Synthesis of substituted tryptanthrin via aryl halides and amines as antitumor and anti-MRSA agents

Article abstract of DOI:10.1016/j.tet.2019.05.030

The natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), and its analogues are found to exhibit potent antitumor and anti-MRSA activities. An efficient and convenient method has been developed for the synthesis of tryptanthrin D-ring derivatives through the reaction of substituted tryptanthrins and secondary amines in moderate to good yields. Some of the new compounds exhibited antitumor activities against the human tumor cell lines A549, HCT116 and MDA-MB-231, with mean IC₅₀ values at low micromolar levels. In addition, some of the compounds showed excellent anti-MRSA activities and were more effective than vancomycin, with MIC values of 0.31–1.25 μg/mL for Mu50,RN4220, and Newman strains.

Full text of DOI:10.1016/j.tet.2019.05.030

Tetrahedron 75 (2019) 130351
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted tryptanthrin via aryl halides and amines as
antitumor and anti-MRSA agents
Xudong Zheng 1, Baolong Hou 1, Rui Wang, Yinyin Wang, Cuiling Wang, Huan Chen, Li Liu,
Jilin Wang, Xiumei Ma, Jianli Liu*
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, 710069,
China
a r t i c l e i n f o
a b s t r a c t
Article history:
The natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), and its analogues are found to
exhibit potent antitumor and anti-MRSA activities. An efficient and convenient method has been
developed for the synthesis of tryptanthrin D-ring derivatives through the reaction of substituted
tryptanthrins and secondary amines in moderate to good yields. Some of the new compounds exhibited
antitumor activities against the human tumor cell lines A549, HCT116 and MDA-MB-231, with mean IC50
values at low micromolar levels. In addition, some of the compounds showed excellent anti-MRSA ac-
Received 15 March 2019
Received in revised form
18 April 2019
Accepted 13 May 2019
Available online 7 October 2019
tivities and were more effective than vancomycin, with MIC values of 0.31e1.25 mg/mL for Mu50,RN4220,
and Newman strains.
Keywords:
Tryptanthrin
CeN bond cross-coupling
Antibacterial agent
Antitumor activity
© 2019 Elsevier Ltd. All rights reserved.
1. Introduction
Tryptanthrin
(Indolo[2,1-b]quinazoline-6,12-dione,TRYP,1a),
which possesses both quinazolinone (AB ring) and indolone (CD
ring) core structures, was first obtained by sublimation of natural
indigo and later isolated from theindigo plant Strobilanthes cusia
and other natural sources [17]. These compounds exhibit anti-
bacterial activities against a variety of pathogenic bacteria and
remarkable in vitro antileishmanial activities against Leishmania
donovani and Trypanosoma brucei [18,19]. In recent years, tryptan-
thrin has attracted much attention as an aryl hydrocarbon receptor
agonist, anti-inflammatory agent, inducer of caspase-3/Fas medi-
ated apoptosis, anti-cancer agent and IDO-1 inhibitor [20,21].
Tryptanthrin has also exhibited the ability to reverse multidrug
resistance in cancer cell lines [22]. In addition, a wide range of
immune modulatory effects has been observed, including the in-
hibition of Th2 development, IgE-mediated degranulation and IL-4
production, as well as NF-kB and immune enhancement [23].
Tryptanthrin derivatives are interesting as structural scaffolds and
have been assigned as privileged structures in drug development
[24e26]. However, the low solubility of tryptanthrin (5.4 mM) and
the moderate anti-bacterial and anti-tumor activities were
considered problematic.
Quinazolines are an important class of heterocycles that widely
occur in natural products and pharmaceuticals and show a wide
range of useful biological and pharmacological activities, including
antibacterial [1,2], antitumor [3], antiplasmodial [4], anti-
inflammatory [5], and antiviral activities [6]. In addition to their
role as photochemotherapeutic agents [7], quinazolines include
DNA-gyrase, PDE5, and EGFR tyrosine kinase inhibitors [8]. Of these
inhibitors, Gefitinib (CP 358774) [9], Erlotinib (ZD 1839) and
Lapatinib (GW572016) belong to a class of quinazolines that have
been designed to selectively inhibit EGF-stimulated signal trans-
duction by reversibly binding at the ATP site of EGFR (Fig. 1) [10].
Indolones are bioactive scaffolds, possessing high reactivity and
synthetic versatility, which has made them valuable synthons/
building blocks of several heterocyclic frameworks of biological
significance [11], such as Sunitinib (Fig. 1) [12]. This scaffold ex-
hibits a broad spectrum of biological properties and diverse modes
of action, including antitumor [13], anti-HIV [14], antimalarial and
anti-tubercular activities [15,16].
To potentially address the solubility issues and to improve the
anti-tumor and anti-microbial activities, analogues were designed
to incorporate solubilizing groups, such as imines, via a CeN bond
cross-coupling reaction in the D ring of TRYP due to the tendency of
* Corresponding author.
E-mail address: jlliu@nwu.edu.cn (J. Liu).
1
Authors contributed equally to this publication.
https://doi.org/10.1016/j.tet.2019.05.030
0040-4020/© 2019 Elsevier Ltd. All rights reserved.

2
X. Zheng et al. / Tetrahedron 75 (2019) 130351
Fig. 1. Biologically and pharmaceutically important quinazolines and indolone.
Scheme 2. Synthesis of tryptanthrin and D-ring-substituted analogues: Reagents and
conditions: (a) HONH3Cl, Cl3CCHO, Na2SO4, H2O, reflux, 1 h; (b) 95% H2SO4, 65 ꢀC, 1 h;
(c) isatoic anhydride, CH2Cl2, Et3N, reflux, 1 h; (d) NMP, imine, 70 ꢀC, 2 h.
D ring substitutions to improve activity. At present, the common
method of performing CeN coupling reactions requires the use of
copper or palladium and a coupling agent or catalyst [27]. Our N-
aryltryptanthrins were synthesized by the direct reaction of halo-
tryptanthrin with a secondary amine. The reaction with NMP as
solvent in moderate did not require a coupling agent or a catalyst,
and the post-treatment was convenient.
by heating at 70e90 ꢀC in N-methyl pyrrolidone (NMP) without a
catalyst. In general, the reactions of 1b with secondary amines led
to the exclusive formation of C-7 position-substituted products 5a-
5h (Scheme 3). It must be noted that even at a higher ratio of
secondary amines, the formation products substituted at the C-9
position was not observed. The purification process was easily
performed due to the high yield of the target compound in each
step, and extraction or column separation is not required.
2. Results and discussion
Treatment of compounds 1c-1e with secondary amines in the
presence of NMP without a catalyst selectively afforded C-7 or C-9
aminotryptanthrin depending on the ratio of the starting materials.
The position of the halogen atom on the D ring of TRYP affected
selectivity and activity during the reaction (Fig. 3). Nucleophilic
substitution reactions occurring on aryl halides are not as easy as
those occurring on aliphatic halides, which require electron with-
drawing groups to accelerate the reaction. The results of our
experiment indicated that the C-7 position exhibits better reac-
tivity compared to the C-9 position due to the C-6 carbonyl group
and the C-8 chlorine atom increasing nucleophilicity. The C-8 po-
sition is the most stable compared to the C-7 and C-9 positions.
When the molar ratio of halotryptanthrin and the secondary amine
was 1:1, the C-7-substituted product was preferentially formed. In
contrast, reaction of halotryptanthrin with an excess of the sec-
ondary amine (molar ratio greater than 1:1) mainly afforded C-7
and C-9 products. The stronger nucleophiles piperidine and
2.1. Chemistry
Tryptanthrin and several D-ring substituted analogues were
synthesized and the development of syntheses of more extensively
modified analogues was performed. Substituted anilines were used
as starting materials to synthesize isatin derivatives with the
following two steps. First, anilines were reacted with chloral hy-
drate and hydroxylamine hydrochloride to produce anilide de-
rivatives. Then, a Beckmann rearrangement was carried out in 95%
H2SO4 to afford isatin derivatives [28]. A number of isatin de-
rivatives have been synthesized according to Scheme 1. These de-
rivatives underwent condensation with isatoic anhydride followed
by heating in a solution of dichloromethane and triethylamine to
form compounds 1a-1h.
An aromatic ring of isatin with o-dichloro groups can form two
products upon electrophilic substitution of a benzene ring. This
result was confirmed according to the Beckmann rearrangement
step b (Scheme 2), as 3,4-dichlorobenzeneamine (2b) was used as
the starting material. Isomers 1b were formed, and the ratio of 1b′
to 1b"was approximately 1:1 by comparing peak areas of 1H NMR
spectra (Fig. 2). Compounds 1b′ and 1b” were not further isolated
at this point due to their very similar polarities. To introduce a
solubilizing group into tryptanthrin, analogues containing imines
in the D-ring were prepared by substituting the chlorine atom of 1b
with appropriate secondary amines (piperidine, morpholine, etc.)
Scheme 1. Synthesis of tryptanthrin and D-ring-substituted analogues: Reagents and
conditions: (a) HONH3Cl, Cl3CCHO, Na2SO4, H2O, reflux, 1 h; (b) 95% of H2SO4, 65 ꢀC,
1 h; (c) CH2Cl2, Et3N, reflux,1 h.
1
Fig. 2. H NMR of 1b0and 1b” (DMSO‑d6).

X. Zheng et al. / Tetrahedron 75 (2019) 130351
3
showed lower activity or gave IC50 values over 100 mM.
These indolo[2,1-b]quinazoline-6,12-dione molecules were
screened for their in vitro anti-bacterial activity against Mu50,
RN4220, and Newman strains by the agar dilution method for
determination of the MIC values along with the standard drug
vancomycin. Based on the results presented in Table 2, some pre-
liminary structureeactivity relationship aspects were deduced. The
substituent present on the aromatic ring had certain effects on
biological activity. Of the various compounds, 1a-1c, 5h, 7c, 7d and
6f showed an excellent activity with MIC values of 0.31e1.25
for Mu50, RN4220, Newman (see Fig. 5), which are higher than
those of vancomycin (2.5, 1.25, and 1.25 g/mL for Mu50, RN4220,
mg/mL
m
and Newman, respectively). Conversely, most of derivatives we
designed are less effective than vancomycin.
3. Conclusions
In summary, we have prepared four representative examples of
the novel indolopyrimidinequinolinone pentacyclic ring system
through the reaction of substituted tryptanthrins and secondary
amines in moderate to good yields. The structure of the new ring
system was proved by spectroscopic methods. Some of the new
compounds exhibited antitumor activities against the human tu-
mor cell lines A549, HCT116 and MDA-MB-231, with IC50 mean
values at low micromolar levels, and some of these compounds also
showed excellent anti-MRSA activities, which were more effective
Scheme 3. Synthesis of tryptanthrin and D-ring-substituted analogues: Reagents and
conditions: (a) HONH3Cl, Cl3CCHO, Na2SO4, H2O, reflux, 1 h; (b) 95% H2SO4, 65 ꢀC, 1 h;
(c) isatoic anhydride, CH2Cl2, Et3N, reflux, 1 h; (d)NMP, imine, 70 ꢀC, 2 h.
than vancomycin with MIC values of 0.31e1.25 mg/mL for Mu50,
RN4220, and Newman strains.
4. Experimental sections
Fig. 3. Halogen atom on D ring of TRYP.
All solvents and chemicals were of research grade and were
used as obtained from Sigma and Aladdin. All chemicals and sol-
vents were of analytical grade and used without further purifica-
tion. Melting points were determined on an X-5 micro melting
point apparatus and were uncorrected. 1H NMR spectra were
recorded on a Bruker AV-200 spectrometer in CDCl3 or DMSO using
TMS as the internal standard. The progress of the reaction was
monitored by TLC. Column chromatography was performed using
silica gel (60e120 mesh size).
morpholine react readily to simultaneously form a mixture of C-7-
and C-9-substituted products, even when the ratio of halo-
tryptanthrin to the secondary amine was 1:1.
2.2. Antiproliferative activity
To determine the activity of the TRYP derivatives in vitro,
cellular-based screening of all the synthesized D ring-substituted
TRYP and Gefitinib was performed on A549, HCT116 and MDA-
MB-231 cell lines. The IC50 values obtained are tabulated in Table 1.
4.1. Cell proliferation assay
The calculated IC50 values, the concentration (
m
M) of a compound
The A549, HCT116, and MDA-MB-231 cell lines were grown in
Dulbecco's modified Eagle's medium (DMEM) supplemented with
10% heat-inactivated fetal bovine serum (FBS), penicillin (100units/
mL), and streptomycin (100 mg/mL) at 37 ꢀC in a humidified envi-
ronment containing 5% CO2 [29]. The A549 cells (5 ꢁ 107/L) were
seeded in 96-well plates and incubated for 24 h. The synthesized
compounds were incubated at six different concentrations (3.125,
that was able to cause 50% cell death with respect to the control
culture, were reported differently for different cancer cells. The
parent compounds 1a-1e exhibited activity against A549, HCT116
and MDA-MB-231 cell lines, in particular, 1b and 1c showed
generally better activity than TRYP, with IC50 values of
0.99,5.11,7.73,3.58, and 20.24 mM, respectively. As shown in Table 1,
target compounds 5b, 5e, 5g, 5h, 6h and 7c have significant anti-
cancer activity (see Fig. 4). Particularly, compounds 5h and 6h
6.25, 12.5, 25, 50, and 100
exhibited IC50 values lower than 3.125
were further tested at six additional concentrations (0.31, 0.63,
1.25, 2.5, 5, and 10 mol/L) to obtain more accurate IC50 values.
m
mol/L) for 48 h. Compounds that
mmol/L.
exhibited activity at less than 2
mM on the three cell lines and were
ten times more potent than TRYP (IC50 values of 74.71 and 17.49
mM
m
for A549 and HCT116, respectively). Twelve compounds (5c, 6a, 6e,
6g, 7d, 7e, 7g, 8b-8d and 8g) exhibited weak activity on one or two
cell lines. The structure-activity relationship (SAR) in these new
compounds demonstrated that 7-N-diethylamine-substituted TRYP
(5h, 6h) have significantly enhanced anti-tumor effects on A549,
HCT116 and MDA-MB-231 cell lines relative to those of parent
compounds 1b and 1c. In the 7-amino-substituted 1b and 1c series,
substitution of the cyclic imide group yielded compounds that
Controls consisted of wells without drugs. For IC50 determination,
the medium was removed and the cells were incubated for 4 h in
the presence of 5
removed and 200
m
M/L MTT at 37 ꢀC. The MTT solution was then
mL of DMSO per well was added. After thorough
mixing, the absorbance of the wells was read in a Spectra Max 190
spectrophotometer at the test and reference wavelengths of
490 nm. The data were analyzed and the IC50 values were calcu-
lated using SPSS 19.0.

4
X. Zheng et al. / Tetrahedron 75 (2019) 130351
Table 1
In vitro antiproliferative effects of synthesized compounds.
Compd
IC50(ìmol/L)a
A549
CLogPb
Compd
IC50(ìmol/L)a
A549
CLogPb
HCT116
MDA-MB-231
HCT116
MDA-MB-231
1a
1b
1c
1d
1e
5a
5b
5c
5d
5e
5f
5g
5h
6a
6b
6c
6d
6e
6f
74.71
0.99
3.58
17.49
5.11
>100
7.73
2.61
3.87
3.35
3.24
3.64
4.20
2.59
3.14
3.19
2.55
3.98
3.29
4.04
3.69
2.08
2.62
2.67
2.04
3.47
6g
6h
6i
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
8g
>100
1.2
>100
2.01
89.72
0.8
2.80
2.78
2.96
3.57
1.96
2.51
2.56
1.92
3.35
2.66
3.97
2.36
2.91
2.96
2.32
3.75
3.06
59.20
55.18
>100
>100
>100
10.68
>100
>100
>100
25.72
1.29
64.19
>100
>100
>100
>100
>100
20.24
>100
>100
>100
31.59
>100
>100
32.78
>100
14.67
1.78
>100
65.79
>100
>100
>100
>100
>100
>100
>100
13.66
>100
>100
>100
>100
>100
>100
>100
52.61
>100
>100
98.02
5.44
>100
>100
>100
89.98
45.65
>100
>100
1.62
>100
67.24
>100
>100
>100
>100
>100
6.46
>100
>100
>100
56.09
>100
34.25
>100
48,29
>100
69.75
58.72
>100
>100
>100
87.34
45.31
8.52
56.03
>100
34.48
>100
>100
22.75
>100
18.64
1.48
>100
>100
>100
>100
41.37
>100
Gefitinib
a
Cell growth was measured using the MTT assay. Values are the average of three independent experiments run in triplicate. Variation was generally 5%.
b
€
ClogP was calculated using QikProp model of version 6.0, Schrodinger, 2013.
4.2. Antibacterial assay
Minimum inhibitory concentration (MIC) was determined ac-
cording to Clinical and Laboratory Standards Institute (CLSI)
guidelines [11]. The MIC50 values were investigated using the agar
dilution method with a spectrophotometer. Compound stock so-
lutions were prepared in DMSO/H2O (50%). Serial two-fold di-
lutions prepared from the stock solutions with sterile H2O were
prepared. For antibiotic sensitivity assays, bacteria in 96-well plates
were incubated with compounds or antibiotic standards at final
concentrations of 0.08e64 ìg/mL. The plates were incubated at
37 ꢀC and read at 24 h.
Fig. 4. Cell toxicity of 1a-1e, 5b, 5e, 5g, 5h, 6h, 7c, 7d and Gefitinib on A549, HCT116
and MDA-MB-231 cells.
4.3. General synthetic procedures
All chemicals and solvents were of analytical grade and used
without further purification. Analytical TLC was performed on
precoated silica gel plates (HG/T2354-92). Melting points were
determined on an X-5 micro melting point apparatus and were
uncorrected. UV spectra were recorded on a 2600UV/VIS spectro-
photometer using methanol as the blank. IR spectra were recorded
on an FT-IR spectrometer (Spectrum Two); 1H NMR spectra were
recorded at 400 MHz on a Bruker Avance-400 MHz spectrometer
with TMS as the internal standard; chemical shifts were given in
parts per million (ppm) and coupling constants in hertz (Hz). Mass
spectra were performed on an LTQ-XL with direct sample injection;
HRMS were performed on an Agilent Technologies 6520B accurate-
Mass Q-TOF LC/MS. Elemental analysis was performed on a Vario EL
III CHNOS analyzer.
Table 2
Anti-Staphylococcus activity of compounds 1a-1c,5h,7c, 7d and 6f against Mu50,
RN4220 and Newman.
Compd MIC(
m
g/mL)
Compd MIC(
mg/mL)
Mu50 RN4220 Newman
Mu50 RN4220 Newman
1a
1b
1c
5h
1.25
1.25
0.63
0.63
1.25
0.63
0.63
0.63
1.25
0.31
0.63
0.63
7c
7d
6f
1.25
1.25
0.63
2.5
0.63
0.63
1.25
1.25
0.63
0.63
1.25
1.25
Van
4.3.1. Synthesis of 1a-1h
4.3.1.1. General procedure for the synthesis of tryptanthrins
a) A 500 mL three-neck round-bottom flask fitted with
a
condenser and a thermometer was charged with chloral hydrate
(16.50 g, 0.1 mol) and 220 mL of water. Then, anhydrous sodium
sulfate (15.00 g), the aniline derivative (0.1 mol), an HCl solution
(5.2%, 70 mL), and hydroxylamine hydrochloride (20.81 g,
0.3 mol, in 95 mL of water) were successively added. After being
heated to reflux for 1 h, the reaction mixture was cooled to room
Fig. 5. Anti-Staphylococcus activity of compounds 1a-1c, 5h, 7c, 7d and 6f against
Mu50, RN4220, and Newman strains.

X. Zheng et al. / Tetrahedron 75 (2019) 130351
5
temperature. The intermediate compounds (anilide derivatives)
4.3.1.5. 7-Chloroindolo[2,1-b]quinazoline-6,12-dione
(1d).
were collected by filtration and dried for use in the next step
without further purification.
Isatoic anhydride (1.63 g, 10 mmol), 6-chloroisatin (1.81 g,
10 mmol), and Et3N (1 mmol) in CH2Cl2 (30 mL) were refluxed for
1 h and then cooled to room temperature in an ice bath. The pre-
cipitate was collected by filtration and dried. A yellow solid was
obtained with a yield of 71%. m. p.> 300 ꢀC; 1H NMR (400 MHz,
b) A 100 mL, three-neck round-bottom flask fitted with a ther-
mometer was charged with concentrated sulfuric acid (10
equiv.). After heating to 50 ꢀC with stirring, the dried product (1
equiv.) from the above step was added over a period of 20 min.
The resulting solution was heated to 65 ꢀC, which was main-
tained for 1h followed by cooling to room temperature in an ice
bath. The precipitate was filtered and dried to yield the target
compounds.
CDCl3)
d
8.60 (d, J ¼ 8.5 Hz, 1H), 8.44 (d, J ¼ 7.9 Hz, 1H), 8.04 (d,
J ¼ 8.1 Hz, 1H), 7.87 (t, J ¼ 7.6 Hz, 2H), 7.77e7.67 (m, 2H). IR (KBr):
1732, 1675, 1594, 1460, 1339, 771 cmꢂ1; ESI-MS m/z: [M ꢂ H]þ:
281.1. Anal. calcd for C15H7ClN2O2:C 63.73,H 2.50, N 9.91; found C
63.68,H 2.55, N 9.94.
4.3.1.6. 7-Chloro-8-methylindolo[2,1-b]quinazoline-6,12-dione (1e).
Isatoic anhydride (1.63 g, 10 mmol), 4-chloro-5-methylisatin
(1.95 g, 10 mmol), and Et3N (1 mmol) in CH2Cl2 (30 mL) were
refluxed for 1 h and then cooled to room temperature in an ice bath.
The precipitate was collected by filtration and dried to obtain the
target compound. A yellow solid was obtained with a yield of 76%.
c) A solution of isatoic anhydride (0.1 mol), isatin (0.1 mmol), and
Et3N (5 mmol) in dichloromethane (10 mL) was refluxed for 1 h
and then cooled to room temperature with an ice bath. The
precipitate was filtered and dried to afford the target
compounds.
m. p.: 302e303 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.47 (d, J ¼ 8.2 Hz,
1H), 8.43 (d, J ¼ 7.8 Hz, 1H), 8.05 (d, J ¼ 8.0 Hz,1H), 7.86 (t, J ¼ 7.5 Hz,
1H), 7.68 (t, J ¼ 7.5 Hz, 1H), 7.63 (d, J ¼ 8.1 Hz, 1H), 2.47 (s, 3H).
IR(KBr): 1724, 1685, 1588, 1461, 1298, 1284, 1165, 777 cmꢂ1
.
4.3.1.2. Indolo[2,1-b]quinazoline-6,12-dione (1a). Isatoic anhydride
(1.63 g, 10 mmol), isatin (1.47 g, 10 mmol), and Et3N (1 mmol) in
CH2Cl2 (30 mL) were refluxed for 1 h and then cooled to room
temperature with an ice bath. The precipitate was collected by
filtration and dried. A yellow solid was obtained with a yield of 90%.
4.3.1.7. 8-Fluoroindolo[2,1-b]quinazoline-6,12-dione
(1f).
Isatoic anhydride (1.63 g, 10 mmol), 5-fluoroisatin (1.65 g,
10 mmol), and Et3N (1 mmol) in CH2Cl2 (30 mL) were refluxed for
1 h and then cooled to room temperature in an ice bath. The pre-
cipitate was collected by filtration and dried to obtain the target
compound. A yellow solid was obtained with a yield of 85%.
m. p.:268e269 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.64 (d, J ¼ 8.1 Hz,
1H), 8.45 (d, J ¼ 7.8 Hz, 1H), 8.04 (d, J ¼ 8.1 Hz, 1H), 7.92 (d,
J ¼ 7.4 Hz, 1H), 7.86 (t, J ¼ 7.7 Hz, 1H), 7.80 (t, J ¼ 7.8 Hz, 1H), 7.68 (t,
J ¼ 7.6 Hz, 1H), 7.46 (t, J ¼ 7.5 Hz, 1H); IR (KBr):3087, 1727, 1685,
m.p.273e276 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.70 (dd, J ¼ 8.8,
1594, 1460, 1313, 757 cmꢂ1
249.2, found:249.2.
;
1ESI-MS for C15H8N2O2 [MþH]þ:calcd
4.1 Hz, 1H), 8.50 (dd, J ¼ 7.9, 1.3 Hz, 1H), 8.09 (d, J ¼ 8.1 Hz, 1H), 7.92
(m, J ¼ 7.6 Hz,1H), 7.75 (t, J ¼ 7.6 Hz, 1H), 7.64 (dd, J ¼ 6.5, 2.7 Hz,
1H), 7.55 (td, J ¼ 8.6, 2.7 Hz, 1H). IR(KBr): 3088, 1723, 1689, 1481,
1302, 772 cmꢂ1; ESI-MS m/z: [MþH] þ: 267.0. Anal. calcd for
4.3.1.3. 8,9-Dichloroindolo[2,1-b]quinazoline-6,12-dione(1b0); 7,8-
dichloroindolo[2,1-b]quinazoline-6,12-dione(1b"). Isatoic anhydride
(10 mmol), a mixture of 5,6-dichloroisatin and 4,5-dichloroisatin
(10 mmol), and Et3N (1 mmol) in CH2Cl2 (30 mL) were refluxed
for 1 h and then cooled to room temperature with an ice bath. The
precipitate was collected by filtration and dried. A yellow solid was
obtained with a yield of 80%. m. p.>300 ꢀC; 1H NMR (400 MHz,
C15H7FN2O2: C 67.67, H 2.65, N 10.52; found C 67.58, H 2.62, N,
10.58.
4.3.1.8. 8-Chloroindolo[2,1-b]quinazoline-6,12-dione
(1g).
Isatoic anhydride (1.63 g, 10 mmol), 5-chloroisatin (1.81 g,
10 mmol), and Et3N (1 mmol) in CH2Cl2 (30 mL) were refluxed for
1 h and then cooled down to room temperature in an ice bath. The
precipitate was collected by filtration and dried to obtain the target
compound. A yellow solid was obtained with a yield of 85%. m. p.
CDCl3)
d
8.81 (s, 1H), 8.44 (d, J ¼ 7.7 Hz, 1H), 8.09e8.02 (m, 1H), 7.98
(s, 1H), 7.89 (t, J ¼ 7.7 Hz, 1H), 7.71 (td, J ¼ 7.6, 3.7 Hz, 1H); 1H NMR
294e296 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.60 (d, J ¼ 8.5 Hz, 1H),
(400 MHz, CDCl3)
d8.57 (d, J ¼ 8.6 Hz, 1H), 8.44 (d, J ¼ 7.7 Hz, 1H),
8.44 (d, J ¼ 7.9 Hz, 1H), 8.04 (d, J ¼ 8.1 Hz, 1H), 7.87 (t, J ¼ 7.6 Hz, 2H),
8.09e8.02 (m, 1H), 7.89 (t, J ¼ 7.7 Hz, 1H), 7.84 (d, J ¼ 8.6 Hz, 1H),
7.71 (td, J ¼ 7.6, 3.7 Hz, 1H). IR(KBr): 3061, 1732, 1685, 1584, 1435,
1337, 1179, 773 cmꢂ1; ESI-MS m/z: 316.9 [MþH]þ. Anal. calcd for
7.77e7.67 (m, 2H). IR (KBr): 1732, 1675, 1594, 1460, 1339, 771 cmꢂ1
;
ESI-MS m/z: [M ꢂ H] þ:281.1. Anal. calcd for C15H7ClN2O2:C 63.73, H
2.50, N 9.91; found C 63.68, H 2.55, N 9.94.
C
15H6Cl2N2O2: C 56.81, H 1.91, N 8.83; found C 56.77, H 1.88, N 8.89.
4.3.1.9. 8-Bromoindolo[2,1-b]quinazoline-6,12-dione
(1h).
4.3.1.4. 8-Fluoro-9-chloroindolo[2,1-b]quinazoline-6,12-dione (1c0);
8-fluoro-7-chloroindolo[2,1-b]quinazoline-6,12-dione (1c").
Isatoic anhydride (10 mmol), a mixture of 5-fluoro-6-chloroisatin
and 5-Fluoro-4-chloroisatin (10 mmol), and Et3N (1 mmol) in
CH2Cl2 (30 mL) were refluxed for 1 h and then cooled to room
temperature in an ice bath. The precipitate was collected by
filtration and dried. A yellow solid was obtained with a yield of 85%.
Isatoic anhydride (1.63 g, 10 mmol), 5-bromoisatin (2.25 g,
10 mmol), and Et3N (1 mmol) in CH2Cl2 (30 mL) were refluxed for
1 h and then cooled to room temperature in an ice bath. The pre-
cipitate was collected by filtration and dried to obtain the target
compound. A yellow solid was obtained with a yield of 81%. m. p.
288e290 ꢀC; 1HNMR (400 MHz, CDCl3)
d
8.54 (d, J ¼ 8.5 Hz, 1H),
8.43 (d, J ¼ 8.0 Hz,1H), 8.07e7.99 (m, 2H), 7.92e7.84 (m, 2H), 7.70 (t,
m.p.>300 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.78 (d, J ¼ 5.8 Hz, 1H),
8.43 (d, J ¼ 7.7 Hz, 1H), 8.08e7.98 (m, 1H), 7.87 (t, J ¼ 7.5 Hz, 1H),
7.76e7.62 (m, 2H). 1H NMR (400 MHz, CDCl3)
J ¼ 7.6 Hz, 1H). IR (KBr): 3069, 1732, 1675, 1593, 1460, 1339 cmꢂ1
ESI-MS for C15H7BrN2O2 [M ꢂ H]þ: calcd 326.97, found 327.0.
;
d
8.60 (dd, J ¼ 8.7,
3.5 Hz, 1H), 8.43 (d, J ¼ 7.7 Hz, 1H), 8.08e7.98 (m, 1H), 7.87 (t,
J ¼ 7.5 Hz, 1H), 7.76e7.62 (m, 1H), 7.53 (t, J ¼ 8.7 Hz, 1H). IR
(KBr):3044, 1731, 1685, 1593, 1471, 776 cmꢂ1; ESI-MS m/z: 301.0
[MþH]þ. Anal. calcd for C15H6ClFN2O2: C 59.92, H 2.01, N 9.32;
found C 59.88, H 2.04, N 9.35.
4.3.2. Synthesis of 5a-5j
A secondary amine (1 mmol) was added to a solution of 1b
(1 mmol) in NMP (5 mL). The mixture was stirred at 70 ꢀC for 2 h
and then cooled to room temperature. Methanol was subsequently
added to the reaction mixture to precipitate the product. The

6
X. Zheng et al. / Tetrahedron 75 (2019) 130351
precipitate was filtered and dried to afford the target compound.
4.3.2.9. 7-(N-4-(2-furanylcarbonyl)-piperazine) -8-chloroindolo [2,1-
b]quinazoline-6,12-dione(5i). Red solid, yield 80%. 1H NMR
(400 MHz, CDCl3)
d
8.42 (dd, J ¼ 9.7, 8.4 Hz, 1H), 8.20 (d, J ¼ 7.1 Hz,
4.3.2.1. 7-(Piperidin-1-yl) -8-chloroindolo[2,1-b]quinazoline-6,12-
dione(5a). Red solid, yield 90%, m. p.248e250 ꢀC; 1H NMR
1H), 8.11 (dd, J ¼ 8.5, 3.2 Hz, 1H), 8.02 (t, J ¼ 7.6 Hz, 1H), 7.91e7.82
(m, 1H), 7.73e7.63 (m, 1H), 7.54 (dd, J ¼ 7.1, 4.3 Hz, 1H), 7.10 (dd,
J ¼ 14.3, 3.4 Hz, 1H), 6.53 (m, 1H), 4.08 (m, 4H), 3.59 (m, 4H).
(400 MHz, CDCl3)
d
8.42 (d, J ¼ 7.8 Hz, 1H), 8.10 (d, J ¼ 8.2 Hz, 1H),
8.00 (d, J ¼ 8.1 Hz, 1H), 7.84 (t, J ¼ 7.1 Hz, 1H), 7.68e7.60 (m, 2H),
3.45 (m, 4H), 1.78 (m, 6H). IR (KBr): 2929, 2857, 1706, 1683, 1552,
1483, 1463, 1337, 1152, 1098, 771 cmꢂ1
.
4.3.3. Synthesis of 6a-6j
A secondary amine (1 mmol) was added to a solution of 1c
(1 mmol) in NMP (5 mL). The mixture was stirred at 70 ꢀC for 2 h
and then cooled to room temperature. Methanol was subsequently
added to the reaction mixture to precipitate the product. The red
precipitate was filtered and dried to afford the target compound.
Some of the residue was purified by column chromatography on
silica gel using petroleum ether/ethyl acetate (1:1) as eluent to
provide the desired product.
4.3.2.2. 7-(Piperazin-1-yl) -8-chloroindolo[2,1-b]quinazoline-6,12-
dione(5b). Red solid, yield 84%, m. p.261e263 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
9.06 (s, 1H), 8.33 (d, J ¼ 7.9 Hz, 1H), 8.19 (d,
J ¼ 8.5 Hz, 1H), 7.96 (d, J ¼ 3.7 Hz, 2H), 7.91 (d, J ¼ 8.5 Hz, 1H), 7.75
(dd, J ¼ 7.8, 4.5 Hz, 1H), 3.58 (m, 4H), 3.32e3.26 (m, 4H). IR (KBr):
3417, 2918, 2796, 2688, 2607, 2473, 1709, 1681, 1589, 1559, 1460,
1338, 1166, 1106, 774 cmꢂ1
.
4.3.3.1. 7-(Piperidine-1-yl))-8- fluoroindolo[2,1-b]quinazoline ꢂ6,12-
dione(6a). Red solid, yield 92%, m. p.225e227 ꢀC; (6a) 1H NMR
4.3.2.3. 7-(Morpholine-1-yl)
-8-chloroindolo[2,1-b]
quinazoline ꢂ6,12-dione(5c). Red solid, yield 80%, m. p.248e250 ꢀC;
(400 MHz, CDCl3)
d
8.40 (m, 2H), 8.15 (d, J ¼ 7.2 Hz, 1H), 8.01 (m,
1H NMR (400 MHz, CDCl3)
d
8.42 (dd, J ¼ 8.0, 1.3 Hz, 1H), 8.19 (d,
2H), 7.88e7.79 (m, 2H), 7.69e7.60 (m, 2H), 7.46 (d, J ¼ 12.3 Hz, 1H),
J ¼ 8.3 Hz, 1H), 8.01 (d, J ¼ 8.0 Hz, 1H), 7.89e7.81 (m, 1H), 7.66 (d,
J ¼ 8.3 Hz, 2H), 3.99e3.91 (t, J ¼ 4 Hz, 4H), 3.60e3.50 (t, J ¼ 4 Hz,
4H). IR (KBr): 3068, 2951, 2842, 1711, 1682, 1588, 1555, 1479, 1443,
7.25e7.18 (m, 1H), 3.59-3.42 (m, 8H), 2.11e1.63 (m, 12H); (6a′) 1H
NMR (400 MHz, CDCl3)
d
8.39 (dd, J ¼ 7.9, 1.2 Hz, 1H), 8.14 (d,
J ¼ 7.2 Hz, 1H), 8.02 (d, J ¼ 8.0 Hz, 1H), 7.88e7.80 (m, 1H), 7.65 (m,
1H), 7.46 (d, J ¼ 12.3 Hz, 1H), 3.59e3.45 (m, 4H), 1.84e1.68 (m, 6H).
IR (KBr): 3042, 2928, 2851, 1683, 1597, 1510, 1485, 1409, 1247,
1336, 1292, 1162, 1107, 774 cmꢂ1
.
4.3.2.4. 7-(N-methyl piperazine -1-yl -8-chloroindolo[2,1-b] quina-
772 cmꢂ1
.
zoline-6,12-dione(5d). Red solid, yield 67%,.m. p.256e259 ꢀC; 1H
NMR (400 MHz, CDCl3)
d
8.45e8.39 (d, J ¼ 7.7 Hz, 1H), 8.15 (d,
4.3.3.2. 7-(Piperazine-1-yl) -8- fluoroindolo[2,1-b]quinazoline-6,12-
dione (6b). Red solid, yield 88%, m. p.>300 ꢀC; 1H NMR (400 MHz,
J ¼ 8.3 Hz, 1H), 8.00 (d, J ¼ 7.7 Hz, 1H), 7.87e7.81 (t, J ¼ 8.3 Hz, 1H),
7.65 (dd, J ¼ 7.6, 5.4 Hz, 2H), 3.57 (t, J ¼ 4.0Hz, 4H), 2.67 (t, J ¼ 4.0Hz,
4H), 2.41 (s, 3H). IR (KBr): 3068, 2971, 2939, 2836, 2785, 1711, 1684,
CDCl3)
d
8.43 (d, J ¼ 7.0 Hz, 1H), 8.15 (d, J ¼ 8.7 Hz, 1H), 8.01 (d,
J ¼ 8.3 Hz, 1H), 7.85 (d, J ¼ 7.5 Hz, 1H), 7.67 (s, 1H), 7.40e7.32 (m,
1H), 4.02 (m, 1H), 3.93 (m, 1H), 3.75 (m, 2H), 3.55 (m, 4H). IR (KBr):
3201, 3046, 2936, 2853, 1679, 1602, 1564, 1510, 1461, 1357, 1295,
1591, 1552, 1446, 1338, 1289, 1155, 1104, 772 cmꢂ1
.
4.3.2.5. 7-(N-4-(2-Hydroxyethyl)piperazine -1-yl) -8-chloroindolo
1234, 1204, 1182, 824, 769 cmꢂ1
.
[2,1-b]quinazoline-6,12-dione(5e). Red solid, yield 70%, m.
p.221e223 ꢀC; 1H NMR (400 MHz, CDCl3)
d8.31 (d, J ¼ 7.8 Hz, 1H),
4.3.3.3. 7-(Morpholine
-1-yl)-8-
fluoroindolo[2,1-b]
8.07 (d, J ¼ 8.4 Hz, 1H), 7.94 (d, J ¼ 3.7 Hz, 2H), 7.83 (d, J ¼ 8.3 Hz,
1H), 7.76e7.69 (m, 1H), 4.48 (t, J ¼ 5.4 Hz, 2H), 3.57 (dd, J ¼ 6.0,
4.0 Hz, 2H), 3.39 (d, J ¼ 4.5 Hz, 4H), 2.63 (m, 4H). IR (KBr): 3179,
3066, 2934, 2826, 1709, 1684, 1591, 1552, 1455, 1338, 1159, 1105,
quinazoline ꢂ6,12-dione(6c). Red solid, yield 56%, m. p.269e270 ꢀC;
1H NMR (400 MHz, CDCl3)
d
8.48e8.35 (m, 2H), 8.17 (d, J ¼ 7.1 Hz,
1H), 8.10e7.96 (m, 3H), 7.85 (dd, J ¼ 7.1, 5.2 Hz, 2H), 7.67 (dd,
J ¼ 11.0, 4.4 Hz, 2H), 7.50 (d, J ¼ 11.9 Hz, 1H), 7.31 (d, J ¼ 8.4 Hz, 1H),
4.00e3.93 (m, 4H), 3.93e3.86 (m, 4H), 3.55 (m, 4H), 3.53e3.40 (m,
4H). IR (KBr): 3066, 2964, 2889, 2844, 1707, 1682, 1596, 1494, 1395,
771 cmꢂ1
.
1296, 1240, 1112, 891, 774 cmꢂ1
.
4.3.2.6. 7-(N-4-(2-Pyridyl)piperazine -1-yl) -8-chloroindolo[2,1-b]
quinazoline-6,12-dione(5f). Red solid, yield 56%, m. p.235e237 ꢀC;
1H NMR (400 MHz, CDCl3) d8.46e8.41 (m, 1H), 8.29e8.19 (m, 2H),
4.3.3.4. 7-(Piperazin7-(N-methyl piperazine -1-yl)-8- fluoroindolo
[2,1-b]quinazoline-6,12-dione(6d). Red solid, yield 70%, m.
8.02 (d, J ¼ 7.4 Hz, 1H), 7.88e7.82 (m, 1H), 7.68 (m, 2H), 6.76 (s, 2H),
3.94e3.86 (m, 2H), 3.67 (d, J ¼ 4.7 Hz, 2H), 3.54 (m, 2H), 3.49 (d,
J ¼ 5.3 Hz, 2H). IR (KBr): 3067, 2996, 2833, 1710, 1684, 1593, 1555,
p.246e249 ꢀC; 1H NMR (400 MHz, CDCl3)
d8.40 (td, J ¼ 8.0, 1.2 Hz,
1H), 8.16 (d, J ¼ 7.2 Hz, 1H), 8.05e7.97 (m, 1H), 7.87e7.79 (m, 1H),
7.70e7.60 (m, 1H), 7.48 (d, J ¼ 9.4 Hz, 1H), 7.29 (d, J ¼ 8.4 Hz, 1H),
3.66e3.49 (m, 4H), 2.63 (m, 4H), 2.39 (d, J ¼ 7.9 Hz, 3H). IR (KBr):
3065, 2922, 2794, 1706, 1683, 1599, 1494, 1456, 1295, 1245, 1140,
1436, 1480, 1436, 1337, 1232, 1158, 1107, 979, 772 cmꢂ1
.
4.3.2.7. 7-(N, N-dimethyl)amino -8-chloroindolo[2,1-b] quinazoline-
6,12-dione(5g). Red solid, yield 51%, m. p.296e298 ꢀC; 1H NMR
1002, 773 cmꢂ1
.
(400 MHz, CDCl3)
d
8.58 (d, J ¼ 8.6 Hz, 1H), 8.43 (d, J ¼ 7.8 Hz, 1H),
8.05 (d, J ¼ 8.2 Hz, 1H), 7.92e7.80 (m, 1H), 7.70 (t, J ¼ 7.6 Hz, 1H),
4.3.3.5. 7-(N-4-(2-Hydroxyethyl)piperazine -1-yl)-8- fluoroindolo
[2,1-b]quinazoline-6,12-dione(6e). Red solid, yield 64%, m.
7.67e7.58 (m, 1H), 3.23 (s, 3H). IR (KBr): 3439, 3082, 2927, 1734,
1686, 1585, 1554, 1439, 1338, 1285, 1224, 1165, 773 cmꢂ1
.
p.251e253 ꢀC; 1H NMR (400 MHz, DMSO)
d 8.36e8.24 (m, 1H), 8.08
(d, J ¼ 7.2 Hz, 1H), 7.93 (m, 2H), 7.73 (dd, J ¼ 9.8, 4.4 Hz, 1H), 7.66 (d,
J ¼ 12.3 Hz, 1H), 4.75e4.37 (m, 2H), 3.60e3.52 (m, 4H), 3.29 (d,
J ¼ 5.6 Hz, 2H), 2.63 (s, 4H). IR (KBr): 3400, 3046, 2941, 2885, 2833,
1709, 1683, 1598, 1566, 1493, 1461, 1396, 1294, 1242, 1046, 1004,
4.3.2.8. 7-(N, N-diethyl) amino -8-chloroindolo[2,1-b] quinazoline-
6,12-dione(5h). Red solid, yield 50%, m. p.228e230 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
8.47 (d, J ¼ 8.6 Hz, 1H), 8.32 (m, 1H), 8.11 (t,
J ¼ 9.1 Hz, 1H), 7.98 (d, J ¼ 3.7 Hz, 1H), 7.94 (d, J ¼ 4.0 Hz, 1H), 7.77
(m, 1H), 3.42 (q, J ¼ 7.1,4.2 Hz, 2H), 1.02 (t, J ¼ 7.1 Hz, 3H). IR (KBr):
3073, 2969, 1711, 1683, 1584, 1553, 1461, 1438, 1336, 1281, 1168,
773 cmꢂ1
.
4.3.3.6. 7-(N-4-(2-Pyridyl)piperazine -1-yl)-8- fluoroindolo[2,1-b]
quinazoline-6,12-dione(6f). Red solid, yield 60%, m. p.250e251 ꢀC;
1103, 770 cmꢂ1
.

X. Zheng et al. / Tetrahedron 75 (2019) 130351
7
1H NMR (400 MHz, DMSO)
d
8.31 (s,1H), 8.21e8.08 (m,1H), 7.94 (m,
4.4 Hz, 2H), 7.50 (d, J ¼ 11.9 Hz, 1H), 7.31 (d, J ¼ 8.4 Hz, 1H),
4.00e3.93 (m, 4H), 3.93e3.86 (m, 4H), 3.55 (m, 4H), 3.53e3.40 (m,
4H). IR (KBr): 3066, 2964, 2889, 2844, 1707, 1682, 1596, 1494, 1395,
2H), 7.71 (d, J ¼ 13.8 Hz, 2H), 7.61 (d, J ¼ 8.5 Hz, 2H), 6.93 (dd,
J ¼ 18.9, 8.2 Hz, 1H), 6.70 (s, 1H), 3.73 (s, 4H), 3.50 (d, J ¼ 36.2 Hz,
4H). IR (KBr): 3063, 2844, 1705, 1682, 1596, 1487, 1438, 1356, 1233,
1296, 1240, 1112, 891, 774 cmꢂ1
.
979, 771 cmꢂ1
.
4.3.4.4. 7-(N-methyl piperazine -1-yl) indolo[2,1-b]quinazoline-6,12-
4.3.3.7. 7-(N, N-dimethyl) amino -8- fluoroindolo[2,1-b] quinazoline-
6,12-dione(6g). Red solid, yield 45%, m. p.296e298 ꢀC; 1H NMR
dione(7d). Red solid, yield 67%, m. p.253e257 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
8.40 (td, J ¼ 9.4, 1.2 Hz, 1H), 8.16 (d, J ¼ 7.2 Hz,
(400 MHz, CDCl3)
d
8.40 (dd, J ¼ 7.9, 1.4 Hz, 1H), 8.05e7.97 (m, 2H),
1H), 8.05e7.97 (m, 1H), 7.87e7.79 (m, 1H), 7.70e7.60 (m, 1H), 7.48
(d, J ¼ 12.1 Hz, 1H), 7.29 (t, J ¼ 8.4 Hz, 1H), 3.66e3.49 (m, 4H), 2.63
(m, 4H), 2.39 (d, J ¼ 7.9 Hz, 3H). IR (KBr): 2937, 2842, 2803, 1688,
7.87e7.79 (m,1H), 7.64 (dd, J ¼ 8.1, 4.1, 1.0 Hz, 1H), 7.44 (d,
J ¼ 13.0 Hz, 1H), 3.27 (d, J ¼ 2.7 Hz, 3H), 3.25 (d, J ¼ 3.5 Hz, 3H). IR
(KBr): 3083, 2969, 1733, 1684, 1582, 1439, 1336, 1282, 1222, 1174,
1595, 1513, 1460, 1406, 1297, 1236, 1131, 771 cmꢂ1
.
1108, 770 cmꢂ1
.
4.3.4.5. 7-(N-4-(2-Hydroxyethyl)piperazine -1-yl) indolo[2,1-b]qui-
4.3.3.8. 7-(N, N-diethyl) amino -8- fluoroindolo[2,1-b] quinazoline-
6,12-dione (6h). Red solid, yield 31%, m. p.240e241 ꢀC; 1H NMR
nazoline-6,12-dione(7e). Red solid, yield 63%, m. p.>300 ꢀC; 1H
NMR (400 MHz, CDCl3)
d1H NMR (400 MHz, DMSO) d 8.30 (t,
(400 MHz, CDCl3)
d
8.44e8.36 (m, 1H), 8.06 (d, J ¼ 7.6 Hz, 1H), 8.01
J ¼ 8.6 Hz, 1H), 7.95 (dd, J ¼ 16.3, 8.3 Hz, 3H), 7.67 (dd, J ¼ 21.6,
13.0 Hz, 2H), 7.03e6.87 (m, 1H), 4.65e4.31 (m, 2H), 3.57 (s, 2H),
3.35e3.25 (m, 4H), 2.62 (d, J ¼ 23.0 Hz, 4H).
(d, J ¼ 8.0 Hz, 1H), 7.83 (dd, J ¼ 10.6, 4.7 Hz, 1H), 7.63 (dd, J ¼ 10.6,
5.4 Hz, 1H), 7.45 (d, J ¼ 13.6 Hz, 1H), 3.60 (d, J ¼ 7.0 Hz, 4H), 1.35 (dd,
J ¼ 8.6, 5.5 Hz, 6H).
4.3.4.6. 7-(N-4-(2-Pyridyl)piperazine -1-yl) indolo[2,1-b] quinazo-
4.3.3.9. 7-(N-4-(2-furanylcarbonyl)-piperazine-1-yl) -8- fluoroindolo
[2,1-b]quinazoline-6,12-dione(6i). Red solid, yield 80%, m.
line-6,12-dione(7f). Red solid, yield 52%, m. p.>300 ꢀC; 1H NMR
(400 MHz, DMSO)
d
8.30 (d, J ¼ 7.6 Hz, 1H), 8.15 (m, 1H), 8.01 (m,
p.297e299 ꢀC 1H NMR (400 MHz, CDCl3)
d
8.42 (m, 1H), 8.24 (d,
1H), 7.93 (m, 1H), 7.70 (d, J ¼ 8.8 Hz, 2H), 7.59 (m, 1H), 6.96 (d,
J ¼ 8.9 Hz, 1H), 6.86 (d, J ¼ 8.9 Hz, 1H), 6.75e6.64 (m, 1H), 3.76 (m,
8H). IR (KBr): 2847, 1682, 1592, 1513, 1483, 1460, 1438, 1406, 1308,
J ¼ 8.4 Hz, 1H), 8.02 (d, J ¼ 7.4 Hz, 1H), 7.90 (m, 1H), 7.70 (d,
J ¼ 8.4 Hz, 2H), 7.57e7.50 (m, 1H), 7.09 (d, J ¼ 3.5 Hz, 1H), 6.53 (m,
1H), 4.07 (m, 4H), 3.74e3.51 (m, 3H), 3.52e3.42 (m, 1H).
1221, 1133, 1024, 768 cmꢂ1
.
4.3.3.10. 7-(N-3- Pipecolinic acid)-8- fluoroindolo[2,1-b] quinazo-
line-6,12-dione(6j). Red solid, yield 47%, m. p.289e290 ꢀC; 1H NMR
4.3.5. Synthesis of 8a-8f
A secondary amine (1 mol) was added to a solution of 1e
(1 mmol) in NMP (5 mL). The mixture was stirred at 70 ꢀC for 2h
and then cooled to room temperature. Methanol was added to the
reaction mixture to precipitate the product. The red precipitate was
filtered and dried to afford the target compound. Some of the res-
idue was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate (1:1) as eluent to provide the desired
product.
(400 MHz, DMSO)
d
8.30 (d, J ¼ 8.5 Hz, 1H), 8.10 (d, J ¼ 7.4 Hz, 1H),
7.93 (s, 2H), 7.75 (d, J ¼ 8.0 Hz, 1H), 7.65 (d, J ¼ 12.3 Hz, 1H), 3.75 (d,
J ¼ 12.4 Hz, 2H), 3.17 (s, 2H), 2.34 (s, 1H), 1.99 (s, 2H), 1.72 (d,
J ¼ 10.7 Hz, 2H). IR (KBr): 3414, 3200, 3050, 2941, 2851, 1729, 1682,
1598, 1564, 1500, 1457, 1410, 1357, 1208, 1151, 1103, 773 cmꢂ1
.
4.3.4. Synthesis of 7a-7f
A secondary amine (1 mmol) was added to a solution of 1d
(1 mmol) in NMP (5 mL). The mixture was stirred at 70 ꢀC for 2 h
and then cooled to room temperature. Methanol was added to the
reaction mixture to precipitate the product. The red precipitate was
filtered and dried to afford the target compound. Some of the res-
idue was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate (1:1) as eluent to provide the desired
product.
4.3.5.1. 7-(Piperidine-1-yl) -8-methylindolo [2,1-b]quinazoline-6,12-
dione(8a). Red solid, yield 90%, m. p.245e247 ꢀC; 1H NMR
(400 MHz, DMSO)
d
8.30 (d, J ¼ 8.0 Hz, 1H), 7.99 (d, J ¼ 7.8 Hz, 1H),
7.93 (d, J ¼ 3.6 Hz, 2H), 7.77e7.67 (m, 1H), 7.56 (d, J ¼ 8.0 Hz, 1H),
3.24 (s, 4H), 2.34 (s, 3H), 1.69 (s, 6H). IR (KBr): 2927, 2846, 1682,
1594, 1570, 1480, 1461, 1343, 1290, 1219, 1122, 775 cmꢂ1
.
4.3.5.2. 7-(Piperazine-1-yl) -8-methylindolo [2,1-b]quinazoline-6,12-
4.3.4.1. 7-(Piperidine-1-yl) indolo[2,1-b]quinazoline-6,12-dione(7a).
dione(8b). Red solid, yield 81%, m. p.>300 ꢀC; 1H NMR (400 MHz,
Red solid, yield 80%, m. p.248e250 ꢀC; 1H NMR (400 MHz, CDCl3)
DMSO)
d
8.31 (s, 1H), 8.13 (d, J ¼ 8.2 Hz, 1H), 7.94 (s, 2H), 7.71 (s, 1H),
d8.33e8.25 (m, 1H), 7.99e7.87 (m, 3H), 7.75e7.66 (m, 1H), 7.62 (d,
7.66 (d, J ¼ 7.7 Hz, 1H), 3.30 (d, J ¼ 7.1 Hz, 8H), 2.35 (d, J ¼ 11.8 Hz,
J ¼ 8.9 Hz, 1H), 6.90 (dd, J ¼ 9.0, 2.2 Hz, 1H), 3.62 (m, 4H), 1.67 (m,
3H). IR (KBr): 2930, 2839, 2793, 1706, 1682, 1594, 1569, 1464, 1386,
6H). IR (KBr): 2926, 2851, 1691, 1597, 1559, 1492, 1445, 1301, 1246,
1374, 1334, 1293, 1234, 1139, 1002, 778 cmꢂ1
.
1172, 1123, 779 cmꢂ1
.
4.3.5.3. 7-(Morpholine-1-yl)
6,12-dione(8c). Red solid, yield 78%, m. p.291e293 ꢀC; 1H NMR
(400 MHz, DMSO)
-8-methylindolo[2,1-b]quinazoline-
4.3.4.2. 7-(Piperazine-1-yl) indolo [2,1-b]quinazoline-6,12-dione(7b).
Red solid, yield 88%, m. p.>300 ꢀC; 1H NMR (400 MHz, CDCl3)
8.43
d
d
8.31 (d, J ¼ 7.8 Hz, 1H), 8.08e8.04 (m, 1H), 7.93
(d, J ¼ 7.0 Hz,1H), 8.15 (d, J ¼ 8.7 Hz,1H), 8.01 (d, J ¼ 8.3 Hz,1H), 7.85
(d, J ¼ 7.5 Hz, 1H), 7.67 (s, 1H), 7.40e7.32 (m, 1H), 4.02 (m, 1H), 3.93
(m,1H), 3.75 (m, 2H), 3.55 (m, 4H). IR (KBr): 3201, 3046, 2936, 2853,
1679, 1602, 1564, 1510, 1461, 1357, 1295, 1234, 1204, 1182, 824,
(d, J ¼ 3.6 Hz, 2H), 7.72 (dt, J ¼ 8.2, 4.3 Hz, 1H), 7.60 (d, J ¼ 8.0 Hz,
1H), 3.82e3.76 (m, 4H), 3.31e3.26 (m, 4H), 2.37 (s, 3H). IR (KBr):
2956, 2859, 1709, 1685, 1594, 1573, 1460, 1372, 1338, 1296, 1228,
1108, 778 cmꢂ1
.
769 cmꢂ1
.
4.3.5.4. 7-(N-methyl piperazine -1-yl) -8-methylindolo[2,1-b]quina-
4.3.4.3. 7-(Morpholine-1-yl) indolo [2,1-b]quinazoline-6,12-
zoline-6,12-dione(8d). Red solid, yield 71%, m. p.232e233 ꢀC; 1H
dione(7c). Red solid, yield 56%, m. p.269e270 ꢀC; 1H NMR
NMR (400 MHz, DMSO)
7.93 (d, J ¼ 3.4 Hz, 2H), 7.72 (dd, J ¼ 8.4, 4.5 Hz, 1H), 7.58 (d,
d
8.30 (d, J ¼ 8.1 Hz, 1H), 8.07e8.01 (m, 1H),
(400 MHz, CDCl3)
d8.48e8.35 (m, 2H), 8.17 (d, J ¼ 7.1 Hz, 1H),
8.10e7.96 (m, 3H), 7.85 (dd, J ¼ 7.1, 5.2 Hz, 2H), 7.67 (dd, J ¼ 11.0,
J ¼ 7.9 Hz, 1H), 3.28 (s, 4H), 3.21e3.09 (m, 3H), 2.33 (d, J ¼ 12.8 Hz,

8
X. Zheng et al. / Tetrahedron 75 (2019) 130351
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Lett. 21 (2011) 4353.
3H), 2.28 (d, J ¼ 2.4 Hz, 3H). IR (KBr): 2930, 2839, 2793, 1706, 1682,
1594, 1569, 1464,1386, 1374,1334, 1293, 1234,1139, 1002, 778 cmꢂ1
.
[7] P. Barraja, L. Caracausi, P. Diana, A. Montalbano, A. Carbone, A. Salvador,
P. Brun, I. Castagliuolo, S. Tisi, F. Dall'Acqua, D. Vedaldi, G. Cirrincione,
ChemMedChem 6 (2011) 1238.
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570;
4.3.5.5. 7-(N-4-(2-Hydroxyethyl)piperazine -1-yl) -8-methylindolo
[2,1-b]quinazoline-6,12-dione(8e). Red solid, yield 59%, m.
p.218e220 ꢀC; 1H NMR (400 MHz, DMSO)
d
8.31 (d, J ¼ 7.7 Hz, 1H),
8.17 (d, J ¼ 2.4 Hz, 1H), 8.12e8.04 (m, 1H), 7.93 (d, J ¼ 3.8 Hz, 2H),
7.79e7.68 (m, 1H), 7.60 (dd, J ¼ 14.1, 7.4 Hz, 2H), 6.95 (d, J ¼ 8.5 Hz,
1H), 6.77e6.66 (m, 1H), 3.68 (d, J ¼ 27.4 Hz, 8H). IR (KBr): 3407,
2818, 1723, 1680, 1595, 1567, 1478, 1459, 1340, 1295, 1235, 1134,
(b) S.H. Yang, D.B. Khadka, S.H. Cho, H.K. Ju, K.Y. Lee, H.J. Han, K.T. Lee, W. Cho,
J. Bioorg. Med. Chem. 19 (2011) 968;
(c) Y.H. Kim, H. Choi, J. Lee, I.C. Hwang, S.K. Moon, S.J. Kim, H.W. Lee, D.S. Im,
S.S. Lee, S.K. Ahn, S.W. Kim, C.K. Han, J.H. Yoon, K.J. Lee, N.S. Choi, Bioorg. Med.
Chem. Lett 18 (2008) 6279;
(d) O. Cruz-Lopez, A. Conejo-Garcia, M.C. Nunez, M. Kimatrai, M.E. Garcia-
Rubino, F. Morales, V. Gomez-Perez, J.M. Campos, Curr. Med. Chem. 18 (2011)
943.
1058, 1011, 774 cmꢂ1
.
4.3.5.6. 7-(N-4-(2-Pyridyl)piperazine -1-yl) -8-methylindolo[2,1-b]
quinazoline-6,12-dione(8f). Red solid, yield 54%, m. p.227e230 ꢀC;
[9] K. Iwata, P.E. Miller, E.G. Barbacci, L. Arnold, J. Doty, C.I. DiOrio, L.R. Pustilnik,
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(1997) 633.
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38 (1997) 633. Abstract 4251.
1H NMR (400 MHz, DMSO)
d
8.30 (d, J ¼ 7.8 Hz, 1H), 8.03 (d,
J ¼ 7.1 Hz, 1H), 7.93 (d, J ¼ 3.7 Hz, 2H), 7.77e7.68 (m, 1H), 7.58 (d,
J ¼ 8.0 Hz, 1H), 4.54 (s, 2H), 3.58 (s, 4H), 3.15 (s, 2H), 2.68 (d,
J ¼ 11.7 Hz, 4H), 2.33 (d, J ¼ 14.5 Hz, 3H). IR (KBr): 2828, 1711, 1682,
[10] Company Press Release, GSK's TYKERB Receives Accelerated Approval for
First-Line Combination Treatment of Hormone Receptor positive,HER2þ/
ErbB2þ Metastatic Breast Cancer, 2010.
1594, 1478, 1434, 1378, 1229, 977, 775 cmꢂ1
.
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6385e6388.
4.3.5.7. 7-(N, N-dimethyl)amino -8- methylindolo [2,1-b] quinazo-
line-6,12-dione(8g). Red solid, yield 34%, m. p.219e220 ꢀC; 1H NMR
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(400 MHz, DMSO) d 8.33e8.25 (m, 1H), 8.04e7.86 (m, 3H), 7.71 (dd,
J ¼ 8.2, 3.9 Hz, 1H), 7.60e7.46 (m, 1H), 3.05 (s, 3H), 2.99 (s, 3H), 2.34
(d, J ¼ 3.9 Hz, 3H). IR (KBr): 2913, 2802,1683,1595,1566,1502,1460,
1344, 1293, 1217, 1127, 1062, 771 cmꢂ1
.
Acknowledgments
We are grateful for the support from the Science and Technology
Program of Xi'an (No. CXY1443WL13), the Foundation of the Edu-
cation Department of Shaanxi Province (15JK2145), the Natural
Science Foundation of Shaanxi Province (No. 2014JM4095,
2018JM7059), the Xi'an City Science and Technology Project (No.
2017085CG/RC048(XBDX001)), the Shaanxi Province education
department key laboratory project (No. 16JS110) and the Shaanxi
Province key R&D project (No. 2018 SF-077).
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Supplementary data to this article can be found online at
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