Iodine- and indium(III) chloride-catalyzed facile syntheses of 1,5- and 1,8-naphthyridines

Article abstract of DOI:10.1080/00397911.2010.493261

Iodine- and InCl₃-catalyzed facile syntheses of 1,5- and 1,8-naphthyridines from 3-aminopyridine and 2-aminopyridines are described. The catalyst InCl₃ could be recovered and reused up to five times efficiently.

Full text of DOI:10.1080/00397911.2010.493261

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Iodine- and Indium(III)
Chloride–Catalyzed Facile Syntheses of
1,5- and 1,8-Naphthyridines
Kaushik C. Chunavala a & Subbarayappa Adimurthy a
a Central Salt and Marine Chemicals Research Institute, Council of
Scientific and Industrial Research (CSIR) , Bhavnagar , Gujarat ,
India
Published online: 29 Apr 2011.
To cite this article: Kaushik C. Chunavala & Subbarayappa Adimurthy (2011) Iodine- and Indium(III)
Chloride–Catalyzed Facile Syntheses of 1,5- and 1,8-Naphthyridines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:12, 1843-1851,
DOI: 10.1080/00397911.2010.493261
To link to this article: http://dx.doi.org/10.1080/00397911.2010.493261
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Synthetic Communications1, 41: 1843–1851, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.493261
IODINE- AND INDIUM(III) CHLORIDE–CATALYZED
FACILE SYNTHESES OF 1,5- AND
1,8-NAPHTHYRIDINES
Kaushik C. Chunavala and Subbarayappa Adimurthy
Central Salt and Marine Chemicals Research Institute,
Council of Scientific and Industrial Research (CSIR),
Bhavnagar, Gujarat, India
GRAPHICAL ABSTRACT
Abstract Iodine- and InCl3-catalyzed facile syntheses of 1,5- and 1,8-naphthyridines from
3-aminopyridine and 2-aminopyridines are described. The catalyst InCl3 could be recovered
and reused up to five times efficiently.
Keywords Amino pyridines; ethylacetoacetate; glycerol; naphthyridines
INTRODUCTION
1,5-Naphthyridines, nitrogen-containing heterocycles, are interesting molecules
because they feature several favorable characteristics for drug development.[1,2]
Recently, marked improvements have been observed in anti-HIV activities in human
trials with several drug candidates, including the derivatives of 4-hydroxy-7-benzyl-
1,5-naphthyridinones.[3] Among naphthyridines (Fig. 1), substituted 1,5- and 1,8-
naphthyridines reported to have extensive medicinal applications.[4] 1,5-Naphthyridine
is a potential ligand for the synthesis of larger metallacycles.[5] In addition, recently the
Received February 5, 2010.
Address correspondence to Subbarayappa Adimurthy, Central Salt and Marine Chemicals
Research Institute, Council of Scientific and Industrial Research (CSIR), Gijubhai Badheka Marg,
Bhavnagar 364 002, Gujarat, India. E-mail: sadimurthy@yahoo.com
1843

1844
K. C. CHUNAVALA AND S. ADIMURTHY
Figure 1. Structures of (a) 1,5-, (b) 1,6-, and (c) 1,8-naphthyridines.
new applications of 4-hydroxy-1,5-naphthyridine metal chelates are reported for
organic light-emitting diodes.[6]
In connection with our research interest of using 1,5-naphthyridine as base and
as well as ligand[7] and its applications,[1–6] we needed a general method to prepare 1,5-
naphthyridine with improved yield and with simplified workup procedure. The most
general method for the synthesis of 1,5-naphthyridines is the Skraup reaction.[8] The
Skraup reaction is a powerful tool for the synthesis of quinolines and naphthyridines.
However, the Skraup reaction generally requires either toxic oxidizing reagents
(arsenic acid)[8b,d] and uses a stoichiometric or excess of oxidizing agents.[4a,8c,g,h,9]
The catalytic methods for the synthesis of these naphthyridines are not explored.[10]
RESULTS AND DISCUSSION
Because of their difficult accessibility and toxicity of these metals, and to avoid
stoichiometric or excess of oxidizing agents, development of less expensive and easily
available catalytic systems for the synthesis of 1,5-naphthyridines is necessary.
Herein, we report a general method for the synthesis of 1,5-naphthyridine using iod-
ine as a less expensive, naturally abundant, benign, sustainable, and result-oriented
protocol with improved yield. We found that only a few reports have been published
so far on the influence of various catalysts and oxidizing agents on the outcome of
1,5-naphthyridines. The careful choice of catalyst, solvent system, and reaction con-
ditions enabled us to develop a convenient protocol for the efficient Skraup reaction
of 3-aminopyridine to get 1,5-naphthyridine with improved yields.
An initial catalytic screening was performed for the reaction of 3-aminopyridine
1, glycerol, and sulfuric acid under various solvents and conditions, and results are
indicated in Table 1. Here, we chose iodine, because it should serve as both catalyst
as well as oxidizing agent. 1,5-Naphthyridine 2 is obtained in good yields using
1–30 mol% of iodine in pure water and 1:1 dioxane–water at 150 ꢀC (Table 1, entries
1–7). At 30 mol% of iodine, 100% conversion was observed with 84% isolated yield of
product 2. When we switched to other solvents such as acetonitrile and methanol, the
reaction was sluggish under these conditions (Table 1, entries 8 and 9).
Likewise, most of the tested catalytic systems are not catalytically active in this
reaction (Table 1, entries 10–16). Note that in entries 17–20, Table 1, pure product
was obtained after completion of the reaction, the solution was made alkaline, and
extraction of the product with suitable solvent and stripping up of the solvent.
Further purification of the crude product by crystallization in n-hexane provided a
white crystalline analytically pure product. We observed better recovery of the pro-
duct by extracting with diethyl ether than with other solvents. These conditions failed

SYNTHESES OF NAPHTHYRIDINES
1845
Table 1. Screening of catalysts and conditions for 1,5-naphthyridine synthesis
Entry
Catalyst (mol%)
Solvent
Time (h)
Product (%)a
1
2
I2 (15)
I2 (25)
I2 (30)
H2O
H2O
22
12
12
20
21
15
15
24
24
24
20
24
20
24
24
20
40
24
24
24
55
49
59
—
63
77
84
—
—
13
43
NDb
47
—
—
40
78
64
62
64
3
H2O
Dioxane
4
I2 (30)
I2 (15)
5
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
CH3CN
6
I2 (25)
I2 (30)
7
8
I2 (30)
I2 (30)
9
CH3OH
10
11
12
13
14
15
16
17c
18c
19c
20c
NaNO2 (10)
NaNO2 (30)
NaNO2 (100)
KI (20)
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
Dioxane=H2O (1:1)
H2O
KIO3 (20)
MnO2 (20)
KMnO4 (20)
I2 (30)
I2 (15)
I2 (20)
I2 (30)
H2O
H2O
aIsolated yields in an average of minimum two runs.
bNot detected because of charring.
cReaction carried out at a 5.0-g scale of 1, and yields reported are crude product.
to provide 1,6- and 1,8-naphthyridines from corresponding 4- and 2-aminopyridines
(Scheme 1).
Initially, the reaction of 3 with 7 was refluxed in ethanol without any catalyst;
trace of product formation was observed (Table 2, entry 1). Iodine (15 mol%) was
Scheme 1. Synthesis of 1,8- (4) and 1,6-naphthyridines (6) under these conditions: (a) glycerol, H2SO4, I2
(30 mol%), dioxane=H2O (1:1), 150 ꢀC, 60 h.

1846
K. C. CHUNAVALA AND S. ADIMURTHY
Table 2. Optimization conditions for the synthesis of 8
Entry
Catalyst (mol%)
Solvent
Time (h)
Product (%)a
1
2
—
I2 (15)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
EtOH
48
48
36
36
24
50
24
24
24
30
36
Traces
17
58
3
InCl3 (5)
InCl3 (10)
InCl3 (15)
InCl3 (15)
FeCl3 (15)
AlCl3 (15)
LaCl3 (15)
InCl3 (15)
InCl3 (15)
4
65
90
5
6
90
68
7
8
55
66
9
10
11
68
95
aIsolated yields of purified product 8.
bReaction carried out at 80 ꢀC.
used as catalyst, and 17% of the desired product 8 was isolated (Table 2, entry 2). Sur-
prisingly, when we used InCl3 (5 mol%) as catalyst in place of iodine, 8 was obtained
in 58% yield (Table 2, entry 3). When the amount of catalyst was increased (10 and
15 mol %) 8 was obtained in good to excellent yield (65% and 90%) respectively
Scheme 2. Proposed mechanism for InCl3-catalyzed synthesis of substituted 1,8-naphthyridines 8.

SYNTHESES OF NAPHTHYRIDINES
1847
Table 3. Synthesis of substituted 1,8-naphthyridines 10
Entry
9
R1
R2
Time (h)
10
Yield (%)a
1
2
3
4
a
b
c
CH3
H
H
CH3
Br
33
48
48
48
a
b
c
86
90
87
83
H
CH3
d
Br
d
aIsolated yields of purified products.
(Table 2, entries 4 and 5). Unlike InCl3, catalytic amounts of other Lewis acids
(15 mol%) gave lower yields (Table 2, entries 7–9).
InCl3 was found to be an efficient catalyst for the regioselective synthesis of
1,8-naphthyridines directly from substituted 2-aminopyridines and ethyl acetoace-
tate under mild conditions. The catalyst can be recovered and recycled up to five
times without loss of catalytic activity and yield. After recovery of the catalyst from
the experimental procedure (general procedures for synthesis of substituted
1,8-naphthyridines 8), the catalyst was recycled for up to five consecutive cycles with
the isolated yield of product 8 ranging from 86 to 90%. Thus, a plausible mechanism
has been proposed for InCl3-catalyzed synthesis of 1,8-naphthyridines (Scheme 2).
However, further investigations are warranted to support this proposal.
Additional reactions of substituted 2-aminopyridine were performed under these
optimized conditions, and results are presented in Table 3.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker 200-MHz Fourier transform
(FT)-NMR DPX-200 in CDCl3 with tetramethylsilane (TMS) as an internal stan-
dard, and [13]C NMR spectra were recorded at 50 MHz. Melting points were
recorded on a Veego capillary instrument and may be uncorrected. Analytical thin-
layer chromatography (TLC) was performed on Aluchrosep silica gel 60=UV254
purchased from Merck with ultraviolet (UV) light. Aminopyridines were purchased
from Spectrochem Mumbai and used as such. Purification of the reaction products
was carried out by column chromatography on basic alumina.
General Procedures for Synthesis of Substituted 1,8-Naphthyridines
(8 as Representative)
To a solution of 1.0 g (10.6 mmol) of 2-aminopyridine 3 and 1.44 g (11.1 mmol,
1.05 eq.) of ethyl acetoacetate 7 in 8.0 mL of ethanol was added 0.351 g (1.59 mmol,

1848
K. C. CHUNAVALA AND S. ADIMURTHY
15 mol%) of InCl3. The reaction mixture was then heated to 100 ꢀC. Reaction was
monitored by gas chromatography–mass spectrometry (GC-MS). After completion
of the reaction, the solvent was removed under reduced pressure, and the crude resi-
due was dissolved in dichloromethane (10 mL) and filtered to recover the catalyst.
The catalyst was further washed with the same solvent (3 ꢁ 2 mL), dried, and
reused.[11] The filtrate containing the product was concentrated and subjected to
column chromatography over basic alumina (ethyl acetate=hexane ¼ 1:9) to afford
pure product 8 (1.53 g, 90% yield) as a white solid, mp 102–104 ꢀC; IR nmax (KBr) ¼
3367, 3203, 2344, 1705, 1632, 1534, 1448, 1187, 1130, 1025, 986, 815, 774, 663 cmꢂ1
.
1H NMR (CDCl3): d(ppm) ¼ 9.03 (d, J ¼ 7 Hz, 1H), 7.74 (t, J ¼ 8.0 & 7.5 Hz, 1H,),
7.6 (d, J ¼ 9 Hz, 1H), 7.1 (t, J ¼ 7 & 6.5 Hz, 1H), 6.3 (s, 1H), 2.4 (s, 3H). 13C NMR
(CDCl3): d(ppm) ¼ 165.2, 157.8, 150.7, 136.2, 127.2, 125.8, 114.5, 103.3, 24.7.
Elemental analysis calcd. for C9H8N2O: C, 67.49; H, 6.43; N, 17.49; Found: C,
67.13, H, 6.43; N, 16.01. LRMS calcd. for C9H8N2O [Na]þ: 183.05; found: 183.13.
Selected Data
4,5-Dimethyl-1,8-naphthyridin-2-ol (10a). White solid, observed melting
point 120–122 ꢀC. IR nmax (KBr) ¼ 3396, 3271, 2357, 1693, 1648, 1529, 1472,
1187, 1038, 992, 818, 759, 681 cmꢂ1. 1H NMR (CDCl3): d(ppm) ¼ 8.93 (d, J ¼ 7.5 Hz,
1H), 7.36 (s, 1H), 6.95 (dd, J ¼ 7.5 Hz, 1H), 6.27 (s, 1H), 2.47 (s, 3H), 2.44 (s, 3H).
13C NMR (CDCl3): d(ppm) ¼ 167.3, 159.7, 152.5, 150.1, 128.3, 125.7, 119.5, 104.2,
26.5, 23.2. Elemental analysis calcd. for C10H10N2O: C, 68.95; H, 5.79; N, 16.08;
found: C, 67.55; H, 5.85; N, 16.30. LRMS calcd. for C10H10N2O [H]þ: 175.09; found:
175.09.
4,6-Dimethyl-1,8-naphthyridin-2-ol (10b). White crystalline solid, observed
melting point 154–155 ꢀC. IR nmax (KBr) ¼ 3424, 3027, 2357, 1695, 1638, 1535, 1443,
1175, 1131, 1047, 993, 835, 700 cmꢂ1. 1H NMR (CDCl3): d(ppm) ¼ 8.84 (s, 1H), 7.60
(dd, J ¼ 9.0 Hz,1H), 7.53 (d, J ¼ 9 Hz, 1H), 6.3 (s, 1H), 2.45 (s, 3H), 2.42 (s, 3H). 13
C
NMR (CDCl3): d(ppm) ¼ 167.5, 166.6, 159.6, 151.5, 141.0, 127.1, 126.5, 104.9, 26.4,
20.1. Elemental analysis calcd. for C10H10N2O: C, 68.95; H, 5.79; N, 16.08; found: C,
68.24; H, 6.12; N, 16.12. LRMS calcd. for C10H10N2O [Na]þ: 197.07; found: 197.20.
6-Bromo-4-methyl-1,8-naphthyridin-2-ol (10c). Light yellowish crystalline
solid, observed melting point 173–174 ꢀC. IR nmax (KBr) ¼ 3621, 3115, 3032, 2991,
1
2362, 1703, 1659, 1519, 1474, 1383, 1170, 1101, 1018, 852, 823, 675 cmꢂ1. H NMR
(CDCl3): d(ppm) ¼ 9.07 (s, 1H), 7.68 (d, J ¼ 9.5 Hz, 1H), 7.40 (d, J ¼ 9 Hz, 1H),
6.29 (s, 1H), 2.39 (s, 3H). 13C NMR (CDCl3): d(ppm) ¼ 165.5, 156.9, 149.3, 139.7,
127.6, 127.0, 110.4, 104.1, 24.89. Elemental analysis calcd. for C9H7BrN2O: C,
45.22; H, 2.95; N, 11.72; found: C, 43.96; H, 2.34; N, 11.46. LRMS calcd. for
C9H7BrN2O [Na]þ: 260.96; found: 260.95.
6-Bromo-4,5-dimethyl-1,8-naphthyridin-2-ol (10d). White crystalline
solid, observed melting point 157–158 ꢀC. IR nmax (KBr) ¼ 3434, 3102, 2924, 2356,
1684, 1632, 1471, 1392, 1163, 1031, 979, 872, 807, 686, 609 cmꢂ1 1H NMR
.
(500 MHz): d(ppm) ¼ 9.15 (s, 1H), 7.43 (s, 1H), 6.2 (s, 1H), 2.51 (s, 3H), 2.43 (s,
3H). 13C NMR (125 MHz): d(ppm) ¼ 167.2, 158.3, 151.1, 149.9, 129.0, 126.5, 116.2,

SYNTHESES OF NAPHTHYRIDINES
1849
104.3, 26.4, 24.3. Elemental analysis calcd. for C10H9BrN2O: C, 47.46; H, 3.58; N,
11.07; found: C, 46.59; H, 3.39; N, 11.05. LRMS calcd. for C10H9BrN2O [Na]þ:
274.98; found: 274.99.
CONCLUSIONS
In summary, we have developed a highly efficient and regioselective method for
the synthesis of 1,5- and 1,8-naphthyridines catalyzed by I2 and InCl3 respectively.
The procedure allows for an easy and practical synthesis of substituted naphthyri-
dines and is especially attractive because of its cheap and easy handling of the cata-
lyst (no sensitivity toward air or moisture). The catalyst can be recovered and reused
efficiently up to five times. This simple procedure offers a very attractive alternative
for the synthesis of motifs that are found in various bioactive molecules.
ACKNOWLEDGMENTS
We thank the Department of Science and Technology, New Delhi, India, for
financial support of this project under the Green Chemistry Task Force Scheme
(No. SR=S5=GC-02A=2006). K. C. is thankful to the Council of Scientific and
Industrial Research, New Delhi, for his fellowship.
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SYNTHESES OF NAPHTHYRIDINES
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10. Unlike quinoline synthesis by catalytic methods [(a) Sridharan, V.; Ribelles, P.; Ramos,
M. T.; Menendez, J. C. Cerium(IV) ammonium nitrate is an excellent, general catalyst
for the Friedlander and Friedlander–Borsche quinoline syntheses: Very efficient access
to the antitumor alkaloid luotonin A. J. Org. Chem. 2009, 74, 5715–5718; (b) Zhang,
X. L.; Wang, Q. Y.; Sheng, S. R.; Wang, Q. Liu, X. L. Efficient Friedlander synthesis
¨
of quinoline derivatives from 2-aminoarylketones and carbonyl compounds mediated
by recyclable PEG-supported sulfonic acid. Synth. Commun. 2009, 39, 3293–3304,]
naphthyridine synthesis is not explored.