A facile synthesis of tetracyclic benzo-pyridonaphthyridines by domino reaction

Article abstract of DOI:10.1016/j.tetlet.2013.02.016

A novel methodology for the synthesis of tetracyclic benzo- pyridonaphthyridines, forming a C-C and a C-N bond in concentrated sulfuric acid at 70 °C in a one-pot is reported. The key substrates (9a-m) are prepared by reacting 2-chloro-6-(4-fluorophenyl)-4-methylnicotinenitrile (7) with various anilines followed by dimethylformamide dimethylacetal. The domino reaction is initiated by the protonation of the b-carbon of the enamine group in 9a-m and terminated by the elimination of dimethylamine.

Full text of DOI:10.1016/j.tetlet.2013.02.016

Tetrahedron Letters 54 (2013) 2014–2017
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Tetrahedron Letters
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A facile synthesis of tetracyclic benzo-pyridonaphthyridines by domino reaction
Vishnu Basetti a,b, Rangarao Pallepati a, Subramanya Hosahalli c, Vijay Potluri a,
⇑
a Aurigene Discovery Technologies Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India
b Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, India
c Aurigene Discovery Technologies Ltd, 9-40, KIADB Industrial Area, Phase II, Electronic City Hosur Road, Bangalore 560100, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel methodology for the synthesis of tetracyclic benzo-pyridonaphthyridines, forming a C–C and a
C–N bond in concentrated sulfuric acid at 70 °C in a one-pot is reported. The key substrates (9a–m)
are prepared by reacting 2-chloro-6-(4-fluorophenyl)-4-methylnicotinenitrile (7) with various anilines
followed by dimethylformamide dimethylacetal. The domino reaction is initiated by the protonation of
the b-carbon of the enamine group in 9a–m and terminated by the elimination of dimethylamine.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 3 December 2012
Revised 29 January 2013
Accepted 4 February 2013
Available online 13 February 2013
Tetracylic alkaloids of the Aporphine class are known to be
associated with diverse biological activities such as anticancer,1
antimicrobial,2 and acetylcholine esterase inhibitors.3 Sampangine
(1) (Fig. 1), an azaoxaaporphine was shown to have antimicrobial
activity. Ascididemin (2) and 12-deoxyascididemin (3) were also
reported to have strong antitrypanosomal activity. These three
proton from the benzylic methyl groups and a molecule of metha-
nol is eliminated to give an activated benzylic methylene and
methoxymethylene imidinium ion. The imidinium ion is trapped
by the benzylic methylene group and subsequent elimination of
another molecule of methanol results in the formation of enamines
(9a–m and 12n–q).11
alkaloids have
a
common 2,7-naphthyridine backbone. We
Compounds 9a–m, with an aniline, a nitrile, and an enamine
functional groups on consecutive carbon atoms of the pyridine ring
are the key functionalities that undergo the domino reaction. Thus,
when 9a–m when treated with concentrated sulfuric acid, under-
went domino reactions wherein a C–C and a C–N bond were
formed in one pot to yield the tetracyclic 5-(4-fluorophenyl)-7-
azasampangines (10a–m).12 Table 1 summarizes the yields for
the transformation from 7 to 10a–m for various derivatives. The
tetracyclic-7-azasampangine derivatives were obtained in good
yields when the anilines are substituted with electron donating
functional groups (Table 1: entries a –m). However, when an
electron withdrawing group like nitro was present (12n–o), the
domino reaction did not proceed (Fig. 3). Instead the substituted
bicyclic 2,7-naphthyridinones (13n–o) were obtained (Table 2:
entries n and o). When phenol or thiophenol were used in place
of the anilines the corresponding naphthyridinone derivatives
13p–q were formed (Table 2: entries p and q).
The acid catalyzed domino reaction to give the tetracyclic-
7-azasampangine (10a–m) may be explained by the mechanism
proposed inFigure 4. The domino reaction is initiated by the proton-
ation of the b-carbon of the dimethylamino enamine group, which
results in an iminium ion. The positively charged iminium ion trig-
gers a series of electron cascades resulting in the formation of a C–C
bond and a C–N bond. The reaction is terminated by the elimination
of dimethyl amine to give the tetracylic-7-azasampangine.
In conclusion, we have developed a facile and robust methodol-
ogy for the synthesis of a variety of benzo-pyridonaphthyridines
using a novel domino reaction.
envisaged that 5-phenyl-7-azasampangine (4) having benzo-
pyridonaphthyridine scaffold could be exploited to elicit enhanced
biological activity similar to Sampangine. The only reported meth-
od for the synthesis of benzo-pyridonaphthyridines is limited with
respect to generating large number of variations.4
Here in we report a facile synthetic methodology involving a
domino reaction in which two bonds are formed to create the com-
plex tetracyclicalkaloid, 5-(4-flurorophenyl)-7-azasampangine5
(10) (Fig. 2). Ethyl acetoacetate and cyanoacetamide were con-
densed under basic conditions to give 2-hydroxy-3-cyano-4-
methyl-6-pyridone (5)6 which upon treatment with POCl3 yielded
2,6-dichloro-4-methylnicotinonitrile (6).7 The chloro group at 6-
position of compound 6 was selectively replaced under Suzuki con-
ditions to give the corresponding 4-flurophenyl derivative (7).8
Compound 7 is a key intermediate for the current methodology.
Compound 7 was reacted with various substituted anilines to pro-
duce the tetrasubstituted pyridine intermediates (8a–m and 11n–
o).9 Intermediates 11p and 11q were obtained by reacting com-
pound 7 with 4-chlorophenol and 4-chlorothiophenol, respec-
tively. The intermediates 8a–m and 11n–q were reacted with
dimethylformamide dimethylacetal (DMF-DMA) to give the enam-
ines (9a–m and 12n–q).10 In this reaction DMF-DMA extracts a
⇑
Corresponding author. Tel.: +91 404 465 7317; fax: +91 404 465 74380.
E-mail addresses: vijay_p@aurigene.com, potluri.vijay@gmail.com (V. Potluri).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.016

V. Basetti et al. / Tetrahedron Letters 54 (2013) 2014–2017
2015
3
1
1
3
N
O
N
N
N
N
N
4
5
4
N
N
N
H
N
N
H
5
7
O
7
12-deoxyascididemin (3)
Sampangine (1)
Ascididemin (2)
5-phenyl-7-azasampangine (4)
Figure 1. Structures of alkaloids with 2,7-naphthyridine backbone.
CN
Cl
CN
CN
OH
O
CN
Cl
i
iii
+
ii
N
O
O
H2N
O
N
H
5
O
Cl
N
F
6
7
N
CN
NH
3
1
NH2
iv
N
11
8
CN
NH
10
N
R1
v
vi
R1
9
F
N
N
H
R1
N
5
7
F
F
R1
8
9
10
Figure 2. Reagents and conditions: (i) KOH, MeOH, reflux, 8 h, 72%; (ii) benzyltriethylammonium chloride, POCl3, 90 °C, 10 h, 65%; (iii) 4-fluorophenylboronic acid, K2CO3,
Pd(PPh3)4, dioxane:water (20:1), 100 °C, 3.5 h, 75%; (iv) Pd2(dba)3, NatBuO, (2-biphenyl) di tert-butylphosphine, toluene, 100 °C, 2–3 h; (v) DMF-DMA, dry DMF, 130 °C, 3 h;
(vi) concd H2SO4, 70 °C, 1 h.
Table 1
Yields for the transformation from 7 to 10a–m
Entry
Anilines
8
9
10
R1
10
Yield (%)
Yield (%)
Yield (%)
a
b
c
56
74
81
68
70
66
10-Isopropyl
10-Et
90
88
82
NH2
NH2
10-Me
NH2
O
d
e
60
59
91
76
9-OMe
76
72
NH2
O
O
9,10-OMe
NH2
f
62
63
40
64
62
86
68
75
—
58
70
60
75
NH2
F
S
g
h
i
10-F
10-SMe
10-Cl
NH2
NH2
NH2
Cl
Cl
j
44
52
70
67
9-Cl
73
NH2
O
O
NH2
k
9,11-OMe
69
(continued on next page)

2016
V. Basetti et al. / Tetrahedron Letters 54 (2013) 2014–2017
Table 1 (continued)
Entry
Anilines
8
9
10
R1
10
Yield (%)
Yield (%)
Yield (%)
Br
O
l
30
48
70
60
10-Br
50
67
NH2
NH2
O
O
m
9,10,11-OMe
N
NH
CN
X
CN
X
CN
Cl
i
ii
iii
O
N
N
N
N
X
Ar-XH
F
F
F
F
R2
R2
R2
13
12
11
7
Figure 3. Reagents and conditions: (i) X = O, S: K2CO3, DMF, 90 °C, 2 h; X = NH: Pd2(dba)3, NatBuO, (2-biphenyl) di tert-butylphosphine, toluene, 100 °C, 2–3 h; (ii) DMF-DMA,
dry DMF, 130 °C, 3 h; (iii) concd H2SO4, 70 °C, 4 h.
Table 2
Yields for the transformation from 7 to 13n–q
Entry
ArXH
X
R2
11
12
13
Yield (%)
Yield (%)
Yield (%)
NH2
n
NH
3-NO2
48
72
45
O2N
O2N
o
p
q
NH
O
4-NO2
4-Cl
28
92
93
80
86
86
51
55
50
NH2
OH
SH
Cl
Cl
S
4-Cl
H
N
N+
N+
H
H
N
H
H
H
N
N
H+
H
N
N
H+
- NH(CH3)2
- H+
R
N
N
H
R
N
N
H
R
N+
H
R
N
N
H
9f
R = 4-fluorophenyl
Figure 4. Proposed mechanism.
10f
Acknowledgments
References and notes
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We thank Aurigene Discovery Technologies Ltd and Jawaharlal
Nehru Technological University for financial support and encour-
agement, respectively. Help from analytical department in record-
ing spectral data is appreciated.
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5. 4-Flurorophenyl substitution at 5-position was chosen for ease of
characterization of the compounds synthesized. The reactions worked
equally well with an unsubstituted phenyl group (4) (data not shown).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.
016.

V. Basetti et al. / Tetrahedron Letters 54 (2013) 2014–2017
2017
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9. General procedure (compounds 8a–m and 11n–o): To a solution of NaOtBu
(4.26 mmol), 2-chloro-6-(4-flurophenyl)-4-methylnicotinonitrile (2.84 mmol)
and aniline (3.69 mmol) in toluene (16 mL) under inert atmosphere were
added Pd2(dba)3 (6 mol %) and (2-biphenyl) di tertiary butyl phosphine
(6 mol %), the reaction mixture was stirred at 100 °C for 2–3 h. The reaction
mixture was filtered through a pad of Celite and the pad washed with excess
toluene. The filtrate was concentrated and the residue was purified by column
chromatography over silica gel (100–200 mesh size) as a stationary phase and
2–3% (v/v) ethyl acetate in hexane as eluent to furnish the desired products.
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12. General procedure for preparation of tetracyclic benzo-pyridonaphthyridines and
naphthyridinones (10a–m and 13n–q): The enamines (9a–m and 12n–q)
(0.78 mmol) were suspended in conc. H2SO4 (6 mL) under inert atmosphere
and the mixture was heated to 70 °C for 45 min to 1 h (for compound 13n–q
reaction time was 4 h). The reaction mixture was cooled and poured into ice
cold water and basified with saturated aqueous sodium carbonate to ꢀpH 9.
The basic aqueous reaction mixture was extracted with ethyl acetate. The ethyl
acetate layers were pooled, washed with water, dried over anhydrous Na2SO4
and concentrated in vacuo to furnish crude product. The pure product was
obtained by column chromatography over silica gel (100–200 mesh size) as a
stationary phase and 1–2% (v/v) methanol in dichloromethane as an eluent.