Solvent-dependent copper-catalyzed indolyl C3-oxygenation and N1-cyclization reactions: Selective synthesis of 3 H-indol-3-ones and indolo[1,2- c] quinazolines

Article abstract of DOI:10.1021/acs.joc.8b00231

A simple and practical procedure for the selective preparation of 3H-indol-3-one and indolo[1,2-c]quinazoline derivatives through copper-catalyzed aerobic oxygenation and intramolecular cyclization reactions of 2-(2-amidoaryl)-1H-indoles in the presence o

Full text of DOI:10.1021/acs.joc.8b00231

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Solvent-Dependent Copper-Catalyzed Indolyl C3-
Oxygenation and N1-Cyclization Reactions: Selective
Synthesis of 3H-Indol-3-ones and Indolo[1,2-c]quinazolines
Shenghai Guo, Fang Wang, Li Tao, Xinying Zhang, and Xuesen Fan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00231 • Publication Date (Web): 07 Mar 2018
Downloaded from http://pubs.acs.org on March 7, 2018
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Solvent-Dependent Copper-Catalyzed Indolyl C3-Oxygenation and N1-Cyclization
Reactions: Selective Synthesis of 3H-Indol-3-ones and Indolo[1,2-c]quinazolines
Shenghai Guo,* Fang Wang, Li Tao, Xinying Zhang, and Xuesen Fan*
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School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic
Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical Media and
Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, P. R.
China. E-mail: shguo@htu.cn; xuesen.fan@htu.cn
Abstract: A simple and practical procedure for the selective preparation of 3H-indol-3-one
and indolo[1,2-c]quinazoline derivatives through copper-catalyzed aerobic oxygenation and
intramolecular cyclization reactions of 2-(2-amidoaryl)-1H-indoles in the presence of acid has
been disclosed. Interestingly, the reaction outcomes are exclusively dependent on the reaction
medium employed. With DMF as the solvent, the amide moiety of indole substrates could act
as an auxiliary to enable the indole's oxygenation reaction with molecular oxygen from air as
the oxidant to give 3H-indol-3-one derivatives in a highly selective manner. On the other
hand, when the reactions were performed in 1,4-dioxane, the amide moiety switched to
participate in an intramolecular indolyl N1-cyclization to afford indolo[1,2-c]quinazolines as
the predominating products.
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Introduction
3H-Indol-3-one derivatives not only are frequently found in naturally occurring alkaloids1
and natural/artificial colorants,2 but also exhibit important antiplasmodial, antiproliferative,
antimicrobial, and potent CYP1A1 enzyme inhibitory activities.3 In addition, they have also
been extensively utilized as key building blocks for the construction of synthetically valuable
indolin-3-one skeletons with a quaternary carbon center at the C2-position through
nucleophilic addition4 and Diels-Alder reactions,5 exemplified by the synthesis of natural
alkaloids (-)-isatisine A6 and 8-desbromohinckdentine A.7 Accordingly, much effort has been
dedicated to the preparation of 3H-indol-3-one derivatives, and several synthetic routes have
been documented. For example, 2-substituted-3H-indol-3-one derivatives have been prepared
via the classical four-step procedure,7a,8 the oxidation of indoles with different oxidants,9 and
the indium-mediated deoxygenation of indolone-N-oxides.3a,10 However, these existing
methods suffer from the disadvantages of multistep processes, low yields, use of
stoichiometric oxidants or expensive metal catalysts, and difficult-to-obtain starting materials.
Therefore, the development of practical and efficient procedures for the preparation of
3H-indol-3-one derivatives in a user-friendly manner remains in high demand in the fields of
organic and pharmaceutical chemistry.
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Recently, the combination of copper catalyst and molecular oxygen has emerged as an ideal
oxygenating reagent for the incorporation of oxygen atom into diverse organic molecules to
deliver more complex oxygen-containing organic compounds via selective oxidative C-H
bond functionalization.11 For example, copper-catalyzed oxygenation reactions of indole
derivatives with the use of molecular oxygen as a green oxidant and reactant have been
successfully utilized in the preparation of various valuable nitrogen-containing heterocyclic
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compounds, such as benzoxazinone, 2,2-bis(3'-indolyl)-indoxyl, quinazolinone, and
tryptanthrin derivatives.12 However, literature searching revealed that, to date, 3H-indol-3-
ones are hardly obtained through copper-catalyzed direct oxygenation of indoles. As a
continuation of our studies on copper-catalyzed aerobic synthesis of N-heterocycles, we
recently found that 3H-indol-3-one derivatives could be successfully obtained through the
direct oxygenation reaction of 2-arylindoles featuring an amido group on the 2-position of
aryl ring by using copper as catalyst and molecular oxygen from air as oxygen-atom source in
acidic conditions. Here, we would like to disclose our preliminary results in this aspect.
Results and Discussion
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Initially, N-(2-(1H-indol-2-yl)phenyl)benzamide (1a) was chosen as a model substrate to
optimize the reaction parameters with regard to copper catalysts, acids, reaction temperature,
and solvents (Table 1). Treatment of 1a (0.4 mmol) with CuI (10 mol %) and HCl (20 mol %)
in DMSO (2 mL) at 120 oC for
4
h
under air could give rise to
N-(2-(3-oxo-3H-indol-2-yl)phenyl)benzamide (2a) in 49% yield (entry 1). The structure of 2a
was unambiguously confirmed by X-ray analysis (see the Supporting Information). To
improve the efficiency, other copper catalysts including CuBr, CuCl, CuBr2, CuCl2, and
Cu(OAc)2 were tested (entries 2-6). Of these catalysts, CuBr showed the highest activity
(56%). Then, we also investigated the effect of different acids such as H2SO4, CF3COOH,
TsOH, and PivOH on this CuBr-catalyzed oxygenation reaction (entries 7-10). Among them,
HCl gave the best result (entries 2 vs. 7-10). Furthermore, the amount of CuBr and HCl was
screened, and the use of 10 mol % of CuBr and 20 mol % of HCl proved to be optimal (Table
S1, in supporting information). Increasing or decreasing the reaction temperature from 120 oC
resulted in a lower yield of 2a (entries 11-12). In following studies, three more solvents
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including DMF, NMP, and DMA (N,N-dimethylacetamide) were also tried (entries 13-15),
and it turned out that DMF was the best reaction medium for the formation of 2a (70%, entry
13). It should be noted that, with the use of DMA as solvent, this reaction not only afforded
2a in 18% yield, but also gave rise to the unexpected 6-phenylindolo[1,2-c]quinazoline (3a)
in 16% yield (entry 15). Moreover, the formation of 2a was obviously suppressed in the
absence of HCl or CuBr (entries 16-17). Finally, it was also observed that under a nitrogen
atmosphere, this reaction afforded a trace amount of 2a along with 77% recovery of 1a (entry
18). When the reaction was performed under an oxygen atmosphere, 2a was obtained in 68%
yield (entry 19).
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Table 1. Optimization of Reaction Conditions for the Synthesis of 2aa
yield (%)b
entry
catalyst
acid
solvent
2a
3a
1
2
CuI
CuBr
CuCl
HCl (0.5 M)
HCl (0.5 M)
HCl (0.5 M)
HCl (0.5 M)
HCl (0.5 M)
HCl (0.5 M)
H2SO4 (0.5 M)
CF3COOH
TsOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
49
nd
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35
20
28
52
30
44
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42
27
14
70
29
18
48
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
16
nd
3
4
CuBr2
CuCl2
Cu(OAc)2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
5
6
7
8
9
10
11c
12d
13
14
15
16
PivOH
HCl (0.5 M)
HCl (0.5 M)
HCl (0.5 M)
HCl (0.5 M)
HCl (0.5 M)
-
NMP
DMA
DMF
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17e
18f
19g
-
HCl (0.5 M)
HCl (0.5 M)
HCl (0.5 M)
DMF
DMF
DMF
3
4
nd
nd
nd
CuBr
CuBr
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aThe reactions were run with: 1a (0.4 mmol), catalyst (0.04 mmol), acid (0.08 mmol), solvent (2 mL), 120
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oC, 4 h, air. bnd = not detected. cThe reaction was run at 140 oC. dThe reaction was run at 100 oC. e1a (79%)
f
g
was recovered. The reaction was run under N2 and 1a (77%) was recovered. The reaction was run under
O2.
With the optimized reaction conditions (Table 1, entry 13) in hand, we next investigated
the scope and limitation of this copper-catalyzed oxygenation reaction leading to
2-aryl-3H-indol-3-ones (2), and the results are demonstrated in Table 2. First, the effect of
different substituents (R1) was examined. It was found that 1H-indoles 1b-1f bearing both
aromatic and aliphatic groups on the amide moiety were all compatible with the optimized
reaction conditions to afford the corresponding 3H-indol-3-one derivatives 2 in moderate
yields. For example, indole substrates with either electron-donating groups (-Me and -OMe)
or electron-withdrawing groups (-Cl, and -NO2) at the para position of the phenyl ring (R1)
underwent this oxygenation reaction smoothly to give rise to the desired oxygenated indoles
2b-2e in 43-61% yields. When 2-aryl-1H-indole (R1 = Me) was employed, this reaction could
also afford the corresponding 3H-indol-3-one (2f) in 44% yield. Next, we also studied the
effect of the substituents (R2) attached to the 2-phenyl unit of indoles (1) on this oxygenation
reaction. The results indicated that indole substrates (1) bearing a methyl, chloro, or
trifluoromethyl group on the 2-phenyl unit took part in this reaction smoothly to yield 2g-2i in
modest yields. In addition, substrates (1) with either electron-donating or
electron-withdrawing groups (R3) on the indole scaffold were well tolerated with the reaction
conditions to provide the corresponding products 2j-2o in 51%-64% yields. To further expand
the substrate scope, we also tested the oxygenation reactions of substrates 1p and 1q.
Unfortunately, the expected oxygenation reactions did not occur possibly due to the low
reactivity of 1p and 1q. Finally, to demonstrate the practicability of the present protocol, a
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gram-scale oxygenation reaction of 1a (1.56 g) was carried out, and it afforded 2a in 72%
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yield.
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Table 2. Scope for the Synthesis of 3H-Indol-3-one Derivatives (2)a,b
2a, 70%/72%c
2d, 61%
2h, 48%
2c, 60%
2b, 55%
2f, 44%
O
H3C
N
NHCOPh
2g, 51%
2e, 43%
2i, 47%
Cl
O
N
NHCOC6H4(4-CH3)
2j, 52%
2n, 64%
2k, 60%
2o, 51%
2l, 60%
2p, not obtained
2m, 63%
2q, not obtained
aReaction conditions: 1 (0.4 mmol), CuBr (0.04 mmol), 0.5 M HCl (0.16 mL), DMF (2 mL), 120 C, air.
o
bYields. c 1a (1.56 g) was used.
Having established a practical route to 3H-indol-3-ones (2) through the copper-catalyzed
direct oxygenation of indoles (1) by using molecular oxygen from air as a green oxidant and
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reactant, we turned our attention back to 6-phenylindolo[1,2-c]quinazoline (3a), which was
isolated as an unexpected byproduct in 16% yield (Table 1, entry 15). As we know,
indolo[1,2-c]quinazolines, as an important class of fused N-heterocycles, are frequently
encountered in naturally occurring alkaloids and synthetic compounds with a broad spectrum
of bioactivities.13 Although several synthetic routes have been developed,14 it is still in high
demand to develop a new alternative for the synthesis of indolo[1,2-c]quinazoline derivatives
by using the indoles (1) as starting materials. To the best of our knowledge, the
N1-cyclization reaction of the indoles (1) promoted by the combination of copper and acid
leading to indolo[1,2-c]quinazolines has not been reported yet.
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Thus, we undertook an extensive study on the selective synthesis of
indolo[1,2-c]quinazoline derivatives from the indoles (1) by tuning the reaction parameters.
After several attempts (Table S2, in supporting information), we found that, with the
replacement of DMF by 1,4-dioxane as the reaction medium, indole (1a) could be exclusively
transformed into the desired 6-phenylindolo[1,2-c]quinazoline (3a) in 72% yield under the
optimal reaction conditions for the preparation of 2a (Table 1, entry 13), suggesting that
reaction medium played a vital role in the selective transformation of 1a to 2a or 3a. With the
optimal reaction conditions established, we then tested the substrate scope for the synthesis of
indolo[1,2-c]quinazolines (3) in detail. As shown in Table 3, various indole substrates (1)
with aromatic and aliphatic substituents (R1) on the amide unit took part in this N-cyclization
reaction to provide the expected indolo[1,2-c]quinazolines 3a-3f in moderate to good yields.
In addition, both electron-donating and electron-withdrawing functional groups (R2) attached
on the 2-phenyl ring of indoles (1) were well compatible with the optimized reaction
conditions to yield the corresponding products 3g and 3h in 60% and 62% yields, respectively.
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Next, we also found that indoles (1) with different functional groups (R3) on the indole
scaffold proved to be good substrates and underwent this reaction smoothly to afford the
desired products 3i-3o. Finally, with 1p and 1q as reactants, these cyclization reactions could
also generate the desired products 3p and 3q in 50% and 65% yields, respectively.
Table 3. Scope for the Synthesis of Indolo[1,2-c]quinazoline Derivatives (3)a,b
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N
N
OCH3
3c, 57%
3a, 72%
3e, 40%
3d, 61%
3h, 62%
3b, 54%
3f, 48%
3g, 60%
Cl
N
N
3i, 53%
3j, 67%
3k, 63%
3o, 50%
3l, 60%
3p, 50%
3n, 45%
3m, 61%
3q, 65%
aReaction conditions: 1 (0.4 mmol), CuBr (0.04 mmol), 0.5 M HCl (0.16 mL), 1,4-dioxane (2 mL), 120 oC,
air. bYields.
To gain some insights into the reaction mechanism for the formation of 2a, several control
experiments were carried out as demonstrated in Scheme 1. First, when indole substrates (4-8)
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and N-Me-protected indole (9) were subjected to the optimized reaction conditions (Table 1,
entry 13), no reaction occurred. These observations suggested that the amide moiety as a key
auxiliary and the free N-H group of indoles (1a) are essential for the copper-catalyzed
oxygenation reaction. Second, this oxygenation reaction could only produce a trace amount of
2a under a nitrogen atmosphere (Table 1, entry 18). Whereas, treatment of 1a with CuBr in
anhydrous DMF under an oxygen atmosphere could afford 2a in 51% yield (Scheme 1, Eq.
1). These results indicated that the newly introduced oxygen atom of 3H-indol-3-one (2a)
derived from dioxygen (O2), rather than from water. Third, the addition of BHT (2.0 equiv.)
as a radical scavenger into the reaction system inhibited this transformation dramatically to
provide 2a in only 8% yield (Scheme 1, Eq. 2), indicating that radical intermediates might be
involved in the oxygenation reaction.
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Scheme 1. Control Experiments
On the basis of the above results and the relevant literatures,15 possible mechanisms for the
formation of 2a and 3a are shown in Scheme 2. In the oxygenation reaction of 1a, although
the detailed mechanism is unclear now, we believe that, with the use of DMF as a polar
solvent and molecular oxygen from air as the oxidant, the chelation assistance of amide
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moiety with CuBr facilitates the formation of copper-superoxide complex I, which might be
more stable in a polar solvent (DMF) than a non-polar one (dioxane). And then, I abstracts a
hydrogen atom from the indolyl NH unit to afford a N-centered radical II, which then
isomerizes to an indolyl C3 radical III. Next, the radical III would react with molecular
oxygen from air to form a peroxy radical IV. Subsequently, the peroxy radical (IV) undergoes
an intramolecular hydrogen abstraction to produce a hydroperoxide intermediate V, which
then undergoes an acid-promoted elimination of water and a dissociation of the copper
catalyst to yield 2a. As for the formation of 3a, when 1,4-dioxane is employed as a non-polar
reaction medium, the carbonyl group of the amide moiety in 1a is firstly activated in the
presence of copper and HCl to generate intermediate VI. Subsequent intramolecular
N-nucleophilic addition reaction affords intermediate VII, which then eliminates water to
furnish 3a.
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Scheme 2. Possible Mechanisms for the Formation of 2a and 3a
Conclusion
In summary, we have successfully achieved a practical protocol for the selective synthesis
of 3H-indol-3-ones and indolo[1,2-c]quinazolines via the copper-catalyzed oxygenation by
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using molecular oxygen as a sole and green oxygenating reagent and intramolecular
N-cyclization reaction under acidic conditions. Notably, the selectivity of the reaction is
exclusively dependent on the reaction solvents. With DMF as the reaction solvent, the indole
substrates undergo a selective C3-oxygenation reaction to give 3H-indol-3-ones as the main
products. Whereas, with 1,4-dioxane as the reaction medium, indolo[1,2-c]quinazolines are
selectively obtained via an intramolecular indolyl N1-cyclization. Further studies on the
reactivities of the obtained 3H-indol-3-ones and the development of novel copper-catalyzed
aerobic oxygenation reaction is currently underway in our laboratory.
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Experimental Section
General Methods. Indoles (1, 6, 8) and pyrrole (1p) were prepared according to the
previously reported literature.16 Indole (9) was synthesized based on a literature procedure.17
Unless noted, other commercial reagents and solvents were used without further purification.
1
Melting points were recorded with a micro melting point apparatus and uncorrected. The H
NMR spectra were recorded at 400 or 600 MHz. The 13C{1H} NMR spectra were recorded at
100 or 150 MHz. High-resolution mass spectra (HRMS) were collected in ESI mode by using
a MicrOTOF mass spectrometer. All reactions were monitored by thin-layer chromatography
(TLC) using silica gel plates (silica gel 60 F254 0.25 mm) and components were visualized
by observation under UV light (254 and 365 nm).
General Procedure for the Preparation of 3H-Indol-3-ones (2). To a mixture of indole 1
(0.4 mmol) in DMF (2 mL) were added CuBr (5.7 mg, 0.04 mmol) and 0.5 M HCl aqueous
solution (0.16 mL, 0.08 mmol) under air and then the resulting mixture was stirred at 120 oC
for 4~7 h. After the reactant 1 was consumed completely, water was added into the reaction
system, followed by extraction with ethyl acetate. The extract was washed with water and
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brine, and then dried over anhydrous Na2SO4. The solvent was evaporated under reduced
pressure and the residue was purified by column chromatography on silica gel to give the
corresponding 3H-indol-3-one 2.
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N-(2-(3-Oxo-3H-indol-2-yl)phenyl)benzamide (2a): Petroleum ether/ethyl acetate (10:1)
as eluent; red solid (91 mg, 70%), mp 145-146 oC. 1H NMR (CDCl3, 600 MHz) δ 7.13 (t, J =
7.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.48-7.53 (m, 6H), 8.07 (d, J =
7.2 Hz, 2H), 8.70 (d, J = 7.8 Hz, 1H), 8.93 (d, J = 8.4 Hz, 1H), 13.22 (s, 1H); 13C{1H} NMR
(CDCl3, 150 MHz) δ 116.4, 120.4, 121.1, 121.5, 123.1, 125.5, 127.8, 128.7, 128.8, 131.4,
132.0, 133.9, 135.5, 137.0, 142.5, 158.4, 160.4, 166.4, 193.2. HRMS (ESI) calcd for
C21H15N2O2 [M + H]+ 327.1128, found 327.1128.
4-Methyl-N-(2-(3-oxo-3H-indol-2-yl)phenyl)benzamide (2b): Petroleum ether/ethyl
acetate (10:1) as eluent; red solid (75 mg, 55%), mp 176-177 oC. 1H NMR (CDCl3, 600 MHz)
δ 2.44 (s, 3H), 7.13 (t, J = 7.8 Hz, 1H), 7.24-7.26 (m, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.50-7.53
(m, 3H), 7.99 (d, J = 7.8 Hz, 2H), 8.70 (d, J = 7.8 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H), 13.17 (s,
1H); 13C{1H} NMR (CDCl3, 150 MHz) δ 21.5, 116.3, 120.2, 121.0, 121.4, 122.9, 125.4,
127.8, 128.7, 129.3, 131.3, 132.5, 133.8, 136.9, 142.5, 142.7, 158.3, 160.2, 166.2, 193.2.
HRMS (ESI) calcd for C22H17N2O2 [M + H]+ 341.1285, found 341.1285.
4-Methoxy-N-(2-(3-oxo-3H-indol-2-yl)phenyl)benzamide (2c): Petroleum ether/ethyl
acetate (10:1) as eluent; red solid (85 mg, 60%), mp 163-164 oC. 1H NMR (CDCl3, 400 MHz)
δ 3.89 (s, 3H), 6.98 (d, J = 8.8 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.21-7.25 (m, 2H), 7.47-7.52
(m, 3H), 8.04 (d, J = 8.4 Hz, 2H), 8.68 (dd, J = 1.2, 8.0 Hz, 1H), 8.91 (d, J = 8.4 Hz, 1H),
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13.10 (s, 1H); C{1H} NMR (CDCl3, 100 MHz) δ 55.5, 113.8, 116.2, 120.1, 120.9, 121.4,
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122.8, 125.3, 127.6, 128.7, 129.7, 131.3, 133.7, 136.9, 142.8, 158.3, 160.2, 162.6, 165.8,
193.1. HRMS (ESI) calcd for C22H17N2O3 [M + H]+ 357.1234, found 357.1246.
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4-Chloro-N-(2-(3-oxo-3H-indol-2-yl)phenyl)benzamide (2d): Petroleum ether/ethyl
acetate (10:1) as eluent; red solid (88 mg, 61%), mp 191-192 oC. 1H NMR (CDCl3, 400 MHz)
δ 7.18-7.22 (m, 1H), 7.28-7.32 (m, 2H), 7.51-7.61 (m, 5H), 8.05-8.08 (m, 2H), 8.76 (dd, J =
1.6, 8.4 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H), 13.28 (s, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ
116.3, 120.2, 120.9, 121.4, 123.2, 125.5, 128.9, 129.2, 131.4, 133.7, 133.8, 137.0, 138.3,
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142.3, 158.1, 160.2, 165.0, 192.9 (one C signal was not observed). HRMS (ESI) calcd for
C21H14ClN2O2 [M + H]+ 361.0738, found 361.0745.
4-Nitro-N-(2-(3-oxo-3H-indol-2-yl)phenyl)benzamide (2e): Petroleum ether/ethyl acetate
o
1
(20:1) as eluent; red solid (64 mg, 43%), mp 186-188 C. H NMR (CDCl3, 600 MHz) δ
7.30-7.31 (m, 1H), 7.35-7.40 (m, 2H), 7.63-7.68 (m, 3H), 8.35 (d, J = 8.4 Hz, 2H), 8.46 (d, J
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= 8.4 Hz, 2H), 8.86 (d, J = 7.8 Hz, 1H), 9.00 (d, J = 8.4 Hz, 1H), 13.53 (s, 1H); C{1H}
NMR (CDCl3, 150 MHz) δ 116.7, 120.4, 121.0, 121.4, 123.9, 125.7, 128.9, 129.2, 131.6,
134.0, 137.3, 141.0, 141.8, 149.9, 158.1, 160.5, 164.1, 192.9 (one 13C signal was not
observed). HRMS (ESI) calcd for C21H14N3O4 [M + H]+ 372.0979, found 372.1010.
N-(2-(3-Oxo-3H-indol-2-yl)phenyl)acetamide (2f): Petroleum ether/ethyl acetate (20:1)
as eluent; red solid (46 mg, 44%), mp 178-179 oC. 1H NMR (CDCl3, 600 MHz) δ 2.25 (s, 3H),
7.10 (t, J = 7.8 Hz, 1H), 7.23-7.28 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.50-7.53 (m, 2H), 8.64
(d, J = 7.8 Hz, 1H), 8.71 (d, J = 8.4 Hz, 1H), 12.35 (s, 1H); 13C{1H} NMR (CDCl3, 150 MHz)
δ 25.6, 115.7, 120.1, 121.4, 122.8, 125.3, 128.7, 131.2, 133.6, 136.9, 142.1, 158.4, 160.2,
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169.3, 193.2 (one C signal was not observed). HRMS (ESI) calcd for C16H12N2NaO2 [M +
Na]+ 287.0791, found 287.0801.
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N-(4-Methyl-2-(3-oxo-3H-indol-2-yl)phenyl)benzamide
(2g):
Petroleum
o
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ether/dichloromethane (1:1) as eluent; red solid (70 mg, 51%), mp 147-149 C. H NMR
(CDCl3, 600 MHz) δ 2.37 (s, 3H), 7.24-7.26 (m, 2H), 7.32 (dd, J = 1.2, 8.4 Hz, 1H),
7.51-7.55 (m, 4H), 7.59 (t, J = 7.2 Hz, 1H), 8.10 (d, J = 7.2 Hz, 2H), 8.49 (s, 1H), 8.84 (d, J =
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8.4 Hz, 1H), 13.15 (s, 1H); C{1H} NMR (CDCl3, 150 MHz) δ 20.9, 116.3, 120.2, 120.9,
121.4, 125.3, 127.7, 128.56, 128.61, 131.3, 131.8, 132.5, 134.6, 135.4, 136.9, 140.2, 158.3,
160.2, 166.0, 193.2. HRMS (ESI) calcd for C22H16N2NaO2 [M + Na]+ 363.1104, found
363.1104.
N-(4-Chloro-2-(3-oxo-3H-indol-2-yl)phenyl)benzamide (2h): Petroleum ether/ethyl
acetate (10:1) as eluent; red solid (69 mg, 48%), mp 186-188 oC. 1H NMR (CDCl3, 600 MHz)
δ 7.31-7.34 (m, 2H), 7.48 (dd, J = 2.4, 9.0 Hz, 1H), 7.55-7.63 (m, 5H), 8.10 (d, J = 7.8 Hz,
2H), 8.74 (d, J = 2.4 Hz, 1H), 8.96 (d, J = 9.0 Hz, 1H), 13.21 (s, 1H); 13C{1H} NMR (CDCl3,
150 MHz) δ 117.4, 121.3, 121.5, 125.6, 127.8, 128.2, 128.7, 129.2, 130.5, 132.2, 133.5, 135.0,
137.1, 141.0, 157.9, 159.3, 166.2, 192.4 (one 13C signal was not observed). HRMS (ESI)
calcd for C21H14ClN2O2 [M + H]+ 361.0738, found 361.0760.
N-(2-(3-Oxo-3H-indol-2-yl)-4-(trifluoromethyl)phenyl)benzamide
(2i):
Petroleum
ether/ethyl acetate (10:1) as eluent; red solid (74 mg, 47%), mp 162-163 oC. 1H NMR (CDCl3,
400 MHz) δ 7.33-7.36 (m, 2H), 7.55-7.64 (m, 5H), 7.76-7.79 (m, 1H), 8.12-8.14 (m, 2H),
13
9.09 (s, 1H), 9.13 (d, J = 9.2 Hz, 1H), 13.42 (s, 1H); C{1H} NMR (CDCl3, 150 MHz) δ
116.0, 120.3, 121.3, 121.4, 123.8 (q, J = 270.2 Hz, 1C), 125.0 (q, J = 32.9 Hz, 1C), 125.8,
127.9, 128.4 (q, J = 4.4 Hz, 1C), 128.8, 129.4, 130.2 (q, J = 4.4 Hz, 1C), 132.4, 134.8, 137.2,
144.9, 157.8, 159.5, 166.6, 192.4. HRMS (ESI) calcd for C22H14F3N2O2 [M + H]+ 395.1002,
found 395.1006.
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N-(2-(5-Methyl-3-oxo-3H-indol-2-yl)phenyl)benzamide (2j): Petroleum ether/ethyl
acetate (10:1) as eluent; red solid (71 mg, 52%), mp 162-163 oC. 1H NMR (CDCl3, 600 MHz)
δ 2.26 (s, 3H), 7.03 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.24
(s, 1H), 7.43-7.46 (m, 3H), 7.50 (t, J = 7.2 Hz, 1H), 8.03 (d, J = 7.2 Hz, 2H), 8.61 (dd, J = 1.2,
8.4 Hz, 1H), 8.88 (d, J = 8.4 Hz, 1H), 13.16 (s, 1H); 13C{1H} NMR (CDCl3, 150 MHz) δ 21.2,
116.5, 120.2, 120.7, 121.6, 123.0, 126.2, 127.8, 128.6, 131.2, 131.9, 133.5, 135.4, 137.1,
139.2, 142.3, 156.0, 159.7, 166.2, 193.4. HRMS (ESI) calcd for C22H17N2O2 [M + H]+
341.1285, found 341.1292.
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N-(2-(5-Chloro-3-oxo-3H-indol-2-yl)phenyl)benzamide (2k): Petroleum ether/ethyl
acetate (10:1) as eluent; red solid (86 mg, 60%), mp 194-196 oC. 1H NMR (CDCl3, 600 MHz)
δ 7.13 (t, J = 7.2 Hz, 1H), 7.18-7.19 (m, 1H), 7.45-7.54 (m, 6H), 8.04 (d, J = 7.2 Hz, 2H),
8.65 (dd, J = 1.2, 7.8 Hz, 1H), 8.92 (d, J = 8.4 Hz, 1H), 13.07 (s, 1H); 13C{1H} NMR (CDCl3,
150 MHz) δ 116.1, 120.4, 121.9, 122.7, 123.2, 125.8, 127.8, 128.7, 131.4, 132.1, 134.2, 134.6,
135.4, 136.3, 142.7, 156.6, 160.3, 166.4, 192.2. HRMS (ESI) calcd for C21H14ClN2O2 [M +
H]+ 361.0738, found 361.0746.
N-(2-(5-Chloro-3-oxo-3H-indol-2-yl)phenyl)-4-methylbenzamide
(2l):
Petroleum
ether/ethyl acetate (20:1) as eluent; red solid (90 mg, 60%), mp 190-192 oC. 1H NMR (CDCl3,
600 MHz) δ 2.47 (s, 3H), 7.20 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.2
Hz, 2H), 7.54-7.60 (m, 3H), 8.02 (d, J = 7.2 Hz, 2H), 8.73 (d, J = 7.8 Hz, 1H), 9.00 (d, J = 7.8
Hz, 1H), 13.10 (s, 1H); 13C{1H} NMR (CDCl3, 150 MHz) δ 21.5, 115.9, 120.3, 121.8, 122.6,
123.0, 125.7, 127.8, 129.3, 131.3, 132.4, 134.1, 134.5, 136.2, 142.6, 142.8, 156.5, 160.2,
166.2, 192.2. HRMS (ESI) calcd for C22H16ClN2O2 [M + H]+ 375.0895, found 375.0906.
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N-(2-(5-Chloro-3-oxo-3H-indol-2-yl)phenyl)-4-methoxybenzamide (2m): Petroleum
ether/ethyl acetate (20:1) as eluent; red solid (98 mg, 63%), mp 198-199 oC. 1H NMR (CDCl3,
400 MHz) δ 3.91 (s, 3H), 7.01 (d, J = 8.4 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 7.2
Hz, 1H), 7.50-7.57 (m, 3H), 8.06 (d, J = 8.8 Hz, 2H), 8.69 (d, J = 7.2 Hz, 1H), 8.95 (d, J = 8.4
Hz, 1H), 13.01 (s, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 55.5, 113.9, 115.9, 120.3, 121.8,
122.6, 122.9, 125.7, 127.6, 129.6, 131.3, 134.2, 134.5, 136.2, 142.9, 156.6, 160.3, 162.7,
165.9, 192.2. HRMS (ESI) calcd for C22H16ClN2O3 [M + H]+ 391.0844, found 391.0843.
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4-Chloro-N-(2-(5-chloro-3-oxo-3H-indol-2-yl)phenyl)benzamide
(2n):
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ether/ethyl acetate (30:1) as eluent; red solid (100 mg, 64%), mp 221-222 C. H NMR
(CDCl3, 600 MHz) δ 7.24 (t, J = 7.8 Hz, 1H), 7.27-7.28 (m, 1H), 7.55-7.63 (m, 5H), 8.08 (d, J
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= 8.4 Hz, 2H), 8.76 (d, J = 7.8 Hz, 1H), 8.98 (d, J = 8.4 Hz, 1H), 13.16 (s, 1H); C{1H}
NMR (CDCl3, 150 MHz) δ 116.1, 120.4, 121.9, 122.6, 123.4, 125.9, 129.0, 129.2, 131.5,
133.8, 134.3, 134.8, 136.3, 138.4, 142.4, 156.4, 160.3, 165.2, 192.1. HRMS (ESI) calcd for
C21H13Cl2N2O2 [M + H]+ 395.0349, found 395.0336.
N-(2-(3-Oxo-5-(trifluoromethyl)-3H-indol-2-yl)phenyl)benzamide (2o): Petroleum
o
1
ether/dichloromethane (1:2) as eluent; red solid (80 mg, 51%), mp 148-150 C. H NMR
(CDCl3, 600 MHz) δ 7.20-7.23 (m, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.2 Hz, 2H),
7.60-7.63 (m, 2H), 7.86-7.88 (m, 2H), 8.11-8.13 (m, 2H), 8.77 (dd, J = 1.8, 8.4 Hz, 1H), 9.01
13
(dd, J = 0.6, 8.4 Hz, 1H), 13.14 (s, 1H); C{1H} NMR (CDCl3, 150 MHz) δ 115.9, 120.5,
121.1, 121.8, 122.6 (q, J = 3.2 Hz, 1C), 123.35, 123.36 (q, J = 271.2 Hz, 1C), 127.8, 128.7,
131.1 (q, J = 33.9 Hz, 1C), 131.8, 132.2, 134.3 (q, J = 3.3 Hz, 1C), 134.9, 135.4, 143.1, 160.9,
161.9, 166.4, 191.9. HRMS (ESI) calcd for C22H14F3N2O2 [M + H]+ 395.1002, found
395.1002.
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General Procedure for the Preparation of Indolo[1,2-c]quinazolines (3). To a mixture of
indole 1 (0.4 mmol) in 1,4-dioxane (2 mL) were added CuBr (5.7 mg, 0.04 mmol) and 0.5 M
HCl aqueous solution (0.16 mL, 0.08 mmol) under air and then the resulting mixture was
stirred at 120 oC for 4~10 h. After the reactant 1 was consumed completely, water was added
into the reaction system, followed by extraction with ethyl acetate. The extract was washed
with water and brine, and then dried over anhydrous Na2SO4. The solvent was evaporated
under reduced pressure and the residue was purified by column chromatography on silica gel
to give the corresponding indolo[1,2-c]quinazoline 3.
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6-Phenylindolo[1,2-c]quinazoline (3a):14f Petroleum ether/ethyl acetate (5:1) as eluent;
yellow solid (85 mg, 72%), mp 187-188 oC. 1H NMR (CDCl3, 400 MHz) δ 6.34 (d, J = 8.4 Hz,
1H), 6.84-6.88 (m, 1H), 7.12 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.36 (td, J = 1.6, 7.6 Hz, 1H),
7.41 (td, J = 1.6, 7.6 Hz, 1H), 7.46-7.55 (m, 5H), 7.63 (d, J = 7.6 Hz, 1H), 7.72 (dd, J = 0.8,
7.6 Hz, 1H), 7.96 (dd, J = 0.8, 7.6 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 94.7, 113.8,
119.4, 119.5, 120.4, 121.7, 122.4, 126.3, 126.8, 127.2, 128.0, 128.2, 129.3, 130.6, 134.2,
134.9, 138.2, 148.3 (one 13C signal was not observed). MS (ESI) m/z 295 [M + H]+.
6-p-Tolylindolo[1,2-c]quinazoline (3b):14f Petroleum ether/ethyl acetate (5:1) as eluent;
yellow solid (67 mg, 54%), mp 154-155 oC. 1H NMR (CDCl3, 600 MHz) δ 2.51 (s, 3H), 6.56
(d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.39 (d, J =
7.2 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.74
(d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.2 Hz, 1H); 13C{1H} NMR (CDCl3,
150 MHz) δ 21.7, 95.7, 115.1, 120.5, 120.6, 121.4, 122.7, 123.4, 127.3, 127.9, 128.2, 129.1,
129.9, 130.4, 131.8, 133.2, 135.3, 139.4, 140.5, 149.6. MS (ESI) m/z 309 [M + H]+.
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6-(4-Methoxyphenyl)indolo[1,2-c]quinazoline (3c):14f Petroleum ether/ethyl acetate (5:1)
as eluent; yellow solid (74 mg, 57%), mp 177-178 oC. 1H NMR (CDCl3, 600 MHz) δ 3.93 (s,
3H), 6.63 (d, J = 9.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H),
7.30 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.61 (d, J = 8.4 Hz,
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2H), 7.76 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H); C{1H}
NMR (CDCl3, 150 MHz) δ 55.5, 95.7, 114.6, 115.1, 120.48, 120.54, 121.4, 122.7, 123.4,
127.3, 127.8, 128.4, 129.1, 129.8, 130.4, 131.8, 135.4, 139.4, 149.3, 161.2. MS (ESI) m/z 325
[M + H]+.
6-(4-Chlorophenyl)indolo[1,2-c]quinazoline (3d):14f Petroleum ether/ethyl acetate (5:1)
as eluent; yellow solid (80 mg, 61%), mp 195-196 oC. 1H NMR (CDCl3, 600 MHz) δ 6.57 (d,
J = 8.4 Hz, 1H), 7.01-7.03 (m, 1H), 7.23 (s, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.47 (t, J = 7.2 Hz,
1H), 7.51 (td, J = 7.2, 1.2 Hz, 1H), 7.56-7.61 (m, 4H), 7.75 (d, J = 7.8 Hz, 1H), 7.79 (d, J =
7.8 Hz, 1H), 8.05 (dd, J = 0.6, 7.2 Hz, 1H); 13C{1H} NMR (CDCl3, 150 MHz) δ 96.0, 114.7,
120.6, 120.7, 121.7, 122.8, 123.6, 127.6, 127.9, 129.2, 129.6, 129.9, 130.4, 131.5, 134.4,
135.2, 136.6, 139.1, 148.2. MS (ESI) m/z 329 [M + H]+.
6-(4-Nitrophenyl)indolo[1,2-c]quinazoline (3e):15e Petroleum ether/ethyl acetate (10:1) as
eluent; yellow solid (54 mg, 40%), mp 188-189 oC. 1H NMR (CDCl3, 400 MHz) δ 6.37 (d, J
= 8.8 Hz, 1H), 6.90-6.94 (m, 1H), 7.15 (s, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.39-7.46 (m, 2H),
7.66-7.70 (m, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.96-7.98 (m, 1H), 8.33 (d, J = 8.8 Hz, 2H);
13C{1H} NMR (CDCl3, 100 MHz) δ 96.3, 114.3, 120.6, 121.0, 121.9, 122.9, 123.9, 124.5,
128.0, 128.1, 129.4, 129.8, 130.5, 131.1, 135.1, 138.8, 141.8, 147.0, 149.0. MS (ESI) m/z 340
[M + H]+.
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6-Methylindolo[1,2-c]quinazoline (3f):14c,14d Petroleum ether/ethyl acetate (20:1) as
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eluent; yellow solid (45 mg, 48%), mp 105-106 C. H NMR (CDCl3, 400 MHz) δ 3.00 (s,
3H), 7.05 (s, 1H), 7.27-7.31 (m, 1H), 7.34-7.39 (m, 2H), 7.44-7.48 (m, 1H), 7.67 (d, J = 8.0
Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H); 13C{1H}
NMR (CDCl3, 100 MHz) δ 25.3, 95.4, 114.7, 120.2, 120.7, 122.0, 122.6, 123.3, 126.7, 126.9,
128.9, 130.4, 131.7, 134.8, 138.9, 148.5. MS (ESI) m/z 233 [M + H]+.
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2-Methyl-6-phenylindolo[1,2-c]quinazoline (3g): Petroleum ether/ethyl acetate (15:1) as
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eluent; yellow solid (74 mg, 60%), mp 197-198 C. H NMR (CDCl3, 600 MHz) δ 2.48 (s,
3H), 6.38 (d, J = 8.4 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.22 (t, J = 7.2 Hz, 1H),
7.29-7.30 (m, 1H), 7.53-7.61 (m, 5H), 7.66 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.85
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(s, 1H); C{1H} NMR (CDCl3, 150 MHz) δ 21.7, 95.4, 114.9, 120.35, 120.45, 121.4, 122.6,
123.3, 127.7, 128.3, 129.3, 130.3, 130.4, 130.5, 131.7, 135.4, 136.1, 137.2, 137.5, 148.6.
HRMS (ESI) calcd for C22H17N2 [M + H]+ 309.1386, found 309.1377.
2-Chloro-6-phenylindolo[1,2-c]quinazoline (3h):14f Petroleum ether/ethyl acetate (10:1)
as eluent; yellow solid (81 mg, 62%), mp 201-202 oC. 1H NMR (CDCl3, 400 MHz) δ 6.46 (d,
J = 9.2 Hz, 1H), 6.97-7.02 (m, 1H), 7.24 (s, 1H), 7.29-7.33 (m, 1H), 7.45 (dd, J = 2.4, 8.4 Hz,
1H), 7.58-7.67 (m, 5H), 7.73 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 2.0 Hz,
1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 96.7, 115.0, 120.8, 121.8, 122.0, 122.3, 123.7,
13
128.2, 129.28, 129.35, 130.2, 130.6, 131.7, 132.9, 134.0, 135.7, 137.7, 149.5 (one C signal
was not observed). MS (ESI) m/z 329 [M + H]+.
10-Methyl-6-phenylindolo[1,2-c]quinazoline (3i):14c Petroleum ether/ethyl acetate (10:1)
as eluent; yellow solid (65 mg, 53%), mp 178-179 oC. 1H NMR (CDCl3, 600 MHz) δ 2.41 (s,
3H), 6.30 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 7.11 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H),
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7.48-7.50 (m, 2H), 7.55-7.58 (m, 2H), 7.60-7.62 (m, 3H), 7.80 (d, J = 8.4 Hz, 1H), 8.02 (d, J
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= 7.8 Hz, 1H); C{1H} NMR (CDCl3, 150 MHz) δ 21.5, 95.4, 114.5, 120.2, 120.7, 122.7,
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123.2, 127.3, 127.9, 128.3, 129.0, 129.3, 130.0, 130.4, 130.8, 133.1, 135.4, 136.1, 139.3,
149.3. HRMS (ESI) calcd for C22H17N2 [M + H]+ 309.1386, found 309.1372.
10-Chloro-6-phenylindolo[1,2-c]quinazoline (3j):14f Petroleum ether/ethyl acetate (10:1)
as eluent; yellow solid (88 mg, 67%), mp 231-232 oC. 1H NMR (CDCl3, 400 MHz) δ 6.31 (d,
J = 9.2 Hz, 1H), 6.89 (dd, J = 2.4, 9.2 Hz, 1H), 7.10 (s, 1H), 7.46 (td, J = 7.2, 1.2 Hz, 1H),
7.53 (td, J = 7.2, 1.6 Hz, 1H), 7.56-7.63 (m, 5H), 7.65 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 0.8,
8.0 Hz, 1H), 8.02 (dd, J = 1.2, 8.0 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 95.1, 115.8,
119.7, 120.2, 121.7, 122.9, 127.6, 128.0, 128.2, 129.2, 129.4, 129.5, 129.9, 130.6, 131.5,
135.6, 136.5, 139.3, 148.9. MS (ESI) m/z 329 [M + H]+.
10-Chloro-6-(p-tolyl)indolo[1,2-c]quinazoline (3k):14f Petroleum ether/ethyl acetate (20:1)
as eluent; yellow solid (86 mg, 63%), mp 195-196 oC. 1H NMR (CDCl3, 400 MHz) δ 2.53 (s,
3H), 6.46 (d, J = 9.2 Hz, 1H), 6.94 (dd, J = 2.0, 8.8 Hz, 1H), 7.21 (s, 1H), 7.42 (d, J = 7.6 Hz,
2H), 7.52-7.57 (m, 4H), 7.73 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 1.2, 8.0 Hz, 1H), 8.11 (dd, J =
1.2, 7.6 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 21.7, 95.0, 116.0, 119.6, 120.2, 121.6,
122.8, 127.5, 128.0, 128.1, 129.2, 129.5, 130.02, 130.04, 131.5, 132.7, 136.6, 139.4, 140.8,
149.1. HRMS (ESI) calcd for C22H16ClN2 [M + H]+ 343.0997, found 343.0992.
10-Chloro-6-(4-methoxyphenyl)indolo[1,2-c]quinazoline (3l): Petroleum ether/ethyl
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acetate (10:1) as eluent; yellow solid (86 mg, 60%), mp 177-178 C. H NMR (CDCl3, 400
MHz) δ 3.93 (s, 3H), 6.51 (d, J = 8.8 Hz, 1H), 6.94 (dd, J = 2.4, 9.2 Hz, 1H), 7.10 (dt, J = 8.8,
2.4 Hz, 2H), 7.15 (s, 1H), 7.46-7.59 (m, 4H), 7.69 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 1.2, 8.0
Hz, 1H), 8.06 (dd, J = 1.2, 7.6 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 55.5, 95.0, 114.7,
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116.0, 119.7, 120.1, 121.6, 122.8, 127.5, 127.91, 127.94, 129.2, 129.5, 129.8, 130.1, 131.5,
136.7, 139.4, 148.9, 161.3. HRMS (ESI) calcd for C22H16ClN2O [M + H]+ 359.0946, found
359.0933.
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10-Chloro-6-(4-chlorophenyl)indolo[1,2-c]quinazoline (3m):14f Petroleum ether/ethyl
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acetate (20:1) as eluent; yellow solid (89 mg, 61%), mp 192-193 C. H NMR (CDCl3, 400
MHz) δ 6.50 (d, J = 9.2 Hz, 1H), 6.99 (dd, J = 2.0, 8.8 Hz, 1H), 7.22 (s, 1H), 7.52-7.65 (m,
6H), 7.74 (d, J = 2.0 Hz, 1H), 7.81-7.83 (m, 1H), 8.10-8.12 (m, 1H); 13C{1H} NMR (CDCl3,
100 MHz) δ 95.3, 115.6, 119.9, 120.2, 121.9, 122.9, 127.9, 128.0, 129.4, 129.6, 129.7, 129.77,
129.81, 131.5, 134.0, 136.5, 136.8, 139.2, 147.8. HRMS (ESI) calcd for C21H12Cl2N2Na [M +
Na]+ 385.0270, found 385.0282.
10-Chloro-6-(trifluoromethyl)indolo[1,2-c]quinazoline (3n): Petroleum ether/ethyl
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acetate (20:1) as eluent; yellow solid (58 mg, 45%), mp 175-176 C. H NMR (CDCl3, 400
MHz) δ 7.29 (s, 1H), 7.38 (dd, J = 2.4, 9.2 Hz, 1H), 7.60-7.63 (m, 2H), 7.79 (d, J = 2.4 Hz,
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1H), 7.89-7.91 (m, 1H), 8.05-8.10 (m, 2H); C{1H} NMR (CDCl3, 100 MHz) δ 96.9, 115.6
(q, J = 7.3 Hz, 1C), 118.8 (q, J = 273.5 Hz, 1C), 120.1, 121.3, 122.8, 123.5, 128.4, 129.0,
129.8, 129.9, 130.2, 131.4, 136.2, 136.3 (one 13C signal was not observed). HRMS (ESI)
calcd for C16H9ClF3N2 [M + H]+ 321.0401, found 321.0393.
6-Phenyl-10-(trifluoromethyl)indolo[1,2-c]quinazoline
(3o):
Petroleum
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ether/dichloromethane (1:2) as eluent; yellow solid (72 mg, 50%), mp 192-193 C. H NMR
(CDCl3, 600 MHz) δ 6.51 (d, J = 9.0 Hz, 1H), 7.20 (dd, J = 1.2, 8.4 Hz, 1H), 7.32 (s, 1H),
7.54 (td, J = 7.8, 1.2 Hz, 1H), 7.58 (td, J = 7.2, 1.2 Hz, 1H), 7.62-7.68 (m, 5H), 7.85 (d, J =
7.8 Hz, 1H), 8.05 (s, 1H), 8.12 (dd, J = 1.2, 7.8 Hz, 1H); 13C{1H} NMR (CDCl3, 150 MHz) δ
96.0, 115.2, 117.9 (q, J = 4.4 Hz, 1C), 120.2, 123.0, 124.7 (q, J = 270.2 Hz, 1C), 125.6 (q, J =
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31.7 Hz, 1C), 127.9, 128.16, 128.21, 129.5, 129.78, 129.80, 130.7, 132.8, 135.5, 136.8, 139.2,
148.9 (one 13C signal was not observed). HRMS (ESI) calcd for C22H14F3N2 [M + H]+
363.1104, found 363.1086.
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5-Phenylpyrrolo[1,2-c]quinazoline (3p):16a Petroleum ether/ethyl acetate (5:1) as eluent;
yellow solid (49 mg, 50%), mp 172-173 oC. 1H NMR (CDCl3, 400 MHz) δ 6.68 (t, J = 3.6 Hz,
1H), 6.92 (dd, J = 1.6, 4.0 Hz, 1H), 7.31 (dd, J = 1.2, 2.4 Hz, 1H), 7.36-7.42 (m, 2H),
7.48-7.50 (m, 3H), 7.77-7.79 (m, 3H), 7.90-7.92 (m, 1H); 13C{1H} NMR (CDCl3, 150 MHz) δ
101.1, 114.0, 114.8, 121.1, 121.6, 127.3, 127.5, 128.3, 128.6, 129.0, 130.6, 130.8, 134.3,
138.3, 147.7. MS (ESI) m/z 245 [M + H]+.
6-Phenylpyrido[2',3':4,5]pyrimido[1,6-a]indole (3q): Dichloromethane/ethyl acetate (2:1)
o
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as eluent; yellow solid (76.8 mg, 65%), mp 192-193 C. H NMR (CDCl3, 400 MHz) δ 6.54
(d, J = 8.8 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.25-7.28 (m, 2H), 7.34-7.37 (m, 1H), 7.51-7.61
(m, 3H), 7.67 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.71 (m,
1H); 13C{1H} NMR (CDCl3, 150 MHz) δ 97.8, 115.2, 115.9, 120.7, 122.2, 122.4, 123.9,
128.4, 129.0, 130.5, 130.7, 131.3, 131.7, 134.7, 135.3, 150.6, 150.9, 152.9. HRMS (ESI)
calcd for C20H13N3Na[M + Na]+ 318.1002, found 318.1011.
Acknowledgments
We thank the National Natural Science Foundation of China (Grants 21202040 and
21572047), Project Funded by China Postdoctoral Science Foundation (2014M552007 and
2015T80771), the Program for Innovative Research Team in Science and Technology in
University of Henan Province (15IRTSTHN003), and the Plan for Scientific Innovation
Talents of Henan Province (184200510012) for financial support.
Supporting Information
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Table Sl, X-ray crystal structure and data of 2a, Table S2, and H and 13C{1H} NMR
spectra of compounds 2a-2o and 3a-3q. This material is available free of charge via the
Internet at ............
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