Copper-Catalyzed Synthesis of Trinuclear N-Fused Hybrid Scaffolds by Double C(sp2)–N Bond Formation between 2-(2-Bromoaryl)indoles and 2-Aminoazoles

Article abstract of DOI:10.1002/ejoc.202000238

2-(2-Bromoaryl)indoles react with 2-aminoazoles by microwave irradiation in DMF in the presence of a catalytic amount of CuI and a base to produce trinuclear N-fused hybrid scaffolds, benzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazolines and imidazo[1,2-a]indolo[1,2-c]quinazolines in moderate to good yields. The reaction seems to proceed via copper-catalyzed C(sp²)-N coupling and subsequent intramolecular cyclocondensation accompanied by ammonia evolution. Complete regioselective C–N cyclization is observed with the reaction of 2-(2-bromophenyl)indole with 2-aminoazoles.

Full text of DOI:10.1002/ejoc.202000238

A Journal of
Accepted Article
Title: Copper-Catalyzed Synthesis of Trinuclear N-Fused Hybrid
Scaffolds by Double C(sp2)-N Bond Formation between 2-(2-
Bromoaryl)indoles and 2-Aminoazoles
Authors: Thi Duyen Diep, Pham Duy Quang Dao, Son Long Ho, and
Chan Sik Cho
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000238
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10.1002/ejoc.202000238
European Journal of Organic Chemistry
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Copper-Catalyzed Synthesis of Trinuclear N-Fused Hybrid
Scaffolds by Double C(sp2)-N Bond Formation between 2-(2-
Bromoaryl)indoles and 2-Aminoazoles
Thi Duyen Diep,[a] Pham Duy Quang Dao, [a] Son Long Ho, [a] and Chan Sik Cho*[a]
[a]
Thi Duyen Diep, Dr. Pham Duy Quang Dao, Dr. Son Long Ho, Prof. Chan Sik Cho*
Department of Applied Chemistry,
Kyungpook National University,
80 Daehakro, Bukgu, Daegu 41566, Republic of Korea.
E-mail: cscho@knu.ac.kr
Supporting information for this article is given via a link at the end of the document.
Abstract: 2-(2-Bromoaryl)indoles react with 2-aminoazoles by
microwave irradiation in DMF in the presence of a catalytic amount
of CuI and a base to produce trinuclear N-fused hybrid scaffolds,
benzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazolines and imidazo[1,2-
a]indolo[1,2-c]quinazolines in moderate to good yields. The reaction
seems to proceed via copper-catalyzed C(sp2)-N coupling and
subsequent intramolecular cyclocondensation accompanied by
ammonia evolution. Complete regioselective C-N cyclization is
observed with the reaction of 2-(2-bromophenyl)indole with 2-
aminoazoles.
scaffold B by CuI-catalyzed double C(sp2)-N coupling between 2-
(2-bromoaryl)indoles and 2-aminobenzimidazole with broad
substrate scope under microwave irradiation (Scheme 1, route d).
The present reaction can also be extended to the reaction of 2-(2-
bromoaryl)indoles with 2-aminoimidazole to produce trinuclear N-
fused hybrid scaffold C (Scheme 1, route d). To the best of our
knowledge, there are no reports on synthetic method and
biological activity of scaffold C except for one report. It is known
that Hu and coworkers obtained scaffold C as side minor product
in copper-catalyzed coupling and cyclization of 2-(2-
bromophenyl)indole with imidazole (Scheme 1, route c).[6]
Introduction
Many challenges on the synthesis of polynuclear N-fused hybrid
scaffolds have been attempted due to their intrinsic biological
activities and optical properties that are not exhibited in each
homonuclear scaffolds.[1] During the course of our continuous
efforts directed toward developing new synthetic methods for
polynuclear N-fused hybrid scaffolds under transition metal-
catalyzed and transition metal-free conditions,[2] we reported on
the synthesis of trinuclear N-fused hybrid scaffold A by base-
promoted
double
C(sp2)-N
coupling
between
2-(2-
bromoaryl)benzimidazoles and 2-aminobenzimidazole under
transition metal-free condition (Scheme 1, route a).[3,4] The
present work started during the course of application of such a
protocol to the reaction with indole analogues to form trinuclear
N-fused hybrid scaffolds, benzo[4,5]imidazo[1,2-c]indolo[1,2-
a]quinazolines B (Scheme 1, route d). In contrast to widely known
synthetic methods and biological activities of each homonuclear
scaffold (indole, quinazoline, and benzimidazole) of scaffold B
and binuclear scaffolds by the combination of such a homonuclear
scaffold, only one report is found for the synthetic method of their
trinuclear N-fused hybrid scaffold B.[5] Lv and coworkers reported
that bis(o-iodophenyl) carbodiimide reacted with indoles in the
presence of CuI and 1,10-phenanthroline to produce scaffold B
via sequential processes such as nucleophilic addition,
tautomerization, Ullmann-type C-N coupling, and intramolecular
C(sp2)-H arylation (Scheme 1, route b).[5] Herein this report shows
another example for the synthesis of trinuclear N-fused hybrid
Scheme 1. Synthetic routes for trinuclear N-fused hybrid scaffolds.
Results and Discussion
In contrast to the case for the reaction of 2-(2-
bromophenyl)benzoimidazole with 2-aminobenzimidazole 2a
shown in route a of Scheme 1,[3] performing the reaction of 2-(2-
1
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Table 1. Optimization of conditions for the reaction of 1a and 2a[a]
Entry
1
[2a]/ [1a]
Catalyst
CuI
Base
Temp (oC)
110
130
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
Time (h)
Conv of 1a (%)
Yield of 3a (%)
Yield of 4 (%)
1
1
1
1
1.2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
KOtBu
NaOtBu
NaOAc
CsF
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
20
100
100
100
100
100
100
100
100
100
92
47
56
70
74
72
72
65
47
41
62
53
57
73
69
69
66
57
36
21
73
26
21
18
18
10
14
12
30
28
27
18
9
2
CuI
3
CuI
4
CuI
5
CuI
6
CuI
7
CuI
8
CuI
9
CuI
10
11
12b)
13c)
14
15
16
17
18d)
19e)
20f)
CuI
CuI
76
CuI
Cs2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
Cs2CO3
K3PO4
100
100
100
89
CuI
6
Cu2O
CuBr
Cu powder
CuCl
CuI
10
15
15
13
0
83
81
51
CuI
42
0
CuI
91
13
[a] Reaction condition: 1a (0.3 mmol), catalyst (0.03 mmol), base (0.6 mmol), DMF (3 mL), under microwave irradiation (100 W of initial power). [b] In the
presence of L-proline (0.06 mmol). [c] In the presence of 1,10-phenanthroline (0.06 mmol). [d] In HMPA in place of DMF. [e] In xylene in place of DMF. [f]
Usual heating (screw-capped vial).
bromophenyl)indole 1a with 2a under similar catalyst-free
conditions scarcely afforded trinuclear N-fused hybrid scaffold 3a
and both substrates were recovered intact. The results of several
attempted cyclizations between 1a and 2a in the presence of a
copper catalyst for the optimization of conditions are listed in
Table 1. Treatment of equimolar amounts of 1a and 2a in DMF in
the presence of a catalytic amount of CuI (10 mol% based on 1a)
Performing the reaction using other bases such as Cs2CO3,
K2CO3, KOtBu, NaOtBu, NaOAc, and CsF under the employed
conditions resulted in lower yields of 3a with incomplete
conversion of 1a in some cases except for Cs2CO3, which showed
an activity similar to that of K3PO4 (Table 1, entries 6-11). Further
addition of ligands such as L-proline and 1,10-phenanthroline
resulted in no significant change of 3a yield (Table 1, entries 12
and 13). The reaction also proceeded with other copper catalysts
such as Cu2O, CuBr, and copper powder with similar catalytic
activities to that of CuI (Table 1, entries 14-16). However, lower
yield of 3a and incomplete conversion of 1a were observed with
CuCl (Table 1, entry 17). Among solvents examined under the
employed conditions, DMF was shown to be the solvent of choice
(Table 1, entries 18 and 19). Usual heating conditions for 20 h
also can be used alternatively for the effective formation of 3a
(Table 1, entry 20).
o
and K3PO4 (2 equiv. to 1a) at 110 C for 1 h under microwave
irradiation afforded 3a in 47% isolated yield along with
concomitant formation of 2-phenyl-1H-indole (4) (26% yield) by a
debromination of 1a (Table 1, entry 1). It is known that aryl halides
are readily hydrodebydrogenated in the presence of a copper
catalyst.[7] The yield of 3a increased with elevating temperature
o
up to 150 C (Table 1, entries 1-3). No significant change of the
yield of 3a was observed with prolonging the reaction time and
higher molar ratio of [2a]/[1a] (Table 1, entries 4 and 5).
2
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On the other hand, similar treatment of 1a with benzimidazole 5
in place of 2a under the employed conditions afforded C-N/C-C
coupling product 6 (34% yield) in preference to C-N/C-N coupling
product 3a (11% yield) (eq 1). As shown in route c of Scheme 1,
it is known that such a similar competition reaction also occurs in
one-pot two-step treatment of 2-(2-bromophenyl)indole with
imidazole under a copper catalytic system.[6] This result indicates
that the present reaction is superior to the reaction of 1a with
benzimidazole in terms of the completely selective formation of
trinuclear N-fused hybrid scaffold 3a.
between 1a and 2a (Scheme 2).[11] In contrast to transition metal-
free formation of trinuclear N-fused hybrid scaffolds from 2-(2-
bromoaryl)benzimidazoles and 2a, the present reaction needs a
Table 2. Scope of reaction[a]
Table
coupling/cyclization
bromoaryl)indoles 1[8] and 2-aminobenzimidazoles 2[9] under the
optimized conditions (Table 1, entries and 6). 2-(2-
2
shows the representative results for the
reactions between various 2-(2-
3
Bromophenyl)indole 1a was readily cyclized with 2-
aminobenzimidazoles 2b-2e having electron-donating and
withdrawing substituents and benzo-fused 2-aminobenzimidazole
2f to give the corresponding trinuclear N-fused hybrid scaffolds
3b-3f in 51-72% yields. In the cases of 2b-2d, the products were
produced as isomeric mixtures (1:1.7 for 3b and 3b’; 1:0.9 for 3c
and 3c’; 1:1 for 3d and 3d’).[10] The isomeric ratios were
1
calculated by the intensity of the clearly separated protons in H
1
NMR spectra (see Supporting Information for H and 13C NMR
spectra).
The
reaction
of
readily
available
2-(2-
bromophenyl)indoles 1b-1e having straight and branched alkyl
chains at indole moiety (R1) with 2a also produced the
corresponding trinuclear N-fused hybrid scaffolds 3g-3j
irrespective of the identity of such alkyl substituents. From the
reaction of 2-(2-bromoaryl)indoles 1f-1h having methyl, methoxy,
and fluoro substituents on bromoaryl moiety (R2) with 2a, the
corresponding trinuclear N-fused hybrid scaffolds 3k-3m were
also formed in 45-74% yields. 2-(2-Bromophenyl)indoles (1i and
1j) containing methyl substituent on indole moiety (R3) also
reacted with 2a to give the cyclized products (3n and 3o) in similar
yields irrespective of the position of methyl substituent, whereas
the present reaction is not tolerant of chloro functional group on
indole moiety (R3). When 2-(2-bromophenyl)indoles 1k-1m were
treated with 2a under the optimized conditions, all afforded
dechlorinated trinuclear N-fused hybrid scaffold 3a in 50-55%
yields. As shown in Table 2, higher product yields were obtained
with Cs2CO3 in several cases. Similar treatment of 2-(2-
bromoaryl)indoles (1a, 1b, and 1f) with commercially available 2-
aminoimidazole sulfate 2g also afforded the corresponding
trinuclear N-fused hybrid scaffolds 3p-3r without the formation of
C-N/C-C coupling products in cases of 1a and 1f as shown in
route c of Scheme 1. The product yields were generally lower than
that obtained with 2-aminobenzimidazoles 2a-2f, and
debromination products along with several identifiable
compounds were formed with complete conversion of 2-(2-
bromoaryl)indoles.
[a] All reactions were carried out with 1 (0.3 mmol), 2 (0.3 mmol), CuI (0.03
mmol), Cs2CO3 (0.6 mmol), and DMF (3 mL) at 150 oC for 1 h under microwave
irradiation (100 W of initial power) unless otherwise stated. Yields using K3PO4
in place of Cs2CO3 are shown in parentheses.
copper catalyst to form such a C-N bond. It appears that this is
attributed to the stability difference of a resonance-stabilized
negatively charged intermediate called a Meisenheimer complex
formed by the nucleophilic attack of the ring nitrogen of 2a to the
carbon attached to Br in 1a (Scheme 3).[12] Because nitrogen is
The reaction pathway seems to proceed via an initial formation of
Ullmann-type product 7 by copper-catalyzed C-N coupling
3
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10.1002/ejoc.202000238
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more electronegative than carbon, the negative intermediate from
1a and 2a is less stable than the one from 2-(2-
bromophenyl)benzimidazole and 2a. We confirmed in a separate
experiment that similar treatment of 1b with benzimidazole 5
under the employed conditions afforded C-N coupled product 9 in
63% yield along with 3g (8% yield) (eq 2). Subsequent
intramolecular nucleophilic addition of indole N-H to C=N of
neighboring guanidine moiety to form an intermediate 8 is
followed by β-elimination to produce 3a along with NH3.[13] Like
the reaction between 2-(2-bromophenyl)benzimidazole and 2a,
the evolution of NH3 was confirmed by both the color change of
Nessler’s reagent[14] and the measurement with LSE-NH3 Monitor
(see supporting information).
Experimental Section
General information: 1H (500 MHz) and 13C NMR (125 MHz) spectra
were recorded on a Bruker Avance Digital 500 spectrometer using TMS as
an internal standard. Melting point were measured by a microscopic
melting point apparatus (Standford Research Inc. MPA100 automatic
melting point apparatus). IR spectra were recorded on Shimadzu FTIR-
8400S infrared spectrophotometer. High-resolution mass data were
obtained using electronic ionization or fast atom bombardment (HRMS-EI
or FAB, magnetic sector-electric sector double focusing mass analyzer) at
the Korea Basis Science Center (Deagu). The pure products were isolated
by TLC (a glass plate coated with Kieselgel 60 GF254, Merck). The starting
2-(2-bromoaryl)indoles[8] and 2-aminobenzimidazoles[9] were synthesized
by known methods. Other commercially available organic and inorganic
compounds were used without further purification.
General procedure for the synthesis of 3: To a 5 mL microwave reaction
tube was added 2-(2-bromoaryl)indole 1 (0.3 mmol), 2-aminoazole 2 (0.3
mmol), CuI (0.006 g, 0.03 mmol), Cs2CO3 (0.195 g, 0.6 mmol), and DMF
(3 mL). After stirring the reaction mixture at room temperature for 10 min,
o
it was heated at 150 C for 1-2 h under microwave irradiation (100 W of
initial power). The reaction mixture was filtered through a short silica gel
column (ethyl acetate) to eliminate inorganic precipitates. Removal of the
solvent left
a crude mixture, which was purified by thin layer
chromatography (dichloromethane/hexane = 1/1) to give 3. Except for
known compounds, 3a[5] and 3p,[6] all new products were characterized
spectroscopically as shown below.
Scheme 2. A plausible reaction pathway.
Benzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3a)[5]: Pale yellow
solid (66 mg, 72%); Rf = 0.34; M.p. 235-237 oC; 1H NMR (500 MHz, CDCl3):
δ = 7.16 (s, 1H), 7.34-7.37 (m , 2H), 7.38-7.43 (m, 2H), 7.48-7.54 (m, 2H),
7.75 (d, J = 7.9 Hz, 1H), 7.87-7.89 (m, 1H), 8.04-8.06 (m , 2H), 8.21 (d, J
= 8.4 Hz, 1H), 9.05 (dd, J = 8.3 and 0.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ = 98.6, 112.4, 115.1, 115.8, 117.2, 119.5, 120.4, 122.4, 123.4,
123.7, 123.8, 124.7, 125.0, 129.1, 129.5, 130.4, 131.2, 131.7, 133.4, 143.0,
143.4; HRMS (FAB) m/z: [M+H]+ calcd for C21H13N3 308.1188, found
308.1185.
Isomeric mixture of 2-methylbenzo[4,5]imidazo[1,2-a]indolo[1,2-
c]quinazoline
and
3-methylbenzo[4,5]imidazo[1,2-a]indolo[1,2-
c]quinazoline (3b and 3b’): Pale yellow solid (55 mg, 57%); Rf = 0.31; 1H
NMR (500 MHz, CDCl3): δ = 2.50 (s, 3H), 2.55 (s, 3H), 7.09-7.12 (m, two
isomers, 3H), 7.18 (dd, J = 8.1 and 0.6 Hz, 1H), 7.27-7.31 (m, two isomers,
2H), 7.36-7.40 (m, two isomers, 2H), 7.44-7.50 (m, two isomers, 4H), 7.62
(s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, two isomers, 2H), 7.77
(s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.99 (dd, J = 7.8 and 1.4 Hz, 1H), 8.00
(dd, J = 7.9 and 1.4 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.3 Hz,
1H), 9.00 (dd, J = 8.3 and 0.7 Hz, 1H), 9.01 (dd, J = 8.3 and 0.7 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ = 21.6, 22.3, 98.5, 112.0, 112.8, 115.0,
115.1, 116.0, 117.1, 117.2, 119.1, 119.7, 120.4, 123.4, 123.6, 123.8, 124.7,
124.8, 125.0, 128.5, 129.1, 129.6, 130.7, 131.4, 131.87, 131.93, 132.3,
133.5, 133.6, 143.2, 143.4, 143.5; IR (KBr): ṽ = 694, 741, 777, 928, 1049,
1148, 1258, 1412, 1450, 1557, 1629, 2851, 2918, 3051 cm-1; HRMS (EI)
m/z: (M+) calcd for C22H15N3 321.1266, found 321.1263.
Scheme 3. Stability difference of Meisenheimer complexes.
Conclusion
Isomeric mixture of 2-chlorobenzo[4,5]imidazo[1,2-a]indolo[1,2-
In summary, the coupling/cyclization reactions of 2-(2-
bromoaryl)indoles with 2-aminoazoles under microwave
irradiation in the presence of CuI and a base conveniently
afforded the corresponding trinuclear N-fused hybrid scaffolds.
Complete regioselective cyclization in the reaction of 2-(2-
bromophenyl)indole with aminoazoles especially renders this
process remarkable. Further studies on mechanistic aspects and
challenges on the construction of polynuclear N-fused hybrid
scaffolds by the present protocol using 2-aminoazoles under
transition metal-catalyzed or transition metal-free conditions are
in progress.
c]quinazoline
and
3-chlorobenzo[4,5]imidazo[1,2-a]indolo[1,2-
c]quinazoline (3c and 3c’): White solid (60 mg, 59%); Rf = 0.37; 1H NMR
(500 MHz, CDCl3): δ = 7.03 (s, 1H), 7.04 (s, 1H), 7.21 (dd, J = 8.7 and 2.1
Hz, 1H), 7.25-7.29 (m, two isomers, 2H), 7.31 (dd, J = 8.5 and 1.9 Hz, 1H),
7.35-7.38 (m, two isomers, 2H), 7.40-7.46 (m, two isomers, 4H), 7.66-7.69
(m, two isomers, 3H), 7.72 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H),
7.89 (d, J = 1.8 Hz, 1H), 7.91-7.93 (m, two isomers, 3H), 7.95 (d, J = 8.4
Hz, 1H), 8.86 (s, 1H), 8.88 (s, 1H); 13C NMR (125 MHz, CDCl3): δ = 98.9,
99.0, 112.7, 112.9, 114.8, 114.9, 115.7, 115.8, 117.16, 117.20, 119.3,
120.0, 120.46, 120.49, 122.4, 123.57, 123.60, 124.0, 124.1, 124.8, 125.2,
125.3, 127.7, 129.0, 129.1, 129.15, 129.21, 129.5, 130.8, 130.9, 131.0,
131.19, 131.25, 133.30, 133.33, 141.6, 143.8, 144.1, 144.2; IR (KBr): ṽ =
4
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European Journal of Organic Chemistry
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696, 741, 777, 928, 1047, 1146, 1261, 1449, 1557, 1632, 3051 cm-1;
δ = 0.89 (t, J = 7.0 Hz, 3H), 1.30-1.32 (m, 4H), 1.38-1.44 (m, 2H), 1.51-
1.57 (m, 2H), 1.78-1.84 (m ,2H), 3.21 (t, J = 8.0 Hz, 2H), 7.33-7.36 (m, 1H),
7.38-7.44 (m, 3H), 7.51-7.55 (m, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.86-7.88
(m, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.21 (dd, J = 8.1 and 1.2 Hz, 1H), 8.28
(dd, J = 8.3 and 0.8 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ = 14.1, 22.7, 25.3, 29.2, 29.3, 29.9, 31.8, 112.4, 115.1, 115.9,
116.0, 118.3, 118.7, 119.3, 122.1, 122.9, 123.6, 124.2, 124.9, 125.3, 125.4,
128.1, 130.4, 130.7, 132.0, 132.4, 143.3, 143.9; IR (KBr): ṽ = 729, 849,
1013, 1179, 1261, 1358, 1462, 1560, 1628, 2849, 2922, 3053 cm-1; HRMS
(EI) m/z: (M+) calcd for C28H27N3 405.2205, found 405.2203.
HRMS (EI) m/z: (M+) calcd for C21H12ClN3 341.0720, found 341.0720.
Isomeric
mixture
of
benzo[4,5]imidazo[1,2-a]indolo[1,2-
c]quinazoline-2-carbonitrile and benzo[4,5]imidazo[1,2-a]indolo[1,2-
c]quinazoline-3-carbonitrile (3d and 3d’): Pale yellow solid (51 mg,
51%); Rf = 0.41; 1H NMR (500 MHz, CDCl3): δ = 7.15 (s, two isomers, 2H),
7.38-7.43 (m, two isomers, 4H), 7.47-7.50 (m, two isomers, 2H), 7.51-7.57
(m, two isomers, 3H), 7.61 (dd, J = 8.3 and 1.4 Hz, 1H), 7.73-7.75 (m, two
isomers, 2H), 7.80 (d, J = 8.3 Hz, 1H), 8.00-8.05 (m, two isomers, 5H),
8.07 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.86-8.89 (m, two isomers, 2H); 13
C
NMR (125 MHz, CDCl3): δ = 99.7, 99.8, 105.0, 107.0, 113.0, 115.0, 115.1,
115.7, 115.8, 116.5, 117.5, 119.4, 119.86, 119.94, 120.7, 123.4, 124.0,
124.1, 124.3, 124.4, 124.9, 125.0, 125.9, 125.95, 125.99, 127.7, 129.3,
129.5, 129.57, 129.64, 130.67, 130.73, 130.9, 133.1, 133.3, 133.4, 143.0,
144.8, 146.4; IR (KBr): ṽ = 700, 735, 785, 935, 1053, 1140, 1267, 1346,
1472, 1555, 1634, 2220, 2851, 2918, 3051 cm-1; HRMS (FAB) m/z: [M+H]+
calcd for C22H12N4 333.1140, found 333.1138.
10-Isopropylbenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline
(3j):
White solid (65 mg, 62%); Rf = 0.31; M.p. 261-262 oC. 1H NMR (500 MHz,
CDCl3): δ = 1.68 (d, J = 7.1 Hz, 6H), 4.08 (sept, J = 7.1 Hz, 1H), 7.33-7.44
(m, 4H), 7.51-7.54 (m, 1H), 7.55-7.58 (m, 1H), 7.86-7.87 (m, 1H), 8.02 (d,
J = 8.1 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1 H), 8.28-8.31 (m, 2H), 9.18 (d, J =
8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 22.4, 26.9, 112.5, 115.2,
116.3, 118.8, 119.3, 121.0, 122.07, 122.12, 122.5, 123.7, 123.9, 124.8,
126.1, 128.3, 128.9, 130.3, 132.3, 133.4, 143.4, 144.0; IR (KBr): ṽ = 710,
743, 935, 1018, 1148, 1258, 1362, 1452, 1558, 1630, 2850, 2961, 3053
cm-1; HRMS (EI) m/z: (M+) calcd for C24H19N3 349.1579, found 349.1581.
2,3-Dimethylbenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3e):
Pale yellow solid (74 mg, 74%); Rf = 0.37; M.p. 248-249 oC; 1H NMR (500
MHz, CDCl3): δ = 2.37 (s, 3H), 2.41 (s, 3H), 7.14 (s, 1H), 7.29-7.32 (m,
1H), 7.37-7.40 (m, 1H), 7.47-7.50 (m, 2H), 7.57 (s, 1H), 7.72 (s, 1H), 7.75
(d, J = 7.9 Hz, 1H), 8.03 (dd, J = 7.9 and 1.4 Hz, 1H), 8.13 (d, J = 8.3 Hz,
1H), 9.01 (d, J = 8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 20.2, 20.8,
98.1, 113.0, 114.9, 115.8, 117.0, 119.8, 120.3, 123.2, 123.6, 124.59,
124.61, 128.7, 129.0, 129.4, 131.1, 131.3, 131.9, 132.3, 133.3, 141.3,
142.9; IR (KBr): ṽ = 704, 739, 795, 858, 1001, 1140, 1279, 1352, 1472,
1599, 1636, 2918, 3049 cm-1; HRMS (EI) m/z: (M+) calcd for C23H17N3
335.1422, found 335.1419.
7-Methylbenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3k): White
solid (71 mg, 74%); Rf = 0.31; M.p. 214-215 oC; 1H NMR (500 MHz, CDCl3):
δ = 2.41 (s, 3H), 6.96 (s, 1H), 7.00 (d, J = 7.8 Hz, 1H), 7.30-7.32 (m, 1H),
7.36-7.39 (m, 2H), 7.45-7.48 (m, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.75 (d, J =
8.0 Hz, 1H), 7.83 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H),
8.99 (d, J = 8.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3): δ = 22.1, 97.7, 112.6,
114.5, 115.3, 115.9, 119.5, 120.3, 122.3, 123.4, 123.5, 123.7, 124.5, 126.0,
129.7, 130.5, 131.5, 131.7, 133.3, 139.7, 143.1, 143.6; IR (KBr): ṽ = 729,
791, 914, 1059, 1161, 1252, 1319, 1412, 1450, 1587, 1632, 2922, 3051,
3115 cm-1; HRMS (EI) m/z: (M+) calcd for C22H15N3 321.1266, found
321.1263.
Indolo[1,2-c]naptho[2’,3’:4,5]imidazo[1,2-a]quinazoline (3f): Pale
yellow solid (65 mg, 61%); Rf = 0.34; M.p. 264-266 oC; 1H NMR (500 MHz,
CDCl3): δ = 7.12 (s, 1H), 7.31-7.34 (m, 1H), 7.38-7.41 (m, 1H), 7.42-7.47
(m, 2H), 7.48-7.51 (m, 1H), 7.54-7.57 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H),
7.94-7.97 (m, 2H), 8.00 (d, J = 7.8 Hz, 1H), 8.19 (s, 1H), 8.27 (d, J = 8.4
Hz, 1H), 8.31 (s, 1H), 9.04 (d, J = 8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3):
δ = 99.3, 109.2, 114.9, 115.8, 116.1, 116.9, 120.5, 123.7, 124.0, 124.4,
124.6, 124.70, 124.74, 127.8, 128.0, 129.3, 129.8, 130.2, 130.9, 131.3,
131.4, 131.8, 133.7, 142.8, 145.8; IR (KBr): ṽ = 704, 743, 795, 844, 1024,
1148, 1256, 1410, 1472, 1599, 1645, 3047, 3113 cm-1; HRMS (EI) m/z:
(M+) calcd for C25H15N3 357.1266, found 357.1263.
8-Methoxybenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline
(3l):
White solid (61 mg, 60%); Rf = 0.28; M.p. 243-244 oC; 1H NMR (500 MHz,
CDCl3): δ = 3.87 (s, 3H), 7.02 (dd, J = 9.1 and 2.8 Hz, 1H), 7.09 (s, 1H),
7.34 (t, J = 7.3 Hz, 1H), 7.38-7.43 (m, 3H), 7.49-7.52 (m, 1H), 7.74 (d, J =
7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 8.08 (d, J =
9.1 Hz, 1H), 9.05 (d, J = 8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 55.8,
98.78, 98.79, 108.18, 108.19, 112.2, 115.97, 116.00, 116.37, 116.41,
119.6, 120.5, 122.3, 123.5, 123.6, 124.0, 129.5, 130.4, 131.3, 133.6, 143.0,
156.7; IR (KBr): ṽ = 581, 600, 729, 786, 872, 1033, 1170, 1249, 1348, 1449,
1560, 1622, 2831, 2935, 3008; HRMS (EI) m/z: (M+) calcd for C22H15N3O
337.1215, found 337.1214.
10-Methylbenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline
(3g):
White solid (63 mg, 65%); Rf = 0.31; M.p. 192-194 oC; 1H NMR (500 MHz,
CDCl3): δ = 2.57 (s, 3H), 7.19-7.22 (m, 1H), 7.26-7.29 (m, 1H), 7.32-7.38
(m, 3H), 7.44-7.47 (m, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 7.9 Hz,
1H), 7.90 (d, J = 8.2 Hz, 1H), 8.02-8.04 (m, 2H), 8.98 (d, J = 8.2 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ = 11.1, 109.9, 112.4, 114.6, 115.7, 118.1,
118.6, 119.2, 122.0, 122.7, 123.5, 124.0, 124.5, 125.2, 125.6, 127.7, 130.3,
130.7, 131.6, 132.1, 143.2, 143.5; IR (KBr): ṽ = 685, 739, 1084, 1258, 1342,
1460, 1557, 1628, 1680, 2857, 2920, 3053 cm-1; HRMS (EI) m/z: (M+)
calcd for C22H15N3 321.1266, found 321.1263.
8-Fluorobenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3m): Pale
yellow solid (44 mg, 45%); Rf = 0.28; M.p. 271-272 oC; 1H NMR (500 MHz,
CDCl3): δ = 7.07 (s, 1H), 7.16-7.20 (m, 1H), 7.31-7.34 (m, 1H), 7.37-7.40
(m, 2H), 7.47-7.51 (m, 1H), 7.63-7.65 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H),
7.84 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 8.09-8.11 (m, 1H), 8.98
(d, J = 8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 99.7, 110.9 (d, J =
24.5 Hz), 112.1, 116.0, 116.3 (d, J = 23.4 Hz), 116.8 (d, J = 8.4 Hz), 119.0
(d, J = 9.1 Hz), 119.8, 120.7, 122.6, 123.7, 123.9, 124.4, 128.2, 129.4,
130.3, 133.6, 143.0 (d, J = 15.4 Hz), 159.5 (d, J = 243.9 Hz); IR (KBr): ṽ =
690, 727, 793, 858, 1043, 1165, 1260, 1418, 1454, 1566, 1630, 2847,
2914, 3064 cm-1; HRMS (EI) m/z: (M+) calcd for C21H12FN3 325.1015,
found 325.1015.
10-Butylbenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3h): White
solid (67 mg, 61%); Rf = 0.34; M.p. 161-163 oC; 1H NMR (500 MHz, CDCl3):
δ = 1.00 (t, J = 7.4 Hz, 3H), 1.50-1.57 (m, 2H), 1.72-1.78 (m, 2H), 3.13 (t,
J = 7.9 Hz, 2H), 7.27-7.45 (m, 5H), 7.48-7.51 (m, 1H), 7.71 (d, J = 7.8 Hz,
1H), 7.82 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 8.09-8.11 (m, 1H),
8.15 (d, J = 8.2 Hz, 1H), 9.05 (d, J = 8.2 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ = 14.0, 23.0, 24.9, 31.4, 112.4, 114.9, 115.7, 115.8, 118.2, 118.5,
119.2, 122.0, 122.8, 123.5, 124.1, 124.7, 125.1, 125.2, 127.9, 130.3, 130.6,
131.8, 132.2, 143.2, 143.7; IR (KBr): ṽ = 731, 853, 1013, 1207, 1261, 1381,
1460, 1560, 1628, 2864, 2951, 3045 cm-1; HRMS (EI) m/z: (M+) calcd for
C25H21N3 363.1735, found 363.1738.
12-Methylbenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3n): Pale
yellow solid (50 mg, 52%); Rf = 0.31; M.p. 248-250 oC; 1H NMR (500 MHz,
CDCl3): δ = 2.55 (s, 3H), 7.14 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.36-7.44
(m, 3H), 7.55-7.58 (m ,2H), 7.90 (d, J = 7.9 Hz, 1H), 8.09-811 (m, 2H), 8.28
(d, J = 8.3 Hz, 1H), 8.91 (d, J = 8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3):
δ = 21.9, 98.4, 112.6, 115.2, 115.5, 117.5, 119.6, 120.3, 122.5, 123.9,
124.9, 125.1, 125.6, 129.1, 130.0, 130.7, 131.4, 131.88, 131.91, 133.2,
143.2, 143.7; IR (KBr): ṽ = 692, 723, 748, 802, 910, 1055, 1144, 1260,
10-Heptylbenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline (3i): White
solid (67 mg, 55%); Rf = 0.31; M.p. 271-274 oC; 1H NMR (500 MHz, CDCl3):
5
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10.1002/ejoc.202000238
European Journal of Organic Chemistry
FULL PAPER
1418, 1464, 1562, 1628, 2853, 2916, 3055 cm-1; HRMS (EI) m/z: (M+)
calcd for C22H15N3 321.1266, found 321.1264.
(NRF)
funded
by
the
Ministry
of
Education
(2017R1D1A1B03028226).
14-Methylbenzo[4,5]imidazo[1,2-a]indolo[1,2-c]quinazoline
(3o):
Keywords: cyclization • nitrogen heterocycles • C-N bond
formation • 2-aminoazoles • copper catalyst
White solid (51 mg, 53%); Rf = 0.32; M.p. 205-207 oC; 1H NMR (500 MHz,
CDCl3): δ = 3.19 (s, 3H), 7.17 (s, 1H), 7.25-7.27 (m, 1H), 7.28 (d, J = 7.5
Hz, 1H), 7.31-7.38 (m, 3H), 7.50-7.56 (m, 2H), 7.78-7.80 (m, 1H), 7.99 (dd,
J = 7.8 and 1,3 Hz, 1H), 8.01-8.03 (m, 1H), 8.20 (d, J = 8.0 Hz, 1H); 13
C
[1]
For recent reviews, see: a) A. R. Katritzky, C. A. Ramsden, J. A. Joule,
V. V. Zhdankin, Handbook of Heterocyclic Chemistry, Elsevier, 2010. b)
J. Alvarez-Builla, J. J. Vaquero in Modern Heterocyclic Chemistry (Eds.:
J. Alvarez-Builla, J. J. Vaquero, J. Barluenga); Wiley-VCH, Weinheim,
2011, Vol. 4, Chapter 22, pp. 1989-2070. c) X.-X. Guo, D.-W. Gu, Z. Wu,
W. Zhang, Chem. Rev. 2015, 115, 1622. d) S. K. Manna, T. Das, S.
Samanta, ChemistrySelect 2019, 4, 8781.
NMR (125 MHz, CDCl3): δ = 24.4, 101.0, 112.1, 115.4, 118.3, 118.6, 119.6,
122.5, 123.7, 124.2, 125.0, 125.1, 126.8, 128.0, 129.1, 131.4, 131.5, 132.0,
133.4, 134.4, 142.4, 144.2; IR (KBr): ṽ = 671, 729, 797, 914, 1020, 1184,
1275, 1404, 1553, 1626, 2923, 3046 cm-1; HRMS (EI) m/z: (M+) calcd for
C22H15N3 321.1266, found 321.1264.
Imidazo[1,2-a]indolo[1,2-c]quinazoline (3p)[6]: Yellow solid (36 mg,
47%); Rf = 0.30; mp 212-213 oC. 1H NMR (500 MHz, CDCl3): δ = 7.19 (d,
J = 0.7 Hz, 1H), 7.31 (d, J = 1.7 Hz, 1H), 7.36-7.41 (m, 2H), 7.44-7.50 (m,
2H), 7.57-7.59 (m, 2H), 7.77-7.79 (m, 1H), 8.08 (dd, J = 7.9 and 1.1 Hz,
1H), 8.82 (dd, J = 8.3 and 0.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ =
97.6, 109.5, 115.0, 115.1, 117.5, 120.5, 122.9, 123.6, 124.8, 125.8, 128.4,
128.96, 129.01, 129.8, 130.9, 132.6, 139.5; HRMS (FAB) m/z: [M+H]+
calcd for C17H11N3 258.1031, found 258.1028.
[2]
For our recent reports on the synthesis of polynuclear N-fused hybrid
scaffolds, see: a) P. D. Q. Dao, H. K. Lee, H.-S. Sohn, N. S. Yoon, C. S.
Cho, ACS Omega 2017, 2, 2953-2958. b) S. L. Ho, P. D. Q. Dao, C. S.
Cho, Synlett 2017, 28, 1811-1815. c) B. W. Yang, P. D. Q. Dao, N. S.
Yoon, C. S. Cho, J. Organomet. Chem. 2017, 851, 136-142. d) P. D. Q.
Dao, S. L. Ho, C. S. Cho, ACS Omega 2018, 3, 5643-5653. e) H. K. Lee,
P. D. Q. Dao, Y. Kim, C. S. Cho, Synthesis 2018, 50, 3243-3249. f) T. D.
Diep, P. D. Q. Dao, C. S. Cho, Eur. J. Org. Chem. 2019, 4071-4079. g)
D. Y. Kim, P. D. Q. Dao, N. S. Yoon, C. S. Cho, Asian J. Org. Chem.
2019, 8, 1726-1731.
9-Methylimidazo[1,2-a]indolo[1,2-c]quinazoline (3q): Yellow solid (35
[3]
[4]
P. D. Q. Dao, H.-J. Lim, C. S. Cho, Green Chem. 2019, 21, 6590-6593.
For our recent reports for transition metal-free cyclizations via homolytic
aromatic substitution (HAS) type pathway, see: a) P. D. Q. Dao, S. L. Ho,
H.-J. Lim, C. S. Cho, J. Org. Chem. 2018, 83, 4140-4146. b) P. D. Q.
Dao, H.-J. Lim, C. S. Cho, ACS Omega 2018, 3, 12114-12121.
G. Yuan, H. Liu, J. Gao, K. Yang, Q. Niu, H. Mao, X. Wang, X. Lv, J. Org.
Chem. 2014, 79, 1749-1757.
o
mg, 43%); Rf = 0.32; M.p. 219-221 C; 1H NMR (500 MHz, CDCl3): δ =
2.75 (s, 3H), 7.28 (d, J = 1.7 Hz, 1H), 7.37-7.41 (m, 2H), 7.43-7.48 (m, 2H),
7.52 (d, J = 1.7 Hz, 1H), 7.56 (dd, J = 8.0 and 1.2 Hz, 1H) 7.74-7.76 (m,
1H), 8.23 (dd, J = 7.9 and 1.2 Hz, 1H), 8.81-8.83 (m, 1H); 13C NMR (125
MHz, CDCl3): δ = 11.3, 109.1, 109.2, 114.9, 118.4, 119.2, 122.3, 123.8,
125.49, 125.53, 125.7, 127.9, 128.5, 130.0, 130.1, 131.4, 139.7; IR (KBr):
ṽ = 692, 745, 812, 864, 957, 1020, 1084, 1128, 1256, 1325, 1377, 1468,
1641, 2729, 2804, 3075 cm-1; HRMS (EI) m/z: (M+) calcd for C18H13N3
271.1109, found. 271.1107.
[5]
[6]
[7]
M. Wang, Y. Jin, H. Yang, H. Fu, L. Hu, RSC Adv. 2013, 3, 8211-8214.
a) F. Alonso, Y. Moglie, G. Radivoy, C. Vitale, M. Yus, Appl. Catal. A:
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Liang, G. Yang, W. Wang, F. Xu, Y. Niu, Q. Sun, P. Xu, Adv. Synth. Catal.
2013, 355, 1284-1290.
6-Methylimidazo[1,2-a]indolo[1,2-c]quinazoline (3r): Pale yellow solid
(39 mg, 48%); Rf = 0.32; M.p. 221-223 oC; 1H NMR (500 MHz, CDCl3): δ
= 2.49 (s, 3H), 7.12 (s, 1H), 7.19 (dd, J = 8.1 and 0.8 Hz, 1H), 7.30 (d, J =
1.7 Hz, 1H), 7.35-7.38 (m, 2H), 7.43-7.46 (m, 1H), 7.56 (d, J = 1.7 Hz, 1H),
7.75-7.77 (m, 1H), 7.95 (d, J = 8.1 Hz, 1H), 8.81 (dd, J = 8.3 and 0.8 Hz,
1H); 13C NMR (125 MHz, CDCl3): δ = 21.8, 96.6, 109.3, 114.7, 114.8, 115.2,
120.2, 122.7, 123.1, 124.5, 126.8, 128.2, 128.9, 129.7, 131.1, 132.4, 139.4,
139.5; IR (KBr): ṽ = 693, 746, 813, 865, 958, 1021, 1046, 1129, 1257, 1326,
1380, 1469, 1605, 1645, 2732, 2799, 3074 cm-1; HRMS (EI) m/z: (M+)
calcd for C18H13N3 271.1109, found. 271.1110.
[8]
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a) Y. Liu, W. W. Jr. McWhorter, J. Am. Chem. Soc. 2003, 125, 4240. b)
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Eur. J. Med. Chem. 2006, 41, 1080-1083.
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17465. b) C. Rao, S. Mai, Q. Song, Org. Lett. 2017, 19, 4726.
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Structure, Wiley, New York, 1992, pp. 641-676. b) F. Terrier, Modern
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536-540.
Experimental procedure for mechanism study: To a 5 mL microwave
reaction tube was added 2-(2-bromophenyl)-3-methyl-1H-indole (1b)
(0.086 g, 0.3 mmol), benzimidazole 5 (0.035 g, 0.3 mmol), CuI (0.006 g,
0.03 mmol), Cs2CO3 (0.195 g, 0.6 mmol), and DMF (3 mL). The work-up
procedure was similar to that described above.
1-(2-(3-Methyl-1H-indol-2-yl)phenyl)-1H-benzo[d]imidazole (9): Pale
yellow solid (61 mg, 63%); Rf = 0.14; M.p. 186-187 oC; 1H NMR (500 MHz,
CDCl3): δ = 1.64 (s, 3H), 6.89-6.93 (m, 1H), 7.02-7.05 (m, 1H), 7.11-7.17
(m, 2H), 7.24-7.26 (m, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.61-7.63 (m, 1H),
7.67-7.69 (m, 3H), 7.71-7.73 (m, 1H ), 8.01(s, 1H), 11.02 (s, 1H); 13C NMR
(125 MHz, CDCl3): δ = 8.6, 108.4, 110.2, 111.0, 118.4, 119.5, 121.4, 122.0,
123.0, 127.1, 128.1, 128.5, 129.5, 129.7, 130.7, 132.7, 133.6, 134.4, 136.0,
142.9, 143.7; IR (KBr): ṽ = 741, 899, 1009, 1225, 1310, 1458, 1499, 1560,
1686, 2856, 2922, 3055 cm-1; HRMS (EI) m/z: (M+) calcd for C22H17N3
323.1422, found. 323.1425.
[14] W. M. Haynes, CRC Handbook of Chemistry and Physics, 97th Ed., CRC
Press, Boca Raton, FL, 2017, Section 8, p 91.
Acknowledgements
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
6
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10.1002/ejoc.202000238
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Cyclization
A promising synthetic method of indole-quinazoline-benzimidazole and indole-quinazoline-imidazole trinuclear N-fused hybrid
scaffolds has been developed by copper-catalyzed C(sp2)-N coupling and cyclization of 2-(2-bromoaryl)indoles with 2-aminoazoles
as new building blocks. Further challenges on the construction of polynuclear N-fused hybrid scaffolds using 2-aminoazoles are
expected.
7
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