A facile one-pot regioselective synthesis of functionalized novel benzo[f]chromeno[4,3-b][1,7]naphthyridines and benzo[f][1,7]naphthyridines via an imino Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2016.12.050

A novel series of functionalized 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 1,3-diphenylbenzo[f][1,7]naphthyridines have been synthesized by an efficient regioselective one-pot multicomponent synthesis through intra and intermolecular imino Diels-

Full text of DOI:10.1016/j.tetlet.2016.12.050

Accepted Manuscript
A facile one-pot regioselective synthesis of functionalized novel benzo[f]chro-
meno[4,3-b][1,7]naphthyridines and benzo[f][1,7]naphthyridines via an imino
Diels-Alder reaction
Sateesh Kumar Arepalli, Byeongwoo Park, Jae-Kyung Jung, Kiho Lee, Heesoon
Lee
PII:
S0040-4039(16)31698-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.050
TETL 48462
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 November 2016
14 December 2016
20 December 2016
Please cite this article as: Kumar Arepalli, S., Park, B., Jung, J-K., Lee, K., Lee, H., A facile one-pot regioselective
synthesis of functionalized novel benzo[f]chromeno[4,3-b][1,7]naphthyridines and benzo[f][1,7]naphthyridines
via an imino Diels-Alder reaction, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.050
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Tetrahedron Letters
A
facile
one-pot
regioselective synthesis of functionalized
novel
benzo[f]chromeno[4,3-b][1,7]naphthyridines and benzo[f][1,7]naphthyridines via an
imino Diels-Alder reaction
a
a
a
b
a
Sateesh Kumar Arepalli , Byeongwoo Park , Jae-Kyung Jung , Kiho Lee and Heesoon Lee 
a
College of Pharmacy, Chungbuk National University, Chungbuk 362-763, Republic of Korea
College of Pharmacy, Korea University, Sejong 339-700, Republic of Korea
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel series of functionalized 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 1,3-
diphenylbenzo[f][1,7]naphthyridines have been synthesized by an efficient regioselective one-
pot multicomponent synthesis through intra and intermolecular imino Diels-Alder reaction. In
this method, we have achieved complete regioselectivity and atom economy with
polysubstituted core motifs in moderate to good yields. The proposed mechanism of this
reaction has also discussed.
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
1
1
3H-Benzo[f]chromeno[4,3-b][1,7]naphthyridines
,3-Diphenylbenzo[f][1,7]naphthyridines
Imino Diels-Alder reaction
Atom economy
One-pot Multicomponent reaction
—
——

Corresponding author. Tel.: +82-43-261-2811; fax: +82-43-268-2732; e-mail: medchem@chungbuk.ac.kr (H. Lee)

2
Introduction
In cancer chemotherapy, topoisomerase I has been identified as most important target by many researchers following to the
1
2a,b
2c
discovery of plant alkaloid camptothecin and its analogues in 1966. The camptothecins such as topotecan, irinotecan and
2d
belotecan were only chemical class of TopI inhibitors approved for clinical use, albeit camptothecin efficiency and applications
have been hindered by many factors. In that process many synthetic analogues such as indenoquinolines have emerged as
alternatives for camptothecin (Scheme 1). In the continuous and extensive research efforts by many researchers result the
2
3
modification of A, B, and D rings of the indenoisoquinoline (Scheme 1), in particular the 5-membered C-ring of the
indenoisoquinoline system was replaced by six-membered nitrogen heterocyclic rings, ensued the dibenzo[c,h][1,6]naphthyridines
4
(
Scheme 1) with potent in vitro anticancer activity and topoisomerase I inhibition. As we know among all heterocyclic systems,
naphthyridine and its derivatives have attracted increasing attention due to its pharmacophore with broad spectrum of potent
5
4b, 6
biological aspects (Fig 1). Although for the construction of the subjected core motifs require multistep methods.
6a
Recently, Michel et al., designed a multistep protocol for the development of new benzo[b]chromeno[6,5-g][1,8]naphthyridin-
6b
7
-ones and benzo[b]chromeno[7,6-g][1,8]-naphthyridin-6-ones as anticancer agents. Chen, W-L et al., also synthesized the
Figure 1. Representative examples of biologically important naphthyridines
benzo[f][1,7]naphthyridines as one of their substrates by hydride- induced anionic cyclization. Over the years, our group actively
7
engaged in the development of novel classes of heterocyclic systems with potential biological applications. As a result in this
report, we wish to describe an efficient regioselective one-pot synthetic method for novel series of 13H-benzo[f]chromeno[4,3-
b][1,7]naphthyridines and 1,3-diphenylbenzo[f][1,7]naphthyridines by hetero Diels-Alder reaction with internal and external
acetylenic dienophiles under mild reaction conditions. Hetero Diels-Alder (HDA) reactions are one of the most mainstays of
8
heterocycles, natural and non-natural product synthesis. Among HDAs, imino Diels-Alder
Scheme 1. Representation of research objective
reactions provide a useful platform for the insertion of nitrogen or oxygen atoms in the ring structures result the construction of
9
biologically and pharmaceutically functionalized heterocycles with regio-, diastereo- and enantio-selectivity.
Results and discussions
Our study was instigated with the optimization of reaction condition for the construction of novel 13H-benzo[f]chromeno[4,3-
b][1,7]naphthyridines (For full optimization table 1 see in supporting information). In an initial experiment, we treated 3-
aminoquinoline 1, and 2a with 20 mol% BF
product (entry 1, Table 1). We also tested different Lewis acid catalysts in DCM and CH
3
.Et
2
O in CH
3
CN solvent at reflux temperature which was failed to afford desired
CN
3
Table 1. Optimization of reaction conditions
o
No
Catalyst
Solvent
Temp( C) Time
Yield
(%)
N.R
a
(
h)
1
2
BF .Et O (20 mol%)
MeCN
MeCN
Reflux
Reflux
24
3
2
CF COOH (20 mol%)
24
N.R
3
3
4
CuI (20 mol%)
MeCN
MeCN
Reflux
Reflux
48
24
N.R
N.R
Sc(OTf) (20 mol%)
3
5
InBr (20 mol%)
MeCN
Reflux
24
N.R
3

3
6
7
8
SnF2 (0.2 eq.)
I2 (0.2 eq.)
DCM
DCM
MeCN
RT
48
24
24
N.R
N.R
N.R
Reflux
Reflux
CuI (10 mol%) /BF .Et O
3
2
(20 mol%)
9
CuI (10 mol%)/InBr (10
MeCN
MeCN
MeCN
MeCN
MeCN
Reflux
Reflux
Reflux
Reflux
Reflux
24
24
24
48
48
10
42
3
o
mol%)/4A M.S
1
0
1
2
3
CuI (10 mol%)/Yb(OTf)3
o
(10 mol%) /4A M.S
69b
38
1
1
1
CuI (20 mol%)/Yb(OTf)3
o
(20 mol%) /4A M.S
CuI (20 mol%)/Sc(OTf)3
o
(20 mol%) /4A M.S
CuI (20 mol%)/La(OTf)3
51
o
(
20 mol%) /4A M.S
14
15
16
17
18
CuI (20 mol%)/Yb(OTf)
Toluene
DCM
Reflux
Reflux
Reflux
Reflux
110
48
48
48
48
48
47c
20 c
3
3
3
3
3
(20 mol%)
CuI (20 mol%)/Yb(OTf)
(20 mol%)
CuI (20 mol%)/Yb(OTf)
1,4-dioxane
DCE
17 c
(20 mol%)
CuI (20 mol%)/Yb(OTf)
22 c
(20 mol%)
CuI (20 mol%)/Yb(OTf)
DMF
N.Rd
(
20 mol%)
a
b
Refers to column purified products and yields were calculated relative to 2a. Reaction conditions: 1 (0.693 mmol; 1.0 equiv), 2a (0.346 mmol; 0.5 equiv),
-10 mL of solvents used in all entries except entries 15-18, where 1.0 mL of Ionic liquids were used; M.S = Molecular Sieves. NMR Yield (TCE as
internal standard; TCE = 1,1,2,2-Tetrachloroethane) Optimized reaction conditions shown in bold. N.R = No Reaction.
c
5
d
1
0
solvents, which have been proven in a catalytic amount to activate imines in cycloaddition reactions but were, failed to provide the
11a
11b
desired product (entries 3-7). As Bota et al and Corey et al introduced copper in Diels-Alder reactions; we also attempted
o
copper use in our screening conditions as shown in table 1. Interestingly, in the combination of CuI, InBr
in CH CN solvent provided the desired product in 10% yield (entry 9, Table 1). This one-pot reaction condition prompted us to
investigate further the reaction in various Lewis acid catalysts and solvents. As anticipated by altering the Lewis acid to Yb(OTf)
3
and 4A Molecular sieves
3
3
(
10 mol%) provided the desired product in 42% yield (entry 10, Table 1). Gratifyingly, when we attempted 20 mol% CuI, 20 mol%
o
Yb(OTf)
3
, in CH
3
CN solvent at reflux temperature with 4A Molecular sieves as additive in one-pot provided the desired
1
intramolecular Imino Diels-Alder product in good yield (69%, entry 11, Table 1). In H NMR spectrum of 3a, two singlets at δ 9.64
ppm, 8.65 ppm and unexpected doublet at δ 9.65 ppm were observed and following careful analysis of COSY spectrum (Supporting
Information), we identified the cyclization occurred through the fourth position of 3-aminoquinoline ring rather than second
position. We also tried with different copper salts but CuI found to be the best choice. To improve the yield, we examined different
solvents such as Toluene, DCM, DMF, DMSO, Dioxane, and DCE including ionic liquids with different transition metal triflates
(
See Table 1in supporting information). Nevertheless, the yield of the desired product was not improved. However, we preferred
Yb(OTf) for further optimization since it owns some advantages such as eco-friendly nature, inexpensive, nontoxic and it has also
been used as a catalyst in many organic transformations. After the different screening results, the optimized one-pot reaction
3
12
o
3 3
condition found to involve 20 mol% CuI, 20 mol% Yb(OTf) , 0.5 equiv. of 4A Molecular sieves in 5-10 mL of CH CN at reflux
temperature afford the desired intramolecular Imino Diels-Alder product. Having the reaction condition in hand, the substrate scope
of this reaction with different O-propargyl salicylaldehydes (2a-m) in one-pot were successfully employed with 3-aminoquinoline
through an intra-
e
Table 2. Substrate scope for intramolecular one-pot [4+2] cycloaddition reaction

4
e
o
Reaction conditions: 1 (0.693 mmol; 1.0 equiv), 2a-m (0.5 equiv), 20 mol% CuI, 20 mol% Yb(OTf)
CH CN at reflux temperature
3
, 4A Molecular Sieves (0.5 equiv.), 5-10 mL of
3
molecular imino Diels-Alder reaction to produce the corresponding 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines (3a-m) as
shown in table 2.
4, 5
13
The literature reports disclosed the naphthyridine and chroman core motifs independently exhibit most significant medicinal
values and also found in numerous natural products as well as in therapeutics. This intramolecular imino Diels-Alder reaction could
provide a value route to the fusion of these core motifs resulting the 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines (3a-m).
Various substitution patterns at R
introduced R = Aryl, Methyl substitutions (internal alkynes) slightly improved the yields of the reaction. This Imino Diels-alder
reaction impartially affects by the electron donating groups at R position (3h) and bulky groups at R , R positions (3g). Overall,
1 2 3 4
, R , R , R as well as R were well tolerated in the reaction condition (Table 2). When we
2
1
3
this intramolecular imino Diels-Alder reaction provided moderate to good yields of 3a-m as shown in Table 2. Having optimized
catalyst system in hand, next we turned our attention towards multicomponent intermolecular imino Diels-Alder reaction by varying
aromatic and hetero aromatic aldehydes with external acetylenic dienophiles provided 1,3-diphenylbenzo[f][1,7]naphthyridines (6a-
n) as shown in Table 3.
f
Table 3. Substrate scope for intermolecular one-pot [4+2] cycloaddition reaction

5
f
o
3
Reaction conditions: 1 (0.693 mmol; 1.0 equiv), 4a-k (0.4 equiv), 5 (0.8 equiv.) 20 mol% CuI, 20 mol% Yb(OTf) , 4A Molecular Sieves (0.5 equiv.), 5-10
g
3
mL of CH CN at reflux temperature. 6dreaction yield ~70% but isolated yield 15%.
In this intermolecular imino Diels-Alder reaction condition found to involve 1.0 equiv of 3-aminoquinoline, 0.4 equiv. of aromatic
o
or heteroaromatic aldehydes (4a-k), 0.8 equiv. of 5, 20 mol% CuI, 20 mol% Yb(OTf)
mL of CH CN at reflux temperature afforded the 1,3-diphenylbenzo[f][1,7]naphthyridines (6a-n) in moderate yields. In the
substrate scope expansion, we tried different substitution pattern at R , R , R , R and R positions; when we tried, any electron
withdrawing groups at R , R position of aldehydes greatly influence the yield of products (6g, 6h, 6i). However, electron-donating
group at R position provided relatively good reaction yield but in the case of 6d, which is, not stable enough to isolate. When we
3
, 0.5 equiv. of 4A Molecular sieves in 5-10
3
1
2
3
4
5
2
3
3
attempted heteroaromatic aldehydes (6l, 6m, 6n) in this reaction, observed complete imine formation but subsequent to [4+2]
cycloaddition reaction provided low yields which is due to steric hindrance between bulky substituted imine and electron rich
14
phenyl acetylenic dienophile. Based on the literature reports, we have depicted the plausible reaction mechanism of CuI/Yb(OTf)
catalyzed intramolecular Imino Diels-Alder reaction in Scheme 2.
3
To explain the mechanism, in the first step the imine (I) formed from 3-aminoquinoline (1) and O-propargylated
salicylaldehydes (2a-m) in presence of Yb(OTf) and then which is involved in [4+2] cycloaddition reaction in presence of CuI
3
produces II and it isomerizes to III which is further oxidized by
Scheme 2. Plausible mechanism for the synthesis of 3a-m.
air to afford the final aromatized 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines (3a-m).
In conclusion, we have developed a simple and efficient one-pot method for the synthesis of novel functionalized 13H-
benzo[f]chromeno[4,3-b][1,7]naphthyridines (3a-m) and 1,3-diphenylbenzo[f][1,7]naphthyridines (6a-n) in moderate to good

6
yields. In this method, we have achieved complete regioselctivity in both intramolecular and intermolecular cyclizations by using
CuI/Yb(OTf) catalyst system in CH CN solvent at reflux temperature. This method has the advantages of easy availability,
3 3
flexibility of starting materials, and it is one of the best examples for an atom-economy and one-pot multicomponent reaction. The
synthesized derivatives also exhibiting most significant biological activities and their related studies under progress, which will be
reported shortly.
Acknowledgments
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education (NRF- 2015R1D1A1A01058142), Korea Research Fellowship Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2016H1D3A1937140) and Medical
Research Center Program (2008-0062275).
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1
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Supplementary Material
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Highlights:
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One-pot multi-component synthetic methodology for novel scaffolds was developed.
It is an atom-economy reaction affording poly-substituted napthyridine core motifs.
This imino diels-alder reaction allows broad substrate scope.
We have achieved complete regioselectivity with inexpensive catalytic system.
Unusual plausible reaction mechanism has also been discussed.

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Graphical Abstract
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A facile one-pot regioselective synthesis of
functionalized novel benzo[f]chromeno[4,3-
b][1,7]naphthyridines and benzo[f] [1,7]naphthyridines
via an Imino Diels-Alder reaction
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Sateesh Kumar Arepalli, Byeongwoo Park, Jae-Kyung Jung, Kiho Leeand Heesoon Lee*