Synthesis of benzo[c][2,7]naphthyridine-6-ones via cascade aromatization/C(sp2)–H amidation of 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tetlet.2017.06.009

A K₂S₂O₈-mediated cascade dehydrogenative aromatization/intramolecular C(sp²)–H amidation of 1,4-dihydropyridines is described. This method provides an efficient access to multisubstituted benzo[c][2,7]naphthyri

Full text of DOI:10.1016/j.tetlet.2017.06.009

Tetrahedron Letters xxx (2017) xxx–xxx
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Synthesis of benzo[c][2,7]naphthyridine-6-ones via cascade
aromatization/C(sp2)–H amidation of 1,4-dihydropyridines
a
a
a
a
Laichun Luo a,b, , Qiang Wang , Xiaozhi Peng , Chunling Hu , Hong Wang
⇑
a College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, China
b Key Laboratory of Resources and Chemistry of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, China
a r t i c l e i n f o
a b s t r a c t
A K2S2O8-mediated cascade dehydrogenative aromatization/intramolecular C(sp2)–H amidation of 1,4-
dihydropyridines is described. This method provides an efficient access to multisubstituted benzo[c]
[2,7]naphthyridine-6-ones in 38–74% yields.
Article history:
Received 8 May 2017
Revised 31 May 2017
Accepted 3 June 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Dihydropyridine
Benzo[c][2,7]naphthyridine-6-one
C(sp2)–H amidation
Aromatization
Cascade reaction
Introduction
2-quinolinone via K2S2O8-mediated C(sp2)–H amidation of Knoeve-
nagel products.11 On the other hand, oxidative aromatization pro-
Phenanthridinone and its aza-analogues are important tricyclic
scaffolds in many natural alkaloids and synthetic products
(Fig. 1).1–3 Among them, benzo[c][2,7]naphthyridine-6-one exhibit
potent inhibitory activities against ROCK, AAK1, and ALK kinases.2
Besides, they are key synthetic blocks for amphimedine alkaloid
and some anti-malarial agents.3 Several synthetic methods
towards benzo[c][2,7] naphthyridine-6-ones have been developed
over the past decades. For instance, they were usually constructed
through intramolecular nucleophilic substitution of 4-phenyl pyr-
idine derivatives in step-wise or one-pot procedures (Sche-
me 1a).2–4 They were also achieved via palladium-catalyzed
arylation or AIBN/Bu3SnH-mediated radical cyclization of nicoti-
namide derivatives (Scheme 1b),5 Pictet-Spengler cyclization of
2-quinolinones with aromatic aldehydes (Scheme 1c),6 and
vides an efficient method for the preparation of arenes and
heterocycles.12–14 In particular, the aromatization of Hantzsch
1,4-dihydropyridines to pyridines were extensively studied.13,14
Inspired by these reports, and in continuation of our interest in
the synthesis of fused pyridine derivatives,11,15 herein we
described an efficient cascade aromatization/C(sp2)–H amidation
of 1,4-dihydropyridines to construct benzo[c][2,7]naphthyridine-
6-ones (Scheme 1e).
Results and discussion
Initially, 1,4-dihydropyridine 1a was used as the model sub-
strate to explore and optimize the reaction conditions. When 1a
was treated with 3 equiv of K2S2O8 in CH3CN/H2O (1:1, v/v) under
reflux (80 °C, oil bath temperature) for 2 h, the desired product 2a
was isolated in 57% yield (Table 1, entry 1). Comparable yields
were obtained when Na2S2O8 or (NH4)2S2O8 was used (Table 1,
entries 2 and 3). However, replacing K2S2O8 with other oxidants
including CuCl2, Ag2O, ceric ammonium nitrate (CAN), tert-butyl
hydroperoxide (TBHP), and H2O2, failed to give the desired product
(Table 1, entries 4–8). Persulfate was a strong oxidant with a high
redox potential of 2.01 V,14f which might make it an effective
oxidant for this cascade reaction. Then, several solvents were
screened. The CH3CN/H2O mixture was found to be superior to
other solvent systems, such as acetone/H2O, THF/H2O, and
CpRuCl-catalyzed cycloaddition of
a,x-diyne with ethyl cyanofor-
mate (Scheme 1d).7
Radical CAH functionalization has been broadly employed as a
powerful tool in heterocycle synthesis.8–11 For example, 3,4-benzo-
coumarins and phenanthridones were efficiently prepared from 2-
arylbenzoic acids9 and amides10 through intramolecular radical
cyclization. And recently, we developed a practical synthesis of
⇑
Corresponding author at: College of Pharmacy, Hubei University of Chinese
Medicine, Wuhan, Hubei 430065, China.
E-mail address: laichunluo@163.com (L. Luo).
http://dx.doi.org/10.1016/j.tetlet.2017.06.009
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Luo L., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.06.009

2
L. Luo et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Table 1
Optimization of reaction conditions.a
Entry
Oxidant
K2S2O8
Na2S2O8
(NH4)2S2O8
CuCl2
Ag2O
CAN
TBHP
H2O2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
Acetone/H2O (1:1)
THF/H2O (1:1)
DMSO/H2O (1:1)
CH3CN/H2O (1:2)
CH3CN/H2O (2:1)
CH3CN/H2O (4:1)
CH3CN/H2O (8:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
2
2
2
2
2
2
2
2
2
2
2
2
1.5
1.5
4
4
1.5
1.5
57
56
53
0
0
0
0
0
23
0
49
52
65
63
24
0
Fig. 1. Representative examples of phenanthridinones and benzo[c][2,7]naph-
thyridine-6-ones.
9
10
11
12
13
14
15
16c
17d
18e
DMSO/H2O (Table 1, entries 9–11). Furthermore, the ratio of
CH3CN to H2O was examined (Table 1, 12–15), and the results
indicated that CH3CN/H2O (2:1, v/v) was the best choice (65%
yield, Table 1, entry 13). When the reaction temperature was
decreased to 50 °C, no desired product was observed (Table 1,
entry 16). Besides, the use of AgNO3 or CuCl as a catalyst did not
improve the yield (Table 1, entries 17 and 18).
62
55
a
With the optimized conditions in hand (Table 1, entry 13), the
scope of the reaction was investigated, and the results were shown
in Table 2. First, dihydropyridines 1b–k with a substituted phenyl
group at the C-4 position were examined. Substituents at the para-
position (Me, OMe, F, Cl, Br, CF3) and meta-position (Me, OMe, Cl) of
the phenyl ring were tolerated, delivering products 2b–k in 38–
74% yields. Among them, a p-Me substituent (1b) was beneficial
to the reaction, while a strong electron-donating (p-OMe) or elec-
tron-withdrawing (p-CF3) group led to a much lower yield. The
CAH amidation exhibited high regioselectivity for substrates 1h–
k, which occurred at the less hindered site. Probably due to the
Reaction conditions: 1a (1 mmol), oxidant (3 mmol), solvent (30 mL), 80 °C (oil
bath).
b
Isolated yields.
Reaction occurred at 50 °C (oil bath).
CuCl (10% mol) was added.
c
d
e
AgNO3 (10% mol) was added.
steric hindrance effect, substrates with an ortho-substituent of
the phenyl ring failed to yield the desired products (not shown).
Then, dihydropyridines 1l–r bearing a substituted aniline moiety
were employed. Substrates with a Me (1l, 1o) or Cl (1m, 1q) group
Scheme 1. Synthetic approaches towards benzo[c][2,7]naphthyridine-6-ones.
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L. Luo et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 2
Synthesis of benzo[c][2,7]naphthyridine-6-ones 2 from 1,4-dihydropyridines 1.a,b
a
Reaction conditions: 1 (1 mmol), K2S2O8 (3 mmol), CH3CN/H2O (2:1, 30 mL), reflux (80 °C, oil bath).
Isolated yields.
b
underwent the reaction smoothly, affording corresponding prod-
ucts in 67–73% yields. In contrast, the presence of an m-OCH3
(1n) or m-NO2 (1p) group reduced the reactivity, which resulted
in a longer reaction time and lower yield. Notably, the reaction
of ortho-dimethyl substituted substrate 1r proceeded well to give
product 2r in 65% yield. Moreover, symmetric substrate 1s contain-
ing two amide groups was also amenable to this protocol, affording
2s as the main product. When polyhydroquinoline 1t was used as a
substrate, tetracyclic product 2t was obtained in 46% yield.
Scheme 2. Preparation of 2a in a two-step manner.
Scheme 3. Plausible reaction mechanism.
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L. Luo et al. / Tetrahedron Letters xxx (2017) xxx–xxx
In order to investigate the mechanism of this reaction, 2 equiv
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.06.
009.
Please cite this article in press as: Luo L., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.06.009