Copper-catalyzed cascade synthesis of 1H-indolo[1,2-c]quinazoline derivatives

Article abstract of DOI:10.1002/ejoc.201200953

A simple, efficient and practical approach to 1H-indolo[1,2-c]quinazoline derivatives has been developed that uses inexpensive and readily-available catalyst and substrates. The method should provide a new strategy for N-fused heterocycles and will show wide application in organic chemistry and medicinal chemistry. A simple, efficient and practical approach to 1H-indolo[1,2-c] quinazoline derivatives has been developed that uses inexpensive and readily-available catalyst and substrates. The method should provide a new strategy for N-fused heterocycles and will show wide application in organic chemistry and medicinal chemistry. Copyright

Full text of DOI:10.1002/ejoc.201200953

FULL PAPER
DOI: 10.1002/ejoc.201200953
Copper-Catalyzed Cascade Synthesis of 1H-Indolo[1,2-c]quinazoline
Derivatives
Hao Zhang,[a] Yibao Jin,[b] Hongxia Liu,[b] Yuyang Jiang,[b] and Hua Fu*[a,b]
Keywords: Synthetic methods / Cascade reactions / Homogeneous catalysis / Copper / Nitrogen heterocycles
A simple, efficient and practical approach to 1H-indolo[1,2-
c]quinazoline derivatives has been developed that uses inex-
pensive and readily-available catalyst and substrates. The
method should provide a new strategy for N-fused heterocy-
cles and will show wide application in organic chemistry and
medicinal chemistry.
Introduction
Nitrogen-containing heterocycles are widely found in
natural products and biologically active molecules.[1] The
indole unit acts as a privileged structural motif of both de-
signed medicinal agents and natural products. For example,
indole derivatives have been used as neurotransmitter, anti-
hypertensive and antibiotic agents,[2] and some of them are
5-HT3 or 5HT1 receptor antagonists used in the treatment
of chemotherapy-induced nausea and vomiting,[3] and clus-
ter headaches.[4] Quinazolines also exhibit a variety of bio-
logical functions. For example, quinazoline derivatives have
been used as tyrosine kinase and cellular phosphorylation
inhibitors,[5] ligands for benzodiazepine and GABA recep-
tors in the central nervous system[6] and DNA binders,[7]
and some of them have acted as anticancer,[8] antiviral,[9]
and antitubercular agents.[10] N-Fused heterocycles of in-
dole and quinazoline frameworks, indoloquinazoline deriv-
atives (Figure 1), are important biological molecules, and
they exhibit antibacterial,[11] antifungal and weak cytotoxic
activity.[12] However, the methods for synthesis of indol-
oquinazoline derivatives are very limited. Recently, great
achievements have been made in copper-catalyzed cross-
couplings[13] and synthesis of N-heterocycles by us[14] and
other research groups.[15] Herein, we report a new and ef-
ficient copper-catalyzed approach to indoloquinazoline de-
rivatives.
Figure 1. Indoloquinazoline-containing indole and quinazoline
frameworks.
Results and Discussion
As shown in Table 1, reaction of 2-(2-bromophenyl)-1H-
indole (1a) with acetamidine hydrochloride (2a) was used
as the model to optimize catalytic conditions including cat-
alysts, bases, solvents and temperature under a nitrogen at-
mosphere. Six catalysts were screened by using K2CO3
(1.5 equiv.) as the base (relative to 1a), and DMSO as the
solvent at 80 °C (Table 1, Entries 1–6), and CuBr afforded
the highest yield (Table 1, Entry 2). Cs2CO3 and Na2CO3
were used as bases (Table 1, Entries 7 and 8), and K2CO3
showed the highest efficiency (Table 1, Entries 2, 7 and 8).
DMF and dioxane were trialed as solvents (Table 1, En-
tries 9 and 10) but were inferior to DMSO (Table 1, En-
tries 2, 9 and 10). The effect of temperature was also investi-
gated (Table 1, Entries 11–13) and 80 °C was a good choice
(Table 1, Entry 2).
The substrate scope of the copper-catalyzed cascade syn-
thesis of 1H-indolo[1,2-c]quinazoline derivatives was inves-
[a] Key Laboratory of Bioorganic Phosphorus Chemistry and tigated under the optimized conditions [CuBr (10 mol-%)
Chemical Biology (Ministry of Education), Department of
as catalyst, K2CO3 (1.5 equiv.) as the base under a nitrogen
Chemistry, Tsinghua University,
atmosphere]. As shown in Table 2, most of the tested sub-
strates afforded good to excellent yields. For the substituted
2-(2-halophenyl)-1H-indoles, aryl iodide (1d) showed
slightly higher reactivity than aryl bromide (1a; Table 2, En-
tries 2 and 6), and no evident difference on the electronic
effect in the substrates was observed. For the amidines,
most of aliphatic amidines provided slightly higher yields
Beijing 100084, P. R. China
Fax: +86-10-62781695
E-mail: fuhua@mail.tsinghua.edu.cn
Homepage: http://chem.tsinghua.edu.cn
[b] Key Laboratory of Chemical Biology (Guangdong Province),
Graduate School of Shenzhen, Tsinghua University,
Shenzhen 518057, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200953.
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Eur. J. Org. Chem. 2012, 6798–6803

Cascade Synthesis of 1H-Indolo[1,2-c]quinazoline Derivatives
Table 1. Copper-catalyzed cascade synthesis of 6-methyl-lH-
indolo[1,2-c]quinazoline (3a) through reaction of 2-(2-bromo-
phenyl)-1H-indole (1a) with acetamidine hydrochloride (2a). Opti-
mization of the reaction conditions.[a]
Table 2. Copper-catalyzed cascade synthesis of lH-indolo[1,2-c]
quinazoline derivatives.[a]
%
Entry Cat.
Base
Solvent
Temp.
Yield[b]
1
2
3
4
5
6
7
8
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
80
80
80
80
80
80
80
80
r.t.
60
100
84
92
89
90
64
82
87
29
62
CuBr
CuCl
Cu2O
Cu(OAc)2
CuBr2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Na2CO3 DMSO
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
10
11
12
13
dioxane
DMSO
DMSO
DMSO
66
trace
69
79
[a] Reaction conditions: 2-(2-bromophenyl)-1H-indole (1a,
0.5 mmol), acetamidine hydrochloride (2a, 1 mmol), catalyst
(0.05 mmol), base (1.5 mmol), solvent (2 mL) under a nitrogen at-
mosphere, reaction time (24 h). [b] Isolated yield.
than aromatic ones. The copper-catalyzed cascade reactions
could tolerate some functional groups including fluoro
(Table 2, Entries 7 and 15), nitro (Table 2, Entries 8 and 16),
chloro (Table 2, Entries 17–22) and ether (Table 2, En-
try 23). The reactions above did not need addition of any
ligand or additive, which demonstrated the ortho-substitu-
ent effect of the benzimidazole group (see Scheme 1).
According to the results above, a possible mechanism for
synthesis of 1H-indolo[1,2-c]quinazoline derivatives was
proposed in Scheme 1. Coordination of substituted 2-(2-
bromophenyl)-1H-indole with CuBr gives I, and oxidative
addition of I gives II. Coupling of II with amidine (N-aryl-
ation) yields intermediate III, and the intramolecular nucle-
ophilic attack of the NH of the indole group to the carbon
of the amidine provides target product 3 releasing NH3.[14j]
Scheme 1. Possible copper-catalyzed mechanism for synthesis of
1H-indolo[1,2-c]quinazoline derivatives.
Eur. J. Org. Chem. 2012, 6798–6803
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H. Zhang, Y. Jin, H. Liu, Y. Jiang, H. Fu
FULL PAPER
Table 2. (Continued)
Table 2. (Continued)
[a] Reaction conditions: Substituted 2-(2-halophenyl)-1H-indole (1,
0.5 mmol), amidine hydrochloride (2, 1 mmol), CuBr (0.05 mmol),
K2CO3 (1.5 mmol), DMSO (2 mL) under a nitrogen atmosphere,
reaction temperature (80–120 °C), reaction time (24 h). [b] Isolated
yield. [c] 1a as substrate. [d] 1b as substrate.
Interestingly, high regioselectivity was observed for N-1 cy-
clization over C-3 cyclization of indoles owing to the higher
nucleophilic power of N-1 over C-3 in the indoles.
Conclusions
A simple and efficient copper-catalyzed cascade method
for the synthesis of 1H-indolo[1,2-c]quinazoline derivatives
has been developed. The present method uses inexpensive
CuBr as the catalyst and readily-available substituted 2-(2-
halophenyl)indoles and amidines as starting materials. The
copper-catalyzed cascade reactions performed well under
mild conditions. Interestingly, no ligand or additive was re-
quired. Therefore, the present method provides a practical
approach to this kind of N-fused heterocycle.
Experimental Section
General: All reactions were carried out under a nitrogen atmo-
1
sphere. H NMR and 13C NMR spectroscopic data were recorded
by using tetramethylsilane (TMS) and the remaining CHCl3 in the
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Eur. J. Org. Chem. 2012, 6798–6803

Cascade Synthesis of 1H-Indolo[1,2-c]quinazoline Derivatives
CDCl3 solvent as the internal standard (1H NMR: TMS at δ = 8.58 Hz, 1 H), 6.94–7.00 (t, J = 8.58 Hz, 1 H), 7.23–7.31 (m, 2 H),
0.00 ppm, CHCl3 at δ = 7.26 ppm. 13C NMR: CDCl3 at δ = 7.49–7.67 (m, 7 H), 7.74–7.77 (d, J = 7.89 Hz, 1 H), 7.82–7.84 (d,
77.4 ppm).
J = 7.2 Hz, 1 H), 8.08–8.11 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 95.9, 115.0, 120.6, 120.7, 121.6, 122.8, 123.5,
127.5, 128.0, 128.3, 129.2, 129.4, 130.5, 131.7, 135.3, 136.1, 139.3,
149.4 ppm. MS (ESI): m/z = 295.2 [M + H]+.
Compounds 1a–f were prepared according to the previous pro-
cedures.[16]
General Procedure for Copper-Catalyzed Synthesis of 1H-
Indolo[1,2-c]quinazoline Derivatives (3): A 25 mL Schlenk tube was
charged with substituted 2-(2-halophenyl)indole (1, 0.5 mmol), am-
idine hydrochloride (2, 1 mmol), and CuBr (0.05 mmol, 7.1 mg),
K2CO3 (0.75 mmol, 104 mg), and DMSO (2 mL). The tube was
sealed and the mixture was allowed to stir at 80–120 °C (see
Table 2) under a nitrogen atmosphere for 24 h. The resulting solu-
tion was cooled to room temperature, and water (8 mL) was added
to the resulting solution. The resulting aqueous solution was ex-
tracted with ethyl acetate (3ϫ 10 mL), the combined organic phase
was dried with anhydrous MgSO4 and concentrated with the aid
of a rotary evaporator. The residue was purified by column
chromatography on silica gel to provide desired product 3.
6-p-Tolylindolo[1,2-c]quinazoline (3f): Eluent: petroleum ether/ethyl
acetate (50:1); yield 116 mg (75%) with 2-(2-bromophenyl)-1H-in-
dole as the substrate and 120 mg (78%) with 2-(2-iodophenyl)-1H-
indole as the substrate, yellow solid, m.p. 160–161 °C. 1H NMR
(CDCl3, 300 MHz): δ = 2.52 (s, 3 H), 6.55–6.58 (d, J = 8.58 Hz, 1
H), 6.96–7.02 (t, J = 7.89 Hz, 1 H), 7.24–7.31 (m, 2 H), 7.39–7.57
(m, 6 H), 7.74–7.77 (d, J = 7.92 Hz, 1 H), 7.80–7.84 (d, J = 7.92 Hz,
1 H), 8.08–8.11 (d, J = 7.56 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 20.6, 94.6, 114.0, 119.4, 119.5, 120.3, 121.6, 122.3,
126.2, 126.8, 127.1, 128.0, 128.8, 129.3, 130.7, 132.1, 134.3, 138.3,
139.4, 148.5 ppm. HRMS: calcd. for C22H16N2 [M + H]+ 309.1392;
found 309.1389.
6-(4-Fluorophenylindolo[1,2-c]quinazoline (3g): Eluent: petroleum
ether/ethyl acetate (50:1); yield 112 mg (72%), yellow solid, m.p.
234–235 °C. 1H NMR (CDCl3, 300 MHz): δ = 6.50–6.53 (d, J =
8.58 Hz, 1 H), 6.99–7.04 (t, J = 8.22 Hz, 1 H), 7.24–7.33 (m, 4 H),
7.46–7.55 (m, 2 H), 764–7.68 (m, 2 H), 7.75–7.82 (m, 2 H), 8.07–
8.09 (d, J = 7.56 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
96.0, 114.8, 116.6 (d, J = 21.5 Hz), 120.6, 120.7, 121.7, 122.8, 123.7,
127.6, 128.0, 129.3, 130.6, 130.7, 131.6, 132.2, 135.3, 139.2, 148.4,
164.0 (d, J = 248.8 Hz) ppm. HRMS: calcd. for C21H13FN2 [M +
H]+ 313.1141; found 313.1128.
6-Methylindolo[1,2-c]quinazoline (3a):[17] Eluent: petroleum ether/
ethyl acetate (50:1); yield 107 mg (92%), yellow solid, m.p. 119–
1
120 °C. H NMR (CDCl3, 300 MHz): δ = 3.15 (s, 3 H), 7.21 (s, 1
H), 7.36–7.54 (m, 4 H), 7.71–7.73 (d, J = 7.56 Hz, 1 H), 7.81–7.84
(d, J = 7.56 Hz, 1 H), 8.03–8.06 (d, J = 7.92 Hz, 1 H), 8.08–8.11
(d, J = 8.25 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 25.5,
95.6, 114.9, 120.3, 120.9, 122.2, 122.7, 123.5, 126.9, 127.0, 129.1,
130.6, 131.8, 135.0, 139.0, 148.6 ppm. MS (ESI): m/z = 233.2 [M
+ H]+.
6-Ethylindolo[1,2-c]quinazoline (3b): Eluent: petroleum ether/ethyl
acetate (50:1); yield 98.9 mg (80%) with 2-(2-bromophenyl)-1H-in-
dole as the substrate and 110 mg (89%) with 2-(2-iodophenyl)-1H-
indole as the substrate, yellow solid, m.p. 90–91 °C. 1H NMR
(CDCl3, 300 MHz): δ = 1.56–1.61 (t, J = 7.56 Hz, 3 H), 3.39–3.46
(q, J = 7.53 Hz, 2 H), 7.20 (s, 1 H), 7.34–7.54 (m, 4 H), 7.73–7.76
(d, J = 8.1 Hz, 1 H), 7.80–7.83 (d, J = 6.87 Hz, 1 H), 8.02–8.06 (d,
J = 7.89 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 10.8,
30.3, 95.5, 115.2, 120.4, 120.8, 122.1, 122.7, 123.3, 126.8, 127.3,
129.0, 130.6, 131.3, 135.3, 139.0, 152.4 ppm. HRMS: calcd. for
C17H14N2 [M + H]+ 247.1235; found 247.1225.
6-(3-Nitrophenyl)indolo[1,2-c]quinazoline (3h): Eluent: petroleum
ether/ethyl acetate (50:1); yield 140 mg (83%), yellow solid, m.p.
210–211 °C. 1H NMR (CDCl3, 300 MHz): δ = 6.48–6.51 (d, J =
8.61 Hz, 1 H), 6.99–7.05 (t, J = 7.89 Hz, 1 H), 7.32–7.37 (m, 2 H),
7.54–7.61 (m, 2 H), 7.80–7.85 (m, 3 H), 8.04–8.06 (d, J = 7.56 Hz,
1 H), 8.13–8.16 (m, 1 H), 8.52–8.55 (d, J = 8.25 Hz, 1 H), 8.63 (s,
1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 96.4, 114.2, 120.7,
121.1, 122.0, 122.9, 123.9, 124.0, 125.3, 128.0,128.1, 129.4, 130.4,
130.6, 131.2, 134.6, 135.2, 137.5, 138.9, 146.7, 148.8 ppm. HRMS:
calcd. for C21H13N2O2 [M + H]+ 340.1086; found 340.1074.
6,10-Dimethylindolo[1,2-c]quinazoline (3i): Eluent: petroleum ether/
6-Propylindolo[1,2-c]quinazoline (3c): Eluent: petroleum ether/ethyl
acetate (50:1); yield 118 mg (91%), yellow solid, m.p. 108–109 °C.
1H NMR (CDCl3, 300 MHz): δ = 1.17–1.22 (t, J = 7.2 Hz, 3 H),
2.01–2.08 (m, 2 H), 3.29–3.34 (t, J = 7.56 Hz, 2 H), 7.15 (s, 1 H),
7.34–7.49 (m, 4 H), 7.70–7.73 (d, J = 7.2 Hz, 1 H), 7.77–7.80 (d, J
= 7.2 Hz, 1 H), 7.93–8.01 (m, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 14.0, 19.7, 38.9, 95.5, 115.1, 120.4, 120.9, 122.1,
122.7, 123.3, 126.8, 127.3, 129.0, 130.6, 131.3, 135.3, 139.0,
151.4 ppm. HRMS: calcd. for C18H16N2 [M + H]+ 261.1392; found
261.1389.
ethyl acetate (50:1); yield 84 mg (68%), yellow solid, m.p. 161–
1
162 °C. H NMR (CDCl3, 300 MHz): δ = 2.46 (s, 3 H), 2.95 (s, 3
H), 6.95 (s, 1 H), 7.05–7.08 (d, J = 8.61 Hz, 1 H), 7.33–7.38 (t, J
= 7.56 Hz, 1 H), 7.42–7.47 (m, 2 H), 7.64–7.67 (d, J = 7.92 Hz, 1
H), 7.75–7.79 (m, 1 H), 7.88–7.91 (m, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 20.3, 24.1, 93.9, 113.2, 119.1, 119.2, 121.4,
122.5, 125.4, 125.7, 127.7, 128.9, 129.6, 131.8, 133.8, 137.9,
147.3 ppm. HRMS: calcd. for C17H14N2 [M + H]+ 247.1235; found
247.1227.
6-Ethyl-10-methylindolo[1,2-c]quinazoline (3j): Eluent: petroleum
ether/ethyl acetate (50:1); yield 98 mg (75%), yellow solid, m.p.
128–129 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.51–1.57 (t, J =
7.23 Hz, 3 H), 2.50 (s, 3 H), 3.30–3.37 (q, J = 7.2 Hz, 2 H), 7.06
(s, 1 H), 7.12–7.15 (d, J = 8.94 Hz, 1 H), 7.36–7.42 (t, J = 7.56 Hz,
1 H), 7.44–7.50 (t, J = 7.56 Hz, 1 H), 7.53 (s, 1 H), 7.70–7.73 (d, J
= 7.89 Hz, 1 H), 7.83–7.86 (d, J = 8.58 Hz, 1 H), 7.95–7.98 (d, J
= 7.56 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 10.7, 21.5,
30.1, 95.1, 114.8, 120.4, 122.6, 123.7, 126.7, 127.2, 128.8, 129.6,
130.9, 132.9, 135.4, 139.1, 152.4 ppm. HRMS: calcd. for C18H16N2
[M + H]+ 261.1392; found 261.1395.
6-Cyclopropylindolo[1,2-c]quinazoline (3d): Eluent: petroleum ether/
ethyl acetate (50:1); yield 120 mg (93%), yellow solid, m.p. 120–
121 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.26–1.32 (m, 2 H), 1.46–
1.51 (m, 2 H), 2.63–2.68 (m, 1 H), 7.19 (s, 1 H), 7.35–7.48 (m, 4
H), 7.68–7.72 (d, J = 7.89 Hz, 1 H), 7.80–7.83 (d, J = 7.56 Hz, 1
H), 7.99–8.02 (d, J = 7.56 Hz, 1 H), 8.43–8.46 (d, J = 8.25 Hz, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 8.0, 17.3, 95.4, 115.5,
120.4, 120.7, 121.9, 122.7, 123.4, 126.8, 127.3, 129.0, 130.6, 131.8,
135.3, 139.0, 151.5 ppm. HRMS: calcd. for C18H14N2 [M + H]+
259.1235; found 259.1230.
6-Phenylindolo[1,2-c]quinazoline (3e):[18] Eluent: petroleum ether/
ethyl acetate (50:1); yield 109 mg (74%), yellow solid, m.p. 205– 10-Methyl-6-propylindolo[1,2-c]quinazoline (3k): Eluent: petroleum
206 °C. 1H NMR (CDCl3, 300 MHz): δ = 6.43–6.46 (d, J = ether/ethyl acetate (50:1); yield 110 mg (80%), yellow solid, m.p.
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H. Zhang, Y. Jin, H. Liu, Y. Jiang, H. Fu
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136–137 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.16–1.21 (t, J =
7.56 Hz, 3 H), 1.99–2.06 (m, 2 H), 2.50 (s, 3 H), 3.25–3.30 (t, J =
7.56 Hz, 2 H), 7.06 (s, 1 H), 7.13–7.17 (d, J = 8.58 Hz, 1 H), 7.36–
10-Chloro-6-ethylindolo[1,2-c]quinazoline (3q): Eluent: petroleum
ether/ethyl acetate (50:1); yield 112 mg (80%), yellow solid, m.p.
1
137–138 °C. H NMR (CDCl3, 300 MHz): δ = 1.56 (t, J = 7.2 Hz,
7.42 (t, J = 7.56 Hz, 1 H), 7.45–7.50 (t, J = 7.56 Hz, 1 H), 7.54 (s, 3 H), 3.33 (q, J = 7.2 Hz, 2 H), 7.07 (s, 1 H), 7.26–7.30 (m, 1 H),
1 H), 7.69–7.72 (d, J = 7.89 Hz, 1 H), 7.77–7.80 (d, J = 8.94 Hz, 1 7.41–7.46 (t, J = 7.2 Hz, 1 H), 7.50–7.55 (t, J = 7.2 Hz, 1 H), 7.72–
H), 7.95–7.98 (d, J = 7.89 Hz, 1 H) ppm. 13C NMR (CDCl3, 7.76 (m, 2 H), 7.88–7.92 (d, J = 9.27 Hz, 1 H), 7.97–8.00 (d, J =
75 MHz): δ = 13.9, 19.5, 21.4, 38.6, 94.9, 114.5, 120.4, 122.5, 123.6,
126.5, 127.1, 128.7, 129.5, 130.8, 132.8, 135.3, 138.9, 151.3 ppm.
HRMS: calcd. for C19H18N2 [M + H]+ 275.1548; found 275.1545.
7.89 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 10.6, 30.1,
94.8, 116.1, 120.0, 122.2, 122.8, 127.0, 127.4, 129.1, 129.4, 129.5,
131.7, 136.6, 139.0, 151.8 ppm. HRMS: calcd. for C17H14ClN2 [M
+ H]+ 281.0846; found 281.0841.
6-Cyclopropyl-10-methylindolo[1,2-c]quinazoline (3l): Eluent: petro-
leum ether/ethyl acetate (50:1); yield 115 mg (84%), yellow solid,
m.p. 137–138 °C. H NMR (CDCl3, 300 MHz): δ = 1.21–1.27 (m,
3-Chloro-6-ethylindolo[1,2-c]quinazoline (3r): Eluent: petroleum
ether/ethyl acetate (50:1); yield 85 mg (61%), yellow solid, m.p.
141–142 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.54–1.59 (t, J =
7.56 Hz, 3 H), 3.35–3.43 (q, J = 7.53 Hz, 2 H), 7.16 (s, 1 H), 7.35–
7.45 (m, 3 H), 7.72–7.73 (d, J = 2.1 Hz, 1 H), 7.79–7.82 (d, J =
7.2 Hz, 1 H), 7.90–7.93 (d, J = 8.2 Hz, 1 H), 8.01–8.04 (d, J =
8.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 10.6, 30.2,
95.9, 115.3, 118.9, 120.9, 122.4, 123.5, 123.8, 127.0, 127.1, 130.5,
131.3, 134.3, 134.5, 140.0, 153.5 ppm. HRMS: calcd. for
C17H13ClN2 [M + H]+ 281.0846; found 281.0841.
1
2 H), 1.41–1.47 (m, 2 H), 2.51 (s, 3 H), 2.55–2.64 (m, 1 H), 7.06 (s,
1 H), 7.12–7.15 (d, J = 8.58 Hz, 1 H), 7.34–7.39 (t, J = 7.56 Hz, 1
H),42–7.47 (t, J = 7.56 Hz, 1 H), 7.55 (s, 1 H), 7.65–7.68 (d, J =
8.25 Hz, 1 H), 7.94–7.98 (d, J = 7.53 Hz, 1 H), 8.25–8.28 (d, J =
8.58 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 7.9, 17.2,
21.6, 94.9, 115.0, 120.4, 120.5, 122.7, 123.5, 126.6, 127.3, 128.8,
130.1, 130.9, 133.0, 135.4, 139.2, 151.4 ppm. HRMS: calcd. for
C19H16N2 [M + H]+ 273.1392; found 273.1384.
10-Methyl-6-phenylindolo[1,2-c]quinazoline (3m): Eluent: petroleum
3-Chloro-6-propylindolo[1,2-c]quinazoline (3s): Eluent: petroleum
ether/ethyl acetate (50:1); yield 120 mg (81%), yellow solid, m.p.
129–130 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.15–1.20 (t, J =
7.2 Hz, 3 H), 1.97–2.04 (m, 2 H), 3.20–3.25 (t, J = 7.53 Hz, 2 H),
7.05 (s, 1 H), 7.28–7.41 (m, 3 H), 7.66–7.67 (d, J = 2.1 Hz, 1 H),
7.73–7.76 (d, J = 7.23 Hz, 1 H), 7.79–7.82 (d, J = 8.58 Hz, 1 H),
7.88–7.91 (d, J = 7.89 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 12.8, 18.3, 37.6, 94.7, 114.0, 117.7, 119.7, 121.3, 122.3, 122.5,
125.7, 129.3, 130.1, 133.1, 133.1, 133.3, 138.8, 151.2 ppm. HRMS:
calcd. for C18H15ClN2 [M + H]+ 295.1002; found 295.0992.
ether/ethyl acetate (50:1); yield 141 mg (91%), yellow solid, m.p.
1
197–198 °C. H NMR (CDCl3, 300 MHz): δ = 2.43 (s, 3 H), 6.30–
6.33 (d, J = 8.58 Hz, 1 H), 6.78–6.81 (d, J = 8.58 Hz, 1 H), 7.18
(s, 1 H), 7.48–7.53 (m, 3 H), 7.59–7.65 (m, 5 H), 7.81–7.84 (d, J =
7.23 Hz, 1 H), 8.07–8.10 (d, J = 7.56 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 21.4, 95.3, 114.5, 120.1, 120.6, 122.7, 123.1,
127.2, 127.8, 128.2, 128.9, 129.3, 130.0, 130.3, 130.7, 133.1, 135.3,
136.0, 139.3, 149.3 ppm. HRMS: calcd. for C22H16N2 [M + H]+
309.1392; found 309.1383.
10-Methyl-6-p-tolylindolo[1,2-c]quinazoline (3n): Eluent: petroleum
3-Chloro-6-cyclopropylindolo[1,2-c]quinazoline (3t): Eluent: petro-
ether/ethyl acetate (50:1); yield 140 mg (87%), yellow solid, m.p.
leum ether/ethyl acetate (50:1); yield 130 mg (89%), yellow solid,
1
171–172 °C. H NMR (CDCl3, 300 MHz): δ = 2.44 (s, 3 H), 2.51
1
m.p. 106–107 °C. H NMR (CDCl3, 300 MHz): δ = 1.25 (m, 2 H),
(s, 3 H), 6.41–6.44 (d, J = 8.94 Hz, 1 H), 6.80–6.83 (d, J = 8.58 Hz,
1 H), 7.17 (s, 1 H), 7.38–7.41 (d, J = 7.89 Hz, 2 H), 7.44–7.56 (m,
5 H), 7.80–7.82 (d, J = 8.25 Hz, 1 H), 8.06–8.09 (d, J = 7.56 Hz, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.5, 21.7, 95.3, 114.8,
120.1, 120.7, 122.8, 123.2, 127.3, 127.9, 128.2, 129.0, 130.0, 130.1,
130.8, 133.1, 133.3, 135.5, 139.5, 140.5, 149.6 ppm. HRMS: calcd.
for C23H18N2 [M + H]+ 323.1548; found 323.1544.
1.43–1.46 (m, 2 H), 2.57–2.61 (m, 1 H), 7.08 (s, 1 H), 7.27–7.41 (m,
3 H), 7.62–7.63 (d, J = 2.07 Hz, 1 H), 7.75–7.78 (d, J = 7.23 Hz, 1
H), 7.81–7.84 (d, J = 8.53 Hz, 1 H), 8.35–8.38 (d, J = 8.61 Hz, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 8.1, 17.1, 95.7, 115.4,
118.9, 120.8, 122.2, 123.6, 123.7, 126.9, 130.5, 131.7, 134.2, 134.5,
140.1, 152.5 ppm. HRMS: calcd. for C18H13ClN2 [M + H]+
293.0846; found 293.0839.
6-(4-Fluorophenyl)-10-methylindolo[1,2-c]quinazoline (3o): Eluent:
3-Chloro-6-phenylindolo[1,2-c]quinazoline (3u): Eluent: petroleum
ether/ethyl acetate (50:1); yield 117 mg (71%), yellow solid, m.p.
187–188 °C. 1H NMR (CDCl3, 300 MHz): δ = 6.44–6.47 (d, J =
8.58 Hz, 1 H), 6.96–7.01 (t, J = 8.58 Hz, 1 H), 7.23 (s, 1 H), 7.27–
7.32 (t, J = 7.89 Hz, 1 H), 7.42–7.45 (d, J = 8.58 Hz, 1 H), 7.58–
7.68 (m, 5 H), 7.74–7.76 (d, J = 8.19 Hz, 1 H), 7.80–7.81 (d, J =
1.38 Hz, 1 H), 7.97–8.00 (d, J = 8.58 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 96.2, 114.9, 119.1, 120.6, 121.8, 123.7, 123.8,
127.5, 127.7, 128.1, 129.3, 130.3, 130.6, 131.6, 134.4, 134.5, 135.6,
140.2, 150.3 ppm. HRMS: calcd. for C21H13ClN2 [M + H]+
329.0846; found 329.0839.
petroleum ether/ethyl acetate (50:1); yield 108 mg (66%), yellow so-
lid, m.p. 230–231 °C. H NMR (CDCl3, 300 MHz): δ = 2.44 (s, 3
1
H), 6.36–6.39 (d, J = 8.58 Hz, 1 H), 6.82–6.85 (d, J = 8.91 Hz, 1
H), 7.17 (s, 1 H), 7.24–7.32 (m, 2 H), 7.46–7.53 (m, 3 H), 7.63–7.68
(m, 2 H), 7.78–7.81 (d, J = 7.56 Hz, 1 H), 8.05–8.08 (d, J = 7.2 Hz,
1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.5, 95.6, 114.4, 116.5
(d, J = 22.2 Hz), 120.4, 120.7, 122.8, 123.3, 127.5, 127.9, 129.1,
129.9, 130.6 (d, J = 8.6 Hz), 130.8, 132.3 (d, J = 3.6 Hz), 133.3,
135.4, 139.3, 148.4, 164.0 (d, J = 248.8 Hz) ppm. HRMS: calcd.
for C22H15FN2 [M + H]+ 327.1298; found 327.1292.
10-Methyl-6-(3-nitrophenyl)indolo[1,2-c]quinazoline (3p): Eluent:
petroleum ether/ethyl acetate (50:1); yield 103 mg (58%), yellow so-
lid, m.p. 247–248 °C. H NMR (CDCl3, 300 MHz): δ = 2.45 (s, 3 ether/ethyl acetate (50:1); yield 133 mg (78%), yellow solid, m.p.
H), 6.33–6.36 (d, J = 8.94 Hz, 1 H), 6.81–6.84 (d, J = 8.58 Hz, 1 176–177 °C. H NMR (CDCl3, 300 MHz): δ = 2.53 (s, 3 H), 6.56–
3-Chloro-6-p-tolylindolo[1,2-c]quinazoline (3v): Eluent: petroleum
1
1
H), 7.21 (s, 1 H), 7.50–7.56 (m, 3 H), 7.77–7.82 (m, 2 H), 8.00–8.03
6.59 (d, J = 8.58 Hz, 1 H), 6.98–7.04 (t, J = 8.58 Hz, 1 H), 7.24 (d,
(d, J = 7.53 Hz, 1 H), 8.07–8.10 (m, 1 H), 8.50–8.52 (d, J = 8.22 Hz, J = 0.69 Hz, 1 H), 7.28–7.34 (t, J = 8.22 Hz, 1 H), 7.40–7.46 (m, 3
1 H), 8.60 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 20.4,
H), 7.54 (d, J = 2.07 Hz, 1 H), 7.56 (d, J = 1.74 Hz, 1 H), 7.75–
7.78 (d, J = 7.89 Hz, 1 H), 7.80–7.81 (d, J = 2.04 Hz, 1 H), 8.00–
94.9, 112.7, 119.5, 119.6, 121.7, 122.5, 122.9, 124.1, 126.9, 128.1,
128.4, 129.3, 129.8, 132.5, 133.4, 134.2, 136.4, 137.8, 145.5, 8.02 (d, J = 8.61 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
147.6 ppm. HRMS: calcd. for C22H15N3O2 [M + H]+ 354.1243;
found 354.1234.
21.7, 96.2, 115.2, 119.1, 120.6, 121.8, 123.7, 123.9, 127.5, 127.6,
128.1, 130.0, 130.4, 131.8, 132.9, 134.4, 134.6, 140.4, 140.9,
6802
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6798–6803

Cascade Synthesis of 1H-Indolo[1,2-c]quinazoline Derivatives
150.7 ppm. HRMS: calcd. for C22H15ClN2 [M + H]+ 343.1002;
found 343.0989.
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3-Methoxy-6-propylindolo[1,2-c]quinazoline (3w): Eluent: petroleum
[10]
[11]
[12]
ether/ethyl acetate (50:1); yield 107 mg (74%), yellow solid, m.p.
1
158–159 °C. H NMR (CDCl3, 300 MHz): δ = 1.22 (t, J = 7.2 Hz,
3 H), 2.07 (m, 2 H), 3.37 (t, J = 7.89 Hz, 2 H), 3.92 (s, 3 H), 7.04–
7.08 (m, 2 H), 7.20–7.21 (d, J = 2.4 Hz, 1 H), 7.31–7.43 (m, 2 H),
7.77–7.80 (d, J = 7.71 Hz, 1 H), 7.93–7.97 (m, 2 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 14.0, 19.7, 38.9, 55.6, 93.8, 108.9, 113.8,
115.0, 116.3, 120.5, 121.5, 123.3, 123.9, 130.9, 131.0, 135.6, 140.5,
152.0, 160.5 ppm. HRMS: calcd. for C19H18N2O [M + H]+
291.1497; found 291.1485.
[13]
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of compounds 3a–w.
Acknowledgments
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The authors wish to thank the National Natural Science Founda-
tion of China (NSFC) (grant numbers 20972083 and 21172128),
and the Ministry of Science and Technology of China (grant
number 2012CB722605) for financial support.
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Received: July 18, 2012
Published Online: October 23, 2012
Eur. J. Org. Chem. 2012, 6798–6803
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6803