An efficient synthesis of indol-3-yl benzonaphthyridines via copper(II) triflate-catalyzed heteroannulation

Article abstract of DOI:10.1016/j.tetlet.2013.04.106

An efficient and convenient method for the synthesis of indol-3-yl benzo[b][1,6]- and benzo[c][2,7]naphthyridines via copper(II) triflate-catalyzed heteroannulation is reported. This method gives new analogues of indole containing benzonaphthyridines from

Full text of DOI:10.1016/j.tetlet.2013.04.106

Tetrahedron Letters 54 (2013) 3635–3638
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An efficient synthesis of indol-3-yl benzonaphthyridines via
copper(II) triflate-catalyzed heteroannulation
⇑
K. S. Prakash, Rajagopal Nagarajan
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient method for the synthesis of indol-3-yl benzo[b][1,6]- and benzo[c][2,7]naph-
thyridines via copper(II) triflate-catalyzed heteroannulation is reported. This method gives new ana-
logues of indole containing benzonaphthyridines from easily accessible starting materials. This
reaction proceeds under mild conditions.
Received 27 January 2013
Revised 24 April 2013
Accepted 28 April 2013
Available online 3 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Benzonaphthyridines
Heterocycles
Heteroannulation
Indoles
Copper(II) triflate
Marine sponges are the source of many biologically active nitro-
gen heterocyclic constituents, which possess a series of 1H-ben-
zo[de][1,6]-naphthyridines.1 Aaptamine (1) was first isolated in
1982 by Nakamura et al.2 Naphthyridines and their benzo/hetero
fused analogues gained considerable attention due to their wide
spectrum of biological activities3 such as anticancer,3a,b anti-HIV-
1 integrase inhibitors,3c antiproliferative activity,3d antimicrobial,3e
and adrenoceptor blocking activities.3f These are reported as allo-
steric inhibitors of Akt1 and Akt2,3g and antagonists of 5-HT4
receptors.3h Furthermore, isoaaptamine (2), was isolated from
sponge in the genus Suberites by Fedoreev et al.4 Later, it was iso-
lated from Aaptos aaptos5a,b and it has been found to have a PKC
inhibitor5c and to inhibit growth of cancer cells.5b,c Pettit et al.
showed that isoaaptamine (2) has significant activity against mur-
ine P388 lymphocytic leukemia cells (ED50 0.28
lg/mL) and a panel
of six human cancer cell lines.6
H
O
N
HN
MeO
MeO
N
MeO
MeO
N
H
N
N
N
OCH(CH3)2
N
N
O
O
Aaptamine (1)
Naphthyridine (2)
Dibenzo[c,h][1,5]naphthyridinedione (3)
(marine natural product)
(HCMV inhibitor)
(Topoisomerase I inhibitor)
Ph
Ph
N
N
N
N
N
NH
NH2
N
O
O
Lophocladine A (4)
Ascididemine (6)
Lophocladine B (5)
Figure 1. Representative structures of related bioactive molecules.
⇑
Corresponding author. Tel.: +91 40 23134831; fax: +91 40 23012460.
E-mail address: rnsc@uohyd.ernet.in (R. Nagarajan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.106

3636
K. S. Prakash, R. Nagarajan / Tetrahedron Letters 54 (2013) 3635–3638
Table 1
Table 3
Optimization of reaction conditionsa
Synthesis of benzo[c][2,7]naphthyridines and substrate scopea
R2
R1
R2
HN
Ph
Ph
N
NH2
NH2
N
N
H
R3
CHO
CHO
3a
N
(2a, 2d and 2e)
N
Cu(OTf)2,
N
N
N
N
1a
2a
CH3CN, rt, 4h
R3
Ph
R1
(3a-3d)
4a
5a
(6a-6e)
Entry
Catalyst
Solvent
Yieldb (%)
Time (h)
Entry
R1
R2
R3
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
Cul
CuBr
THF
THF
THF
THF
35
40
55
52
50
62
58
56
30
35
—
6
8
6
7
8
6
6
6
6
6
6
1
2
3
4
5
H
H
H
H
OMe
H
H
H
H
H
6a
6b
6c
6d
6e
92
90
94
90
92
Cu(OTf)2
Ag(OTf)
AgNO3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
Me
Cl
H
THF
CH3CN
CH3Cl
Dioxane
Toluene
DMF
H
n-Butyl
a
Unless otherwise noted, all reactions were carried out in 5 mL of CH3CN under
optimized conditions. 0.5 mmol of quinoline alkynylaldehyde, 0.5 mmol of anilines,
and 0.7 mmol of indoles were stirred at room temperature. 5 mol % of Cu(OTf)2 was
used.
10
11
CH3CN
b
Isolated yields after column chromatography.
a
Reaction conditions: 0.5 mmol of 1a, 0.5 mmol of 2a, 0.7 mmol of indole (3a)
catalyst 5 mol %, and 1 mmol of Na2SO4 as additive at room temperature.
b
Isolated yields.
Table 2
Synthesis of benzo[b][1,6]naphthyridines and substrate scopea
R3
R4
N
R3
R2
N
NH2
R4
R5
CHO
(2a-2e)
N
Cu(OTf)2,
CH3CN, rt, 6h
N
N
R1
R2
(3a-3d)
R1
(1a-1e)
(4a-4j)
Entry
R1
R2
R3
R4
R5
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Tolyl
n-Hexyl
TMS
Ph
H
Me
Cl
OMe
Br
H
H
H
H
H
H
H
H
H
H
H
OH
OMe
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
4a
4b
4c
4d
4e
4f
4g
4h
4i
62
60
64
68
70
72
74
73
68
58
—
Figure 2. ORTEP diagram of 4f. Hydrogen atoms are omitted for clarity.
10
11c
12
H
H
H
4j
—
4k
H
H
Representative molecules of related naphthyridine are shown in
Figure 1.
72
a
Unless otherwise noted, all reactions were carried out in 5 mL of CH3CN under
We envisioned that benzonaphthyridines can be synthesized by
6-endo mode iminoannulation of quinoline alkynyl aldehydes.
Electrophilic activation of alkynes followed by annulation toward
intramolecular addition reactions of heteronucleophiles has be-
come a useful tool for the synthesis of new heterocyclic com-
pounds.11 Recently, there has been immense synthetic interest in
the 6-endo-mode cyclization of 2-(1-alkynyl)arylaldimine using
various transition metals and Lewis acid catalysis for the synthesis
of isoquinolines and 1,2-dihydroisoquinolines motif.12 A wide vari-
ety of functionalized terminal acetylenes participate in this metal-
catalyzed and Lewis acid catalyzed cyclization process to afford the
desired nitrogen heterocycles.13
Recently, our group reported the synthesis of benzo[b]-, indo-
lo[2,3-b]-, carbazolo[2,3-b]carbazole derivatives,14a ellipticinium,
ellipticine derivatives,14b and benzimidazoellipticine derivatives14c
by 6-endo-mode type cyclization of carbazole alkynyl aldehydes. In
continuation of our research interest in heteroannulation,14 herein
we report a convenient synthesis of indol-3-yl benzo[b][1,6]- and
benzo[c][2,7]naphthyridines via copper(II)-triflate catalyzed het-
eroannulation (Tables 2 and 3).
optimized reaction conditions. 0.5 mmol of quinoline alkynylaldehydes, 0.5 mmol
of anilines, and 0.7 mmol of indoles were stirred at room temperature. 5 mol % of
Cu(OTf)2 was used
b
Isolated yields after column chromatography.
Complex mixture found in TLC.
c
Most recently, 5-(3-chlorophenylamino)-benzo[c][2,6]naph-
thyridine-8-carboxylic acid (CX-4945), found to be the first clinical
stage inhibitor of protein kinase CK2 for the treatment of cancer7
and dibenzo[c,h][1,5]naphthyridinediones were reported as topoi-
somerase I (Top1) inhibitors.8 Lophocladine A (4) and Lophocladine
B (5) are 2,7-naphthyridine alkaloids, in which, 4 exhibited affinity
for NMDA receptors and it was found to be a d-opioid receptor
antagonist. Lophocladine B (5) showed cytotoxicity to NCI-H460
human lung tumor and MDA-MB-435 breast cancer cell lines.9
Very recently, bis-aaptamine alkaloids (suberitine A–D) were
isolated from the marine sponge Aaptos suberitoides and showed
that they have potent cytotoxicity against P388 cell lines.10 These
remarkable biological applications of naphthyridine molecules
prompted us to synthesize benzonaphthyridine derivatives.

K. S. Prakash, R. Nagarajan / Tetrahedron Letters 54 (2013) 3635–3638
3637
R4
N
R2NH2
N
H2O
R2
R1
R2
R1
CHO
R2
R1
R4
N
N
N
R1
Cu(OTf)2
Indol-3-ylbenzonaphthyridines
(TfO)2Cu
6-endo cyclization
Scheme 1. Possible mechanism for formation of benzonaphthyridines.
At the outset, we optimized the reaction condition using various
catalysts and solvents. The results are summarized in Table 1. Ini-
tially, we started with CuI in THF solvent at room temperature (Ta-
ble 1, entry 1) and the expected product was obtained in 35% yield.
Hence, we screened other catalysts and solvents as shown in Ta-
ble 1. CuBr gave a low yield of 40% in THF (Table 1, entry 2). Other
catalysts, such as Cu(OTf)2, AgOTf, and AgNO3 gave moderate yield
of 55%, 52%, and 50% in THF (Table 1, entries 3–5). Without catalyst
no reaction was observed (Table 1, entry 11). For all the above opti-
mization, we used 5 mol % catalyst loading. Increasing the amount
of catalyst also did not improve the yield of the product. So 5 mol %
Cu(OTf)2 was used for further solvent optimization. We screened
other solvents such as, toluene, dioxane, chloroform, and DMF (Ta-
ble 1, entries 7–10). Here, the best result was obtained in acetoni-
trile as solvent (Table 1, entry 6). Under optimized conditions,
within 6 h complete conversion of starting material was observed
in TLC.
copper(II) triflate-catalyzed heteroannulation. On the other hand,
all of the synthesized compounds have yet another vital nucleus,
indole, which is known to be part of many biologically important
molecules. This approach is general and an efficient method for
the construction of diverse indol-3-yl benzonaphthyridine skele-
tons under mild reaction conditions17. Moreover, generality and
biological significance of naphthyridine motif make it highly
valuable.
Acknowledgments
We thank DST (Project number: SR/S1/OC-70/2008) for finan-
cial assistance and for the single-crystal X-ray diffractometer facil-
ity in our school. K.S.P. thanks UGC, India for a Senior Research
Fellowship.
Supplementary data
Having optimized reaction conditions in hand, we focused our
attention on the exploration of the substrate scope. With other
substrates, such as various anilines and indoles, the corresponding
products were isolated successfully (Table 2, entries 2–8). Simi-
larly, other quinoline alkynylaldehyde substrates could be handled
without any trouble and also gave the corresponding
benzo[b][1,6]naphthyridines in good yields (Table 2, entry 9, 10,
and 12).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
106.
References and notes
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Considering the biological importance of 2,7-naphthyridine
core (Fig. 1), we planned to synthesize 3,4-dihydro-4-(1H-in-
dol-3-yl)-2,3-diphenylbenzo[c][2,7]naphthyridine (6a), by per-
forming the reaction with 4-(2-phenylethynyl)quinoline-3-
carbaldehyde (5a), aniline, and indole derivatives under the
same optimized condition. The requisite precursor 5a was pre-
pared from the Sonogashira coupling of 4-chloroquinoline-3-
carbaldehyde and phenylacetylene.16a,b In this case, the expected
product is formed in excellent yield (92%) with lesser reaction
time (Table 3, entry 1). Then, we examined the scope of this
reaction by changing the substrates such as various substituted
anilines and indoles. These substrates were well tolerated and
excellent yield was obtained. The results are summarized in
Table 3.
Mechanism for the formation of benzonaphthyridines is shown
in Scheme 1. As depicted in Scheme 1, initial step is the formation
of an imine. Subsequent activation of alkyne by Cu(OTf)2 and then
6-endo-dig type annulation lead to the formation of a six-mem-
bered ring. Then, nucleophilic addition of indole delivers the prod-
uct benzonaphthyridines.
7. Siddiqui-Jain, A.; Drygin, D.; Streiner, N.; Chua, P.; Pierre, F.; O’Brien, S. E.;
Bliesath, J.; Omori, M.; Huser, N.; Ho, C.; Proffitt, C.; Schwaebe, M. K.; Ryckman,
D. M.; Rice, W. G.; Anderes, K. Cancer Res. 2010, 70, 10288.
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77, 5167.
In summary, we have developed an efficient methodology for
the
synthesis
of
new
indol-3-yl
benzo[b][1,6]-
and
benzo[c][2,7]naphthyridines in moderate to excellent yields via

3638
K. S. Prakash, R. Nagarajan / Tetrahedron Letters 54 (2013) 3635–3638
9. Gross, H.; Goeger, D. E.; Hills, P.; Mooberry, S. L.; Ballantine, D. L.; Murray, T. F.;
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T.; Singh, A. P. J. Org. Chem. 2010, 75, 7691; (b) Amaresh, R. R.; Perumal, P. T.
Indian J. Chem. Sect. B 1997, 36, 541. Reported procedure was followed for the
Sonogashira coupling reaction for preparing quinoline alkynylaldehydes (1a–e
and 5a).
12. For selected examples: see, (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63,
5306; (b) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042; (c)
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17. General procedure for the synthesis of benzonaphthyridines: An oven-dried 10 mL
round-bottomed flask equipped with a teflon coated magnetic stirring bar is
charged with 0.5 mmol of 2-(2-phenylethynyl)quinoline-3-carbaldehyde,
0.5 mmol of amine and 1 mmol of Na2SO4, 5 mL of acetonitrile. Then,
0.7 mmol of indole and copper(II) triflate (5 mol %) added to the reaction
mixture. The reaction mixture is allowed to stir until complete conversion was
observed by TLC. The reaction mass is poured into crushed ice slowly and
extracted with ethyl acetate. The organic layer is washed with water, dried
over anhydrous sodium sulfate and the solvent is removed under vacuum. The
crude product is purified using column chromatography (eluent: 30% ethyl
acetate in hexanes). The product is eluted in 30% eluent as a light yellow solid.
We followed the same procedure for synthesis of other benzo[b][1,6]- and
benzo[c][2,7]naphthyridines (4a–4k and 6a–6e).
1,2-Dihydro-1-(1H-indol-3-yl)-2,3-diphenylbenzo[b][1,6]naphthyridine
Yield: 62%; mp 156–158 °C. IR (KBr): 3052, 1600, 1577, 1434, 1403, 1386,
1263, 1094, 749 cmÀ1 1H NMR (400 MHz, TMS, CDCl3): 8.24 (br s, 1H), 8.15 (d,
(4a):
.
J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.71–7.69 (m, 1H), 7.64–
7.58 (m, 3H), 7.41–7.36 (m, 2H), 7.26–7.21 (m, 5H), 7.19–7.11 (m, 5H), 6.95–
6.93 (m, 2H), 6.63 (s, 1H). 13C NMR (100 MHz, TMS, CDCl3): 151.9, 148.9, 147.9,
147.0, 137.3, 136.4, 131.9, 129.3, 128.8, 128.7, 128.5, 128.3, 128.2, 127.6, 127.5,
127.4, 125.1, 125.0, 122.9, 122.8, 122.3, 120.1, 118.9, 117.9, 112.0, 111.7, 102.6
(aromatic C), 62.1 (aliphatic C). HRMS (ESI-MS) calcd for C32H23N3; 450.1970
(M+H), found: 450.1970.
15. CCDC-908173 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif; Molecular formula:
C
33H25N3, a = 15.190(4), b = 10.3275(17), c = 16.424(4), b = 108.46(3), space
group P21/n.