Synthesis of benzo[c][2,7]naphthyridines by one-pot multicomponent reaction using ceric(IV) ammonium nitrate

Article abstract of DOI:10.1080/00397911.2013.870208

A new, one-pot, three-component reaction for the synthesis of benzo[c][2,7]-naphthyridines has been achieved from aromatic amines, aromatic aldehydes, and N-carbethoxy-4-piperidone in the presence of a catalytic amount of ceric ammonium nitrate in good yields at room temperature. The advantages of this procedure are mild reaction conditions, low toxicity, and the use of inexpensive reagents. Apart from milder and environmentally benign conditions, this method involves a simple, reliable approach to give good yields of the desired products and is compatible with a wide range of functional groups.

Full text of DOI:10.1080/00397911.2013.870208

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Synthesis of Benzo[c]
[2,7]Naphthyridines by One-Pot
Multicomponent Reaction Using Ceric(IV)
Ammonium Nitrate
M. S. R. Murty a , Mohana Rao Katiki a , B. Ramalingeswara Rao a &
Kesur R. Ram a
a Medicinal Chemistry and Pharmacology Division , Indian Institute of
Chemical Technology , Hyderabad , India
Accepted author version posted online: 10 Feb 2014.Published
online: 14 May 2014.
To cite this article: M. S. R. Murty , Mohana Rao Katiki , B. Ramalingeswara Rao & Kesur R. Ram
(2014) Synthesis of Benzo[c][2,7]Naphthyridines by One-Pot Multicomponent Reaction Using Ceric(IV)
Ammonium Nitrate, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:11, 1664-1670, DOI: 10.1080/00397911.2013.870208
To link to this article: http://dx.doi.org/10.1080/00397911.2013.870208
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Synthetic Communications1, 44: 1664–1670, 2014
Copyright # Indian Institute of Chemical Technology
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.870208
SYNTHESIS OF BENZO[c][2,7]NAPHTHYRIDINES BY
ONE-POT MULTICOMPONENT REACTION USING
CERIC(IV) AMMONIUM NITRATE
M. S. R. Murty, Mohana Rao Katiki, B. Ramalingeswara Rao,
and Kesur R. Ram
Medicinal Chemistry and Pharmacology Division, Indian Institute of
Chemical Technology, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A new, one-pot, three-component reaction for the synthesis of benzo[c][2,7]-
naphthyridines has been achieved from aromatic amines, aromatic aldehydes, and
N-carbethoxy-4-piperidone in the presence of a catalytic amount of ceric ammonium nitrate
in good yields at room temperature. The advantages of this procedure are mild reaction con-
ditions, low toxicity, and the use of inexpensive reagents. Apart from milder and environ-
mentally benign conditions, this method involves a simple, reliable approach to give good
yields of the desired products and is compatible with a wide range of functional groups.
Keywords Ceric ammonium nitrate; multicomponent reaction; naphthyridines; one-pot
synthesis
INTRODUCTION
Multicomponent reactions (MCRs) have emerged as a powerful synthetic strat-
egy because of their efficiency, atom economy, high selectivity, and convenience in
the construction of diverse chemical libraries of ‘‘drug-like’’ molecules.[1–3] MCRs
are convergent reactions, in which three or more starting materials react to give a
highly complex product in one pot. Typically, purification of products resulting from
MCRs is also simple because all the organic reagents employed are consumed and
incorporated into the target compound. The usefulness of MCRs is even greater if
they provide access to ‘‘privileged medicinal scaffolds’’ such as naphthyridines.[4]
Received October 1, 2013.
Address correspondence to M. S. R. Murty, Medicinal Chemistry and Pharmacology Division,
Indian Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: msrmurty@ymail.com
1664

BENZO[C][2,7]NAPHTHYRIDINES
1665
Figure 1. Pharmaceutical compounds and alkaloids containing benzo[c][2,7]naphthyridines.
Naphthyridines are a class of heterocyclic compounds that exhibit a broad
spectrum of biological activities. Substituted benzo[c][2,7]naphthyridine derivatives
have been described to exhibit anti-inflammatory[5] and antimalarial[6] activities.
Dialkoxybenzo[c][2,7]naphthyridines,[7] exemplified by the imidazole substituted
derivative 1 and the pyridyl substituted derivative 2, were potent inhibitors of
PDK-1 (Fig. 1). Among the vast number of alkaloids isolated from living organisms,
until now only two tricyclic benzo[c][2,7]naphthyridines have been described, namely
perlolidine 3 from the perennial ryegrass (Loliumperenne)[8] and the 4-pyridylben-
zo[c][2,7]naphthyridine subarine 4 from a singaporean ascidian[9] (Fig. 1). Keeping
in mind the important properties of naphthyridines, we describe here a detailed report
of the synthesis of benzo [c][2,7]naphthyridines.
Lewis acid–catalyzed multicomponent organic transformations are gaining
increasing popularity because of their economic and ecological efficacy.[10] Ceric(IV)
ammonium nitrate (CAN) is a convenient and widely used reagent for a wide array
of synthetic transformations because of its many advantages such as solubility in
organic solvents, low toxicity, high reactivity, ease of handling, and commercially
availability. Besides, CAN is able to catalyze various organic transformations not
only based on its electron transfer capacity but also with its lewis acidic property
in C–C bond forming reaction.[11,12]
The synthesis of napthonaphthyridines using iodine as catalyst under reflux con-
ditions with prolonged reaction time was reported.[13] Herein, we report a new one-pot,
three-component reaction for the synthesis of ethyl 5-aryl-1, 2-dihydrobenzo[c]
[2,7]naphthyridine-3(4H)-carboxylate derivatives 4 by the reaction of aromatic amines,
aromatic aldehydes, and N-carbethoxy-4-piperidone in the presence of CAN as cata-
lyst in good yield in relatively short reaction time at room temparature (Scheme 1). The
present method offers a highly efficient method under mild reaction conditions with
good yields. To the best of our knowledge, there are no reports on the synthesis of
these compounds via MCR using CAN as the catalyst.
Scheme 1. Synthesis of substituted benzo[c][2,7]naphthyridines 4a–4f.

1666
M. S. R. MURTY ET AL.
Table 1. Screening of reaction conditions using catalystsa
Entry
Catalyst
Time (h)
Yieldb (%)
1
2
No catalyst
AlCl3
BiCl3
24
6
0
61
70
57
72
66
69
45
50
84
3
6
4
FeCl3
ZrCl4
6
5
6
6
Sc(OTf)3
ZnCl2
6
7
6
8
AcOH
p-TsOH
CAN
24
24
5
9
10
aReaction conditions: The reaction was performed with aniline
(1 mmol), benzaldehyde (1 mmol), N-carbethoxy-4-piperidone (1 mmol),
and catalyst (10 mol%) in acetonitrile (5 mL) at room temperature.
bIsolated yields after column chromatography.
RESULTS AND DISCUSSION
The catalyst played an important role in the formation of substituted
benzo[c][2,7]naphthyridine. Initially, aniline, benzaldehyde, and N-carbethoxy-4-
piperidone were selected as representative substrates to investigate the reaction con-
ditions. Without the catalyst, it was observed that no conversion to product was
obtained even after 24 h (Table 1, entry 1). Then, we focused our attention on using
various Lewis and Brønsted acid catalysts, which might help to reduce the reaction
time and improve the yields of the target compounds. The common Lewis acids such
as AlCl3, BiCl3, FeCl3, ZrCl4, Sc(oTf)3, and ZnCl2 (Table 1, entries 2–7) and Brønsted
acid catalysts such as AcOH and p-TsOH (Table 1, entries 8 and 9) afforded the
desired product but only in moderate yields. Among the Lewis and Brønsted acid
catalysts tested, we observed that CAN could efficiently catalyze the reaction to
afford the desired product 4a in good yield in relatively short reaction time at room
temperature (Table 1, entry 10).
Table 2. Screening of reaction conditions using mol% and solventsa
Entry
Solvent
Mol (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
H2O
5
79
84
82
0
10
20
10
10
10
10
10
10
CH3OH
CHCl3
CH2Cl2
C6H6
77
74
65
71
73
THF
aReaction conditions: The reaction was performed with aniline
(1 mmol), benzaldehyde (1 mmol), N-carbethoxy-4-piperidone (1 mmol),
and CAN in the given solvent (5 mL) at room temperature for 5 h.
bIsolated yields after column chromatography.

BENZO[C][2,7]NAPHTHYRIDINES
1667
To further improve the yield and to optimize the reaction conditions, the same
reaction was carried out in the presence of 5, 10, and 20 mol% of CAN under similar
conditions (Table 2, entries 1–3). Employing a lower percentage of CAN reduced the
yield. A greater percentage loading of the catalyst slightly decreased the yield. The
Table 3. Synthesis of benzo[c][2,7]naphthyridines 4a
Entry
Amine
Aldehyde
Product
Time (h)
Yieldb (%)
1
5
84
2
3
6
6
73
75
4
4
83
5
6
6
5
77
81
aReaction conditions: The reaction was performed with anilines (1 mmol), aromatic aldehydes (1 mmol),
N-carbethoxy-4-piperidone (1 mmol), and 10 mol% of CAN in acetonitrile (5 mL) at room temperature.
bIsolated yields after column chromatography.

1668
M. S. R. MURTY ET AL.
best results were obtained with 10 mol% of CAN (Table 2, entry 2). We next
performed the solvent effect on the outcome of the reaction. The model reaction
was carried out with 10 mol% of CAN in solvents such as CH3CN, CH3OH, CHCl3,
CH2Cl2, C6H6, and THF at room temperature (Table 2, entries 2, 5–9). It was
observed that acetonitrile was the most effective solvent, and the reaction proceeded
smoothly, giving the maximum yield (Table 2, entry 2). It is noteworthy that when
water was used as the solvent, no product was observed even after a prolonged
reaction time (Table 2, entry 4).
To extend the range of substrates using the optimal reaction conditions, the
reaction of aromatic amines and aromatic aldehydes with N-carbethoxy-4-piperidone
were performed for the preparation of benzo[c][2,7]naphthyridines 4(a–f) (Table 3,
entries 1–6). Aromatic amines bearing substituents, such as 2-fluoro and 4-bromo,
afforded the desired products 4b and 4c in good yields (Table 3, entries 2 and 3).
The reactions of aromatic aldehydes containing substituents such as 4-methyl and
4-bromo groups reacted smoothly to provide the corresponding naphthyridines 4d
and 4e in good yields (Table 3, entries 4 and 5).
However, in the case of an electron-withdrawing group such as nitro group the
yield of the product was not satisfactory. This observation could be explained by the
formation of more stable imine due to extra conjugation in the presence of nitro
group. This stable imine is less reactive and inhibited the formation of corresponding
Scheme 2. Proposed mechanism for the synthesis of benzo[c][2,7]naphthyridines.

BENZO[C][2,7]NAPHTHYRIDINES
1669
product. In addition to aromatic aldehydes, heterocyclic aldehyde such as thiophene-
2-carboxaldehyde also furnished the expected product 4f (Table 3, entry 6).
Mechanistically, first aniline 1 condenses with aldehyde 2 to give an imine A,
which is activated by CAN to give intermediate B. Nucleophilic attack of the enol
form C of N-carbethoxy-4-piperidone 3 on CAN activated intermediate B leads to
the formation of intermediate D, which subsequently undergoes intramolecular
cyclization to give intermediate E. On dehydration this intermediate results in
tetrahydrobenzo[c][2,7] naphthyridine F. Finally, aerial oxidation of F affords the
product 4 (Scheme 2).
EXPERIMENTAL
Typical Procedure for the Synthesis of Ethyl 5-Phenyl-1,2-
dihydrobenzo[c][2,7]naphthyridine-3(4H)-carboxylate (4a)
CAN (10 mol%) was added to a mixture of aniline (1 mmol), benzaldehyde
(1 mmol), and N-carbethoxy-4-piperidone (1 mmol) in acetonitrile (10 mL) at room
temperature. The reaction mixture was allowed to stir, after completion of the reaction
as indicated by thin-layer chromatography (TLC), and 10 mL of ethyl acetate was
added and washed with brine (2 ꢀ 10 mL). The organic layer was separated, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude
product, which was purified by silica-gel column chromatography using ethyl acetate–
hexane (1:10) as eluent, to afford the pure yellow oil product 4a. Yield: 277 mg, 84%.
Data
IR (KBr): 2981, 1692, 1598, 1474, 1433, 1380, 1319, 1237, 1171, 1118, 1067,
1015, 919, 817, 765 cmꢁ1 1H NMR (300 MHz, CDCl3) d: 7.62–7.58(m, 1H);
.
7.46–7.32(m, 8H); 4.75–4.66(br s, 2H); 4.15 (q, J ¼ 7.3 Hz, 2H); 3.81 (t, J ¼ 6.6 Hz,
2H); 2.65 (t, J ¼ 6.6 Hz, 2H); 1.34–1.19 (m, 3H). 13C NMR (75 MHz, CDCl3) d:
155.0, 137.2, 134.3, 131.3, 130.0, 130.4, 129.4, 128.7, 128.2, 127.3, 114.9, 61.6, 44.8,
40.7, 14.7. ESI-HRMS: [MþH]þ, calcd. for C21H20N2O2: 333.1603, found: 333.1613.
CONCLUSION
In summary, we have described an efficient and simple three-component,
one-pot approach for the synthesis of substituted benzo[c][2,7]naphthyridine deriva-
tives from aromatic amines, aromatic aldehydes, and N-carbethoxy-4-piperidone in
acetonitrile using CAN as the catalyst at room temperature via intramolecular
cyclization step as the key reaction. All the products were obtained in good purity
and good yields. We hope that this novel class of compounds will meet with success
as biologically active substances.
FUNDING
The authors M. R. K., R. R. B., and K. R. R. are thankful to the Council of
Scientific and Industrial Research (CSIR) and University Grants Commission

1670
M. S. R. MURTY ET AL.
(UGC), New Delhi, India, for the award of research fellowships. The authors thank
CSIR, New Delhi, for financial support as a part of XII five-year plan program
under title ORIGIN (CSC-0108).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
REFERENCES
1. Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl. 2000, 39, 3168.
´
2. Zhu, J.; Bienayme, H., Eds. Multicomponent Reactions; Wiley-VCH: Weinheim, Germany,
2005.
3. Dou, G. L.; Shi, C. L.; Shi, D. Q. J. Comb. Chem. 2008, 10, 810.
4. (a) Kumar, V.; Jaggi, M.; Singh, A. T.; Madaan, A.; Sanna, V.; Singh, P.; Sharma, P. K.;
Irchhaiya, R.; Burman, A. C. Eur. J. Med. Chem. 2009, 44, 3356; (b) Andaloussi, M.;
Moreau, E.; Masurier, N.; Lacroix, J.; Gaudreault, R. C.; Chezal, J. M.; Laghdach,
A. El.; Canitrot, D.; Debiton, E.; Teulade, J. C.; Chavignon, O. Eur. J. Med. Chem.
2008, 43, 2505.
5. Go¨rlitzer, K.; Bode, M.; Frohberg, P.; Drutkowski, G. Pharmazie 2004, 59, 15.
6. (a) Go¨rlitzer, K.; Enge, C.; Jones, P. G.; Jomaa, H.; Wiesner, J. Pharmazie 2006, 61, 975;
(b) Gorlitzer, K.; Enge, C.; Jones, P. G.; Jomaa, H.; Wiesner, J. Pharmazie 2007, 62, 89.
¨
7. Kim, K.; Wissner, A.; Floyd, M. B.; Fraser, H. L.; Wang, Y. D.; Dushin, R. G.; Hu, Y.;
Olland, A.; Guo, B.; Arndt, K. Bioorg. Med. Chem. Lett. 2009, 19, 5225.
8. White, E. P.; Reifer, I. New Zealand J. Sci. Technol. 1945, 27B, 38.
´
9. Nilar, Sidebottom, P. J.; Carte, B. K.; Butler, M. S. J. Nat. Prod. 2002, 65, 1198.
10. (a) Dai, W. M.; Li, H. Tetrahedron 2007, 63, 12866; (b) Ghosh, R.; Maiti, S.;
Chakraborty, A.; Chakraborty, S.; Mukherjee, A. K. Tetrahedron 2006, 62, 4059; (c)
Church, T. L.; Byrne, C. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc.
2007, 129, 8156.
11. Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862.
12. Sridharan, V.; Menendez, J. C. Org. Lett. 2008, 10, 4303.
13. Wang, X. S.; Li, Q.; Wu, J. R.; Yao, C. S.; Tu, S. J. J. Heterocycl. Chem. 2009, 46, 1229.