N2 until the sub-
strate was consumed completely (monitored by TLC). After
being cooled to room temperature, an additional 500 mL of
EtOAc was added. The mixture was subsequently washed with
Procedure for the synthesis of the imidazoindolone 8. An
oven-dried Schlenk tube was charged with a magnetic stir bar,
substrate 7 (0.5 mmol, 1 equiv), Cu2O (0.025 mmol, 5 mol%),
1608 | Org. Biomol. Chem., 2012, 10, 1602–1611
This journal is © The Royal Society of Chemistry 2012

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sat. Na2CO3 (3 × 100 mL) and brine (3 × 100 mL). The organic
phase was dried over Na2SO4, then flashed through a plug of
basic alumina (200–300 mesh), and the plug was washed with
additional EtOAc (3 × 50 mL). The combined filtrate was con-
centrated in vacuo to give the corresponding product 5. The
product could be further purified by recrystallization in petrol/
EtOAc.
153.7, 145.1, 129.3, 129.0, 127.6, 125.2, 123.1, 120.51, 120.48,
119.9, 116.0, 114.2, 114.16, 85.2; HRMS (ESI) calcd. for
C16H8F3NO2 [M + Na]+: 326.0399; found: 326.0398.
8-Chloro-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-one (2f).
Pale yellow solid; mp 185–186 °C; IR (KBr): v 3117, 3070,
1
1705, 1593, 1466, 1448, 1360, 1068, 875, 749, 647 cm−1; H
NMR (400 MHz, CDCl3): δ 8.47 (d, J = 8.4 Hz, 1H), 8.27
(d, J = 7.6 Hz, 1H), 7.70–7.73 (m, 1H), 7.50 (s, 1H), 7.33–7.39
(m, 2H), 7.26–7.27 (m, 1H), 6.08 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ 156.4, 153.9, 146.5, 135.8, 130.3, 129.1, 128.1,
127.2, 124.3, 122.8, 119.3, 116.9, 116.5, 114.1, 83.7; HRMS
(ESI) calcd. for C15H8ClNO2 [M + H]+: 270.0316; found:
270.0317.
Characterization data for the products 2a–2n
12H-Benzo[5,6][1,3]oxazino[3,2-a]indol-12-one
(2a). Pale
yellow solid; mp 150–152 °C; IR (KBr): v 3127, 1714, 1702,
1625, 1597, 1576, 1468, 1453, 1367, 1336, 1208, 1101, 875,
1
753, 646 cm−1; H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 8.4
Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.71–7.75 (m, 1H), 7.58–7.60
(m, 1H), 7.35–7.40 (m, 4H), 6.18 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ 156.7, 153.9, 145.7, 135.5, 129.0, 128.1, 127.8,
124.7, 124.0, 122.6, 119.6, 116.4, 115.9, 114.3, 84.2; HRMS
(ESI) calcd. for C15H9NO2 [M + H]+: 236.0706; found:
236.0703.
8-Chloro-3-methyl-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-
one (2g). White solid; mp 210–212 °C; IR (KBr): v 3070, 2911,
1709, 1594, 1458, 1378, 1355, 1164, 1114, 1065, 910, 806, 759,
1
730 cm−1; H NMR (400 MHz, CDCl3): δ 8.45 (d, J = 8.4 Hz,
1H), 8.11 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.23–7.25 (m, 1H),
7.15 (d, J = 7.6 Hz, 1H), 7.10 (s, 1H), 6.03 (s, 1H), 2.48 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 156.5, 153.9, 147.5, 146.7,
130.2, 129.1, 127.8, 127.2, 125.6, 122.6, 119.2, 116.8, 116.5,
111.6, 83.5, 22.0; HRMS (ESI) calcd. for C16H10ClNO2
[M + H]+: 284.0473; found: 284.0476.
3-Methyl-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-one (2b).
Pale yellow solid; mp 154–155 °C; IR (KBr): v 3055, 2922,
1703, 1615, 1605, 1577, 1456, 1428, 1384, 1361, 1331, 1165,
1
763 cm−1; H NMR (400 MHz, CDCl3): δ 8.59 (d, J = 7.6 Hz,
1H), 8.17 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H),
7.34–7.37 (m, 2H), 7.14–7.18 (m, 2H), 6.14 (s, 1H), 2.50(s,
3H); 13C NMR (100 MHz, CDCl3): δ 156.8, 154.0, 147.3,
145.9, 129.0, 127.9, 127.8, 125.4, 124.6, 122.5, 119.5, 116.5,
115.9, 111.8, 84.0, 22.0; HRMS (ESI) calcd. for C16H11NO2
[M + H]+: 250.0863; found: 250.0862.
2,8-Dichloro-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-one (2h).
Pale yellow solid; mp 217–219 °C; IR (KBr): v 3120, 1716,
1621, 1597, 1575, 1475, 1431, 1400, 1360, 1069, 918, 862,
1
771, 698 cm−1; H NMR (400 MHz, CDCl3): δ 8.44 (d, J = 8.8
Hz, 1H) 8.23 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H),
7.26–7.32 (m, 2H), 6.09 (s, 1H); 13C NMR (100 MHz, CDCl3):
δ 154.2, 152.3, 145.8, 135.7, 130.7, 129.9, 129.0, 127.5, 123.1,
119.4, 118.1, 116.9, 115.9, 115.2, 84.2; HRMS (ESI) calcd. for
C15H7Cl2NO2 [M + Na]+: 325.9746; found: 325.9750.
1-Methyl-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-one (2c).
White solid; mp 147–149 °C; IR (KBr): v 3117, 3055, 2922,
1710, 1624, 1598, 1577, 1485, 1470, 1454, 1388, 1371, 1204,
1
752 cm−1; H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 8.0 Hz,
9-Bromo-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-one (2i).
Pale yellow solid; mp 201–203 °C; IR (KBr): v 3131, 1708,
1H), 8.15 (d, J = 8.0 Hz, 1H), 7.53–7.58 (m, 2H), 7.34–7.37 (m,
2H), 7.25 (t, J = 7.2 Hz, 1H), 6.18 (s, 1H), 2.50 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 157.0, 152.2, 145.8, 136.7, 128.9,
127.8, 126.0, 125.7, 124.6, 123.5, 122.5, 119.5, 115.9, 114.0,
84.1, 15.5; HRMS (ESI) calcd. for C16H11NO2 [M + H]+:
250.0863; found: 250.0861.
1622, 1604, 1594, 1471, 1436, 1401, 1359, 878, 817, 751 cm−1
;
1H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.29 (d, J = 7.6
Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.34–7.45 (m, 4H), 6.12
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 156.5, 153.9, 145.8,
135.8, 129.4, 128.2, 127.9, 126.6, 124.3, 120.7, 118.9, 116.5,
115.5, 114.0, 84.0; HRMS (ESI) calcd. for C15H8BrNO2
[M + Na]+: 335.9631; found: 335.9646.
2-Chloro-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-one (2d).
Pale yellow solid; mp 213–214 °C; IR (KBr): v 3127, 3050,
1702, 1629, 1603, 1472, 1453, 1436, 1382, 1360, 1334, 1272,
8-Bromo-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-one (2j).
Pale yellow solid; mp 204–206 °C; IR (KBr): v 3130, 1704,
1200, 823, 790, 768, 743, 694 cm−1 1H NMR (400 MHz,
;
1
CDCl3): δ 8.55–8.57 (m, 1H), 8.25–8.26 (m, 1H), 7.65 (dd, J1 =
8.8 Hz, J2 = 2.4 Hz, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.30–7.38
(m, 3H), 6.17 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 155.5,
152.3, 145.3, 135.5, 129.6, 128.9, 127.7, 127.5, 125.0, 122.9,
119.7, 118.1, 115.9, 115.4, 84.7; HRMS (ESI) calcd. for
C15H8ClNO2 [M + H]+: 270.0316; found: 270.0326.
1621, 1592, 1467, 1443, 1401, 875, 771, 749, 646 cm−1; H
NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 8.25 (s, 1H),
7.65–7.71 (m, 2H), 7.34–7.38 (m, 3H), 6.06 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ 156.4, 153.8, 146.3, 135.8, 129.5, 128.1,
127.5, 125.4, 124.3, 122.2, 118.1, 117.2, 116.5, 114.1, 83.6;
HRMS (ESI) calcd. for C15H8BrNO2 [M + Na]+: 335.9631;
found: 335.9640.
3-(Trifluoromethyl)-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-
one (2e). Yellow solid; mp 211–213 °C; IR (KBr): v 3134,
1704, 1643, 1623, 1458, 1438, 1401, 1336, 1131, 929, 770,
8-(Benzyloxy)-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-one
1
(2k). Pale yellow solid; mp 202–204 °C; H NMR (400 MHz,
1
693 cm−1; H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 6.8 Hz,
CDCl3): δ 8.48 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H),
7.70 (t, J = 7.6 Hz, 1H), 7.47–7.49 (m, 2H), 7.33–7.42 (m, 5H),
7.12–7.13 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 5.15
1H), 8.43 (d, J = 8.0 Hz, 1H), 7.57–7.63 (m, 3H), 7.38 (m, 2H),
6.21 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 156.1, 155.5,
This journal is © The Royal Society of Chemistry 2012
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(s, 2H); 13C NMR (100 MHz, CDCl3): δ 156.5, 153.7, 146.2,
135.3, 128.9, 128.5, 127.9, 127.8, 127.4, 125.4, 124.0, 123.6,
119.6, 116.7, 116.3, 111.3, 104.2, 84.2, 70.4; HRMS (ESI)
calcd. for C22H15NO3 [M + Na]+: 364.0944; found: 364.0956.
3-Chloroindolo[2,1-b]quinazolin-12(5H)-one (5c). Pale yellow
solid; mp 212 °C (decomposed); IR (KBr): v 3127, 1639, 1614,
1570, 1542, 1485, 1456, 1401, 1287, 1241, 1123, 1090, 753.0,
1
697 cm−1; H NMR (400 MHz, d6-DMSO): δ 7.94 (d, J = 8.8
Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.59 (b, 1H), 7.43–7.48 (m,
2H), 7.28–7.31 (m, 1H), 6.92 (s, 1H), 6.65–6.70 (m, 2H); 13C
NMR (100 MHz, d6-DMSO): δ 154.0, 151.7, 147.0, 138.0,
137.4, 131.8, 130.6, 128.4, 126.5, 123.1, 119.3, 115.6, 115.3,
108.0, 82.0; HRMS (ESI) calcd. for C15H9ClN2O [M + H]+:
269.0476; found: 269.0481.
7H-Naphtho[2′,1′:5,6][1,3]oxazino[3,2-a]indol-7-one (2l). Pale
yellow solid; mp 222–224 °C; IR (KBr): v 3127, 1705, 1614,
1596, 1577, 1510, 1453, 1442, 1398, 763 cm−1 1H NMR
;
(400 MHz, CDCl3): δ 8.64 (d, J = 7.2 Hz, 1H), 8.52 (d, J = 7.2
Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H),
7.67–7.74 (m, 3H), 7.61–7.63 (m, 1H), 7.37–7.39 (m, 2H), 6.32
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 157.0, 151.4, 145.7,
136.9, 129.8, 128.8, 128.0, 127.6, 127.2, 124.6, 123.8, 122.6,
122.5, 121.9, 119.7, 119.6, 115.9, 109.0, 84.3; HRMS (ESI)
calcd. for C19H11NO2 [M + Na]+: 308.0682; found: 308.0690.
5-Phenylindolo[2,1-b]quinazolin-12(5H)-one (5d). Pale yellow
solid; mp 195 °C (decomposed); IR (KBr): v 3130, 1686, 1608,
1597, 1581, 1572, 1492, 1484, 1475, 1467, 1450, 1401, 1365,
1340, 1314, 867, 753, 698 cm−1 1H NMR (400 MHz, d6-
;
DMSO): δ 8.61 (d, J = 6.8 Hz, 1H), 8.28 (d, J = 6.8 Hz, 1H),
7.62–7.74 (m, 6H), 7.43 (s, 1H), 7.22–7.27 (m, 3H), 6.60 (d, J =
7.6 Hz, 1H), 5.31 (s, 1H); 13C NMR (100 MHz, d6-DMSO): δ
158.9, 142.1, 140.4, 138.2, 135.4, 131.6, 130.4, 130.2, 130.0,
129.7, 128.5, 124.7, 121.3, 120.9, 118.8, 115.9, 114.2, 113.1,
83.8; HRMS (ESI) calcd. for C21H14N2O [M + H]+: 311.1179;
found: 311.1188.
6H-Naphtho[2′,3′:5,6][1,3]oxazino[3,2-a]indol-6-one
Pale yellow solid; mp 267–269 °C; IR (KBr): v 3130, 1699,
1619, 1597, 1477, 1461, 1400, 767, 741 cm−1 1H NMR
(2m).
;
(400 MHz, CDCl3): δ 8.92 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H),
8.05 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H),
7.62 (t, J = 7.6 Hz, 1H), 7.52–7.57 (m, 2H), 7.35–7.37 (m, 2H),
6.16 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 156.8, 149.9,
146.0, 136.9, 130.5, 129.7, 129.64, 129.59, 128.0, 127.1, 125.9,
124.8, 122.8, 119.6, 116.0, 114.5, 112.1, 110.0, 84.5; HRMS
(ESI) calcd. for C19H11NO2 [M + Na]+: 308.0682; found:
308.0688.
12H-Benzo[5,6][1,3]thiazino[3,2-a]indol-12-one (5e). Yellow
solid; mp 164–166 °C; IR (KBr): v 3123, 1674, 1520, 1437,
1
1401, 1371, 1360, 1340, 748 cm−1; H NMR (400 MHz, d6-
DMSO): δ 8.67 (m, 1H), 8.44 (d, J = 6.4 Hz, 1H), 7.62–7.70
(m, 3H), 7.51 (m, 1H), 7.36 (m, 2H), 7.01 (s, 1H); 13C NMR
(100 MHz, d6-DMSO): δ 159.7, 135.4, 134.3, 133.3, 131.0,
129.3, 127.0, 126.7, 126.2, 125.1, 123.7, 123.2, 119.8, 116.8,
104.6; HRMS (ESI) calcd. for C15H9NOS [M + Na]+: 274.0297;
found: 274.0302.
6-(Trifluoromethyl)-12H-benzo[5,6][1,3]oxazino[3,2-a]indol-12-
1
one (2n). White solid; mp 189–191 °C; H NMR (400 MHz,
CDCl3): δ 8.62 (d, J = 7.2 Hz, 1H), 8.33 (d, J = 7.2 Hz, 1H),
7.79 (t, J = 7.2 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.41–7.50 (m,
4H); 13C NMR (100 MHz, CDCl3): δ 156.1, 153.4, 136.2,
128.2, 128.15, 128.06, 125.6, 125.2, 124.1, 123.7, 121.8, 118.6,
116.9, 116.1, 116.0, 114.1; HRMS (ESI) calcd. for C16H8F3NO2
[M + Na]+: 326.0399; found: 326.0407.
Characterization data for the product 8
tert-Butyl-3-oxo-2,3-dihydro-1H-imidazo[1,2-a]indole-1-car-
boxylate (8)13j. White solid; mp 175–177 °C; 1H NMR
(400 MHz, CDCl3): δ 7.85 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 6.8
Hz, 1H), 7.17–7.26 (m, 2H), 6.17 and 5.86 (s, 1H), 4.53 (s, 2H),
1.63 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 162.7, 149.8,
135.1, 127.5, 124.9, 122.5, 120.1, 113.2, 86.6, 53.9, 28.2.
Characterization data for the products 5a–5e
Indolo[2,1-b]quinazolin-12(5H)-one (5a). Yellow solid; mp
180 °C (decomposed); IR (KBr): v 3126, 1648, 1607, 1582,
1525, 1449, 1401, 1302, 1215, 1165, 757 cm−1 1H NMR
;
Acknowledgements
(400 MHz, CDCl3): δ 8.17 (d, J = 8.0 Hz, 1H), 7.34–7.38 (m,
2H), 7.26–7.28 (m, 2H), 7.16–7.20 (m, 1H), 6.70–6.77 (m, 2H),
6.39 (b, 1H), 5.94 (s, 1H); 13C NMR (100 MHz, CDCl3): δ
155.0, 149.5, 147.5, 137.9, 132.9, 130.9, 129.6, 127.4, 126.2,
121.8, 119.4, 116.52, 116.50, 110.9, 79.7; HRMS (ESI) calcd.
for C15H10N2O: [M + H]+: 235.0866; found: 235.0864.
This work was financially supported by the Zhejiang Provincial
Natural Science Foundation (No. Y4110044), the National
Natural Science Foundation of China (No. 20802070), and the
College Science and Technology Innovation Program of
Zhejiang Province (No. 2011R404051).
4-Methylindolo[2,1-b]quinazolin-12(5H)-one (5b). Pale yellow
solid; mp 194 °C (decomposed); IR (KBr): v 3115, 1637, 1606,
Notes and references
1
1591, 1567, 1463, 1400, 1281, 1238, 1124, 760, 740 cm−1; H
NMR (400 MHz, d6-DMSO): δ 7.91 (d, J = 7.6 Hz, 1H), 7.75
(d, J = 7.6 Hz, 1H), 7.44–7.47 (m, 2H), 7.26–7.34 (m, 2H),
7.18–7.19 (m, 1H), 6.67 (s, 1H), 6.59 (t, J = 7.2 Hz, 1H), 2.15
(s, 3H); 13C NMR (100 MHz, d6-DMSO): δ 155.1, 149.2, 147.1,
137.5, 134.3, 131.8, 128.2, 126.9, 126.2, 123.6, 123.2, 119.2,
115.1, 108.9, 81.8, 18.3; HRMS (ESI) calcd. for C16H12N2O
[M + H]+: 249.1022; found: 249.1018.
1 R. J. Sundberg, Indoles, Academic Press, San Diego, 1996, 175.
2 (a) M. Fedouloff, F. Hossner, M. Voyle, J. Ranson, J. Powles, G. Riley
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15 The substrate (a) o-gem-dibromovinyl salicylanilide 1 could be facilely
and efficiently prepared from the corresponding o-gem-dibromovinylani-
line and salicylic acid with PCl3 as the promoter in refluxing PhMe. For
details, see Experimental section. Some related references: S. K. Dubey,
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21, 1178; (b) H. Singh, A. K. Singh, S. Sharma and R. N. Iyer, J. Med.
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16 The substrate 2-amino-N-(2-(2,2-dibromovinyl)phenyl)-benzamides
4
could be facilely and efficiently prepared from the corresponding o-gem-
dibromovinylaniline and o-aminobenzoyl chloride in refluxing CHCl3.
For details, see Experimental section. A related reference: J. Tani,
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17 The first large-scale experiment using 1a as the substrate was carried out
in the presence of 5 mol% Cu2O. It was found that a small amount of the
substrate still remained over 24 h (observed by TLC), and the desired
product 2a was obtained in 83% yield. However, increasing the catalyst
loading to 10 mol% gave better results (in 94% yield) within 15 h. There-
fore, 10 mol% Cu2O was chosen as the catalyst for the large-scale
domino reactions
18 A blank test of the reaction of 1c was performed without the copper(I)
catalyst, and the monocyclized product 3a could be obtained only in trace
amount after 6 h (2c was not detected)
19 F. Y. Kwong and S. L. Buchwald, Org. Lett., 2003, 5, 793.
20 Special notes for the treatments of the products: Surprisingly, although
all of the cyclized products were stable when they were dry, most of these
compounds seemed to be rather sensitive to some solvents such as
CH2Cl2 and CHCl3. Contact with these solvents would lead to the for-
mation of an unidentified substance with strong polarity. Therefore, once
the sample was dissolved in CDCl3, its NMR spectrum should be
recorded immediately. These products were also sensitive to silica gel.
Basic alumina should be used instead of silica gel when they were
purified by column chromatography
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