# Three-Component One-Pot Synthesis of Novel Benzo[b]1,8-naphthyridines Catalyzed by Bismuth(III) Chloride

Authors: Tangali R. Ravikumar Naik; Halehatty S. Bhojya Naik; Halehatty R. Prakasha Naik; P. J. Bindu
Journal: Research Letters in Organic Chemistry
 (2008)

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## Abstract

A novel and efficient three-component one-pot synthesis of benzo[b]1,8-naphthyridines by 2-amino-4-methylquinoline, aromatic aldehydes, and malononitrile was done. The reaction was catalyzed by an acidic Bismuth(III) chloride, functionalized Bismuth(III) chloride, at room temperature to give various benzo[b]1,8-naphthyridines in high yields. The Bismuth(III) chloride is an environmentally friendly catalyst.


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## Body

## 1. Introduction

One of the most important reactions in organic chemistry
for the formation of carbon—carbon bonds—is
the multicomponent reactions (MCRs) and much effort has been devoted to the development of this
reactions in recent years [1, 2].Among the nitrogen heterocycles,
naphthyridines and their derivatives represent an important class of
organic molecules that attract the interest of both synthetic and medicinal
chemists. Functionalized naphthyridines have found applications as pharmaceuticals,
fungicides, bactericides, herbicides, and insecticides as well as useful
synthetic blocks in the preparation of several alkaloids [3–6]. Many
syntheses of naphthyridines are known, but due to their importance, the
development of new synthetic approaches remains an active research area [7, 8].Various
procedures are available for the synthesis of benzo[b]1,8-naphthyridines.
However, there are several disadvantages associated with these methodologies
including unsatisfactory yields, long conversion times and inflammable organic
solvents. In recent years, we have initiated our efforts on the development of
simple methods for the synthesis of naphthyridines derivatives [9–11]. Hence,
now we report herein a useful, general approach towards the formation of benzo[b]1,8-naphthyridines in one-pot operation (Scheme 1). This
method permits the condensation of aromatic 2-amino-4-methylquinoline 1, aldehyde 2, and malononitrile 3using Lewis acid catalysts under mild
conditions to afford diverse benzo[b]1,8-naphthyridines (4a–h) and is also
amenable to small library production using solid-phase techniques.Scheme 1
The
synthesis of benzo[b]1,8-naphthyridines.In addition, there has been an intense interest in the selection of
different catalysts in development of new methods for MCRs. The utility of
different metal salts such as mercuric salts, lead salts, zinc chloride,
cadmium chloride, and indium chloride, lanthanide compounds, InBr3, ZrCl4 [12, 13], as potential catalyst in variety of
synthetic reactions was recognized in recent years. However, the expensiveness and
toxicity of some metal salts hampers their wide applications in organic
synthesis. On the other hand, in recent years, economically affordable
ecofriendly catalysts received some interest in various organic reactions. The application of some of these
catalysts such as Cu(II) salts [14], Fe(II)/Fe(III) salts
[15], nickel salts, and Bismuth(III) salts [16, 17] as catalysts in organic synthesis, has been investigated extensively. Bismuth
trichloride has received considerable attention as an inexpensive, nontoxic, and
readily available catalyst for various organic transformations, affording the
corresponding products in excellent yields with high selectivity (Scheme 1).Equimolar of various substituted aromatic aldehyde 2 reacted well
with 2-amino-4-methylquinoline 1 and malononitrile 3 in presence
of 10 mol% of BiCl3 catalyst in CH3CN solvent to give the corresponding
substituted naphthyridine 4a-h in 93–97% yields. In
each experiment, molar ratio 1:1:1.5 of the three components 1, 2, and 3 were used as reactants. The method is very simple and it can be used as derivatives
of substituted 2-amino-4-methylquinoline 1, different substituted aromatic
aldehyde 2, and malononitrile 3 to prepare different substituted
naphthyridine derivatives (Table 1).Table 1
One-pot
synthesis of benzo[b]1,8-naphthyridines.
EntryRR1R2ProductaYield(%)b1HHH4a932CH3HH4b953OCH3HH4c954ClHH4d975CH3CH3H4e936HHCH34f957HHOCH34g968HHCl4h96Alla the products were
characterised by IR, H1 NMR, and mass spectra.Yieldsb of isolated products.


## 2. Experimental

Melting points were recorded on an open capillary tube with a Buchi melting point apparatus
and are uncorrected. Elemental analyses were carried out using Perkin-Elmer
24°C CHN-analyzer. IR spectra were recorded on an FT-IR infrared spectrophotometer. H1-NMR spectra were obtained using a 300 MHz on a
Bruker spectrometer (chemical shifts in δ ppm). Mass spectra were recorded on an
LC MS Mass spectrometer.


### 2.1. General Procedure

A mixture of 2-amino-4-methylquinoline (1 mmol), aromatic aldehyde (1.5 mmol),
and malononitriles (1 mmol) in anhydrousCH3CN (15 mL) was stirred
at room temp for 30 minutes. BiCl3 (20 mol%) was added over a period of 20 minutes. The resulting
mixture was stirred for 4-5 hours. After
completion of the reaction as indicated by TLC, the reaction mixture was
diluted with water (30 mL) and extracted with ethyl acetate (3×15mL). The
organic layer was separated, dried (Na2SO4), and concentrated,
and the resulting product was recrystalized to afford pure benzo[b]1,8-naphthyridines 4a. The same procedure was used for the synthesis of 4b–h. The
physicochemical data for the synthesized compounds are as shown below.4a: M.p. 160–163°C. IR (KBr): 3251;
1723; cm−1. H1 NMR (DMSO d6): 1.20 (s, 3H,
CH3), 6.33 (s, 2H, NH2), 6.80–7.40 (m, 5Harom), 7.45 (d, 1H, J=8.5),
7.51 (d, 1H, J=8.5), 7.70–7.72 (m, 2Harom), 21.5,
89.2, 118.5 (CN), 121.4, 124.5, 126.7, 127.5, 127.6, 127.7, 129.4, 129.5,
129.6, 129.5, 129.4, 138.3, 138.8, 146.8, 152.6, 160.6, 162.5 (NH2), mass m/z:310.4b: M.p.
162–165°C. IR
(KBr): 3251; 1723; cm−1. H1 NMR (DMSO d6):
1.26 (s, 3H, CH3), 1.80 (s, 3H, CH3), 6.30 (s, 2H, NH2), 6. 68–7.25 (m,
5Harom), 7.36 (d, 1H, J=8.5), 7.42–7.45 (m, 3Harom), 21.3,
24. 9, 89.0, 118.4 (CN), 121.3, 124.2, 126.8, 127.3, 127.6, 127.4, 129.2,
129.5, 129.3, 129.4, 129.7, 138.0, 138.7, 146.7, 152.4, 160.3, 162.4 (NH2), mass m/z:324.4c: M.p. 171–173°C. IR (KBr): 3251;
1723; cm−1. 1H NMR (DMSO d6): 1.22 (s, 3H,
CH3), 3.10 (s, 3H, OCH3), 6.25 (s, 2H, NH2), 6.70–7.13 (m, 5Harom), 7.26 (d,
1H, J=8.5), 7.33–7.40 (m, 3Harom), 20.8, 25.4, 88.9, 118.3 (CN),
121.5, 124.5, 126.7, 127.6, 127.6, 127.8, 129.4, 129.7, 129.8, 129.8, 129.9,
138.3, 138.5, 146.8, 152.5, 160.4, 162.7 (NH2), mass m/z:340.4d: M.p.
178–180°C. IR
(KBr): 3251; 1723; cm−1. H1 NMR (DMSO d6):
1.15 (s, 3H, CH3), 6.20 (s, 2H, NH2), 6.80–7.36 (m, 5Harom), 7.40 (d, 1H, J=8.5),
7.58–7.60 (m, 3Harom), 21.7, 89.5, 118.2 (CN), 121.3, 124.4, 126.5, 127.3,
127.6, 127.5, 129.5, 129.6, 129.5, 129.5, 129.7, 132.5(Cl), 138.5, 138.8,
146.8, 152.6, 160.5, 162.7 (NH2),
mass m/z:344.4e: M.p. 170–173°C. IR (KBr): 3251;
1723; cm−1. H1 NMR (DMSO d6): 1.23 (s, 3H,
CH3), 1.65 (s, 3H, CH3), 1.93 (s, 3H, CH3), 6.20 (s, 2H, NH2), 6.70–6.92 (m, 5Harom),
7.08 (d, 1H, J=8.5), 7.20–7.30 (m, 3Harom), 20.5,
23. 5, 24. 7, 89.4, 118.4 (CN), 121.5, 124.4, 126.4, 127.5, 127.6, 127.7,
129.4, 129.5, 129.6, 129.8, 129.9, 138.5, 138.6, 146.8, 152.6, 160.5, 162.9 (NH2), mass m/z:338.4f: M.p.
162–164°C. IR
(KBr): 3251; 1723; cm−1. H1 NMR (DMSO d6):
1.16 (s, 3H, CH3), 1.95 (s, 3H, CH3), 6.20 (s, 2H, NH2), 6.66–6.90 (m, 5Harom),
6.95 (d, 1H, J=8.5), 6.98–7.20 (m, 3Harom), 21.6,
25.2, 88.7, 118.0 (CN), 121.5, 124.6, 126.7, 127.5, 127.6, 127.6, 129.5, 129.6,
129.6, 129.7, 129.8, 138.5, 138.7, 146.8, 152.6, 160.5, 162.6 (NH2), mass m/z:324.4g: M.p.
171–173°C. IR
(KBr): 3251; 1723; cm−1. H1 NMR (DMSO d6):
1.21 (s, 3H, CH3), 3.00 (s, 3H, OCH3), 6.20 (s, 2H, NH2), 6.71–7.04 (m,
5Harom), 7.10 (d, 1H, J=8.5), 7.29–7.35 (m, 3Harom), 21.2,
26.3, 89.3, 117.9 (CN), 121.5, 124.2, 126.6, 127.5, 127.5, 127.6, 129.4, 129.4,
129.5, 129.6, 129.6, 138.7, 138.9, 146.7, 152.6, 160.5, 162.7 (NH2), mass m/z:340.4h: M.p. 176–179°C. IR (KBr): 3251;
1723; cm−1. H1 NMR (DMSO d6): 1.15 (s, 3H,
CH3), 6.20 (s, 2H, NH2), 6.75–7.20 (m, 5Harom), 7.32 (d, 1H, J=8.5),
7.35–7.38 (m, 3Harom), 21.7, 89.2, 118.3 (CN), 121.3, 124.2, 126.5, 127.3,
127.4, 127.4, 129.2, 129.3, 129.3, 129.3, 129.3, 131.5(Cl), 138.0, 138.7,
146.7, 152.4, 160.3, 162.2 (NH2),
mass  m/z:344.Elemental Analysis
4a. C20H14N4 Calc: C, 77.40;
H, 4.55; N, 18.05; Found: C, 77.38; H, 4.53; N, 18.03.
4b. C21H16N4 Calc: C, 77.76;
H, 4.97; N, 17.27; Found: C, 77.74; H, 4.96; N, 17.24.
4c. C21H16N4O Calc: C,
74.10; H, 4.74; N, 16.46; Found: C, 74.11; H, 4.72; N, 16.43.
4d. C20H13CIN4 Calc: C, 69.67;
H, 3.80; N, 16.25; Found: C, 69.65; H, 3.78; N, 16.23.
4e. C22H18N4 Calc: C, 78.08;
H, 5.36; N, 16.56; Found: C, 78.06; H, 5.34; N, 16.53.
4f. C21H16N4 Calc: C, 77.76;
H, 4.97; N, 17.27; Found: C, 77.75; H, 4.95; N, 17.25.
4g. C21H16N4O Calc: C,
74.10; H, 4.74; N, 16.46; Found: C, 74.07; H, 4.73; N, 16.47.
4h. C20H13CIN4 Calc: C, 69.67;
H, 3.80; N, 16.25; Found: C, 69.68; H, 3.79; N, 16.24.


## 2.1. General Procedure

A mixture of 2-amino-4-methylquinoline (1 mmol), aromatic aldehyde (1.5 mmol),
and malononitriles (1 mmol) in anhydrousCH3CN (15 mL) was stirred
at room temp for 30 minutes. BiCl3 (20 mol%) was added over a period of 20 minutes. The resulting
mixture was stirred for 4-5 hours. After
completion of the reaction as indicated by TLC, the reaction mixture was
diluted with water (30 mL) and extracted with ethyl acetate (3×15mL). The
organic layer was separated, dried (Na2SO4), and concentrated,
and the resulting product was recrystalized to afford pure benzo[b]1,8-naphthyridines 4a. The same procedure was used for the synthesis of 4b–h. The
physicochemical data for the synthesized compounds are as shown below.4a: M.p. 160–163°C. IR (KBr): 3251;
1723; cm−1. H1 NMR (DMSO d6): 1.20 (s, 3H,
CH3), 6.33 (s, 2H, NH2), 6.80–7.40 (m, 5Harom), 7.45 (d, 1H, J=8.5),
7.51 (d, 1H, J=8.5), 7.70–7.72 (m, 2Harom), 21.5,
89.2, 118.5 (CN), 121.4, 124.5, 126.7, 127.5, 127.6, 127.7, 129.4, 129.5,
129.6, 129.5, 129.4, 138.3, 138.8, 146.8, 152.6, 160.6, 162.5 (NH2), mass m/z:310.4b: M.p.
162–165°C. IR
(KBr): 3251; 1723; cm−1. H1 NMR (DMSO d6):
1.26 (s, 3H, CH3), 1.80 (s, 3H, CH3), 6.30 (s, 2H, NH2), 6. 68–7.25 (m,
5Harom), 7.36 (d, 1H, J=8.5), 7.42–7.45 (m, 3Harom), 21.3,
24. 9, 89.0, 118.4 (CN), 121.3, 124.2, 126.8, 127.3, 127.6, 127.4, 129.2,
129.5, 129.3, 129.4, 129.7, 138.0, 138.7, 146.7, 152.4, 160.3, 162.4 (NH2), mass m/z:324.4c: M.p. 171–173°C. IR (KBr): 3251;
1723; cm−1. 1H NMR (DMSO d6): 1.22 (s, 3H,
CH3), 3.10 (s, 3H, OCH3), 6.25 (s, 2H, NH2), 6.70–7.13 (m, 5Harom), 7.26 (d,
1H, J=8.5), 7.33–7.40 (m, 3Harom), 20.8, 25.4, 88.9, 118.3 (CN),
121.5, 124.5, 126.7, 127.6, 127.6, 127.8, 129.4, 129.7, 129.8, 129.8, 129.9,
138.3, 138.5, 146.8, 152.5, 160.4, 162.7 (NH2), mass m/z:340.4d: M.p.
178–180°C. IR
(KBr): 3251; 1723; cm−1. H1 NMR (DMSO d6):
1.15 (s, 3H, CH3), 6.20 (s, 2H, NH2), 6.80–7.36 (m, 5Harom), 7.40 (d, 1H, J=8.5),
7.58–7.60 (m, 3Harom), 21.7, 89.5, 118.2 (CN), 121.3, 124.4, 126.5, 127.3,
127.6, 127.5, 129.5, 129.6, 129.5, 129.5, 129.7, 132.5(Cl), 138.5, 138.8,
146.8, 152.6, 160.5, 162.7 (NH2),
mass m/z:344.4e: M.p. 170–173°C. IR (KBr): 3251;
1723; cm−1. H1 NMR (DMSO d6): 1.23 (s, 3H,
CH3), 1.65 (s, 3H, CH3), 1.93 (s, 3H, CH3), 6.20 (s, 2H, NH2), 6.70–6.92 (m, 5Harom),
7.08 (d, 1H, J=8.5), 7.20–7.30 (m, 3Harom), 20.5,
23. 5, 24. 7, 89.4, 118.4 (CN), 121.5, 124.4, 126.4, 127.5, 127.6, 127.7,
129.4, 129.5, 129.6, 129.8, 129.9, 138.5, 138.6, 146.8, 152.6, 160.5, 162.9 (NH2), mass m/z:338.4f: M.p.
162–164°C. IR
(KBr): 3251; 1723; cm−1. H1 NMR (DMSO d6):
1.16 (s, 3H, CH3), 1.95 (s, 3H, CH3), 6.20 (s, 2H, NH2), 6.66–6.90 (m, 5Harom),
6.95 (d, 1H, J=8.5), 6.98–7.20 (m, 3Harom), 21.6,
25.2, 88.7, 118.0 (CN), 121.5, 124.6, 126.7, 127.5, 127.6, 127.6, 129.5, 129.6,
129.6, 129.7, 129.8, 138.5, 138.7, 146.8, 152.6, 160.5, 162.6 (NH2), mass m/z:324.4g: M.p.
171–173°C. IR
(KBr): 3251; 1723; cm−1. H1 NMR (DMSO d6):
1.21 (s, 3H, CH3), 3.00 (s, 3H, OCH3), 6.20 (s, 2H, NH2), 6.71–7.04 (m,
5Harom), 7.10 (d, 1H, J=8.5), 7.29–7.35 (m, 3Harom), 21.2,
26.3, 89.3, 117.9 (CN), 121.5, 124.2, 126.6, 127.5, 127.5, 127.6, 129.4, 129.4,
129.5, 129.6, 129.6, 138.7, 138.9, 146.7, 152.6, 160.5, 162.7 (NH2), mass m/z:340.4h: M.p. 176–179°C. IR (KBr): 3251;
1723; cm−1. H1 NMR (DMSO d6): 1.15 (s, 3H,
CH3), 6.20 (s, 2H, NH2), 6.75–7.20 (m, 5Harom), 7.32 (d, 1H, J=8.5),
7.35–7.38 (m, 3Harom), 21.7, 89.2, 118.3 (CN), 121.3, 124.2, 126.5, 127.3,
127.4, 127.4, 129.2, 129.3, 129.3, 129.3, 129.3, 131.5(Cl), 138.0, 138.7,
146.7, 152.4, 160.3, 162.2 (NH2),
mass  m/z:344.Elemental Analysis
4a. C20H14N4 Calc: C, 77.40;
H, 4.55; N, 18.05; Found: C, 77.38; H, 4.53; N, 18.03.
4b. C21H16N4 Calc: C, 77.76;
H, 4.97; N, 17.27; Found: C, 77.74; H, 4.96; N, 17.24.
4c. C21H16N4O Calc: C,
74.10; H, 4.74; N, 16.46; Found: C, 74.11; H, 4.72; N, 16.43.
4d. C20H13CIN4 Calc: C, 69.67;
H, 3.80; N, 16.25; Found: C, 69.65; H, 3.78; N, 16.23.
4e. C22H18N4 Calc: C, 78.08;
H, 5.36; N, 16.56; Found: C, 78.06; H, 5.34; N, 16.53.
4f. C21H16N4 Calc: C, 77.76;
H, 4.97; N, 17.27; Found: C, 77.75; H, 4.95; N, 17.25.
4g. C21H16N4O Calc: C,
74.10; H, 4.74; N, 16.46; Found: C, 74.07; H, 4.73; N, 16.47.
4h. C20H13CIN4 Calc: C, 69.67;
H, 3.80; N, 16.25; Found: C, 69.68; H, 3.79; N, 16.24.


## 3. Conclusion

In summary, we have established a new
methodology, based on a three-component reaction to obtain new substituted
benzo[b]1,8-naphthyridines derivatives catalyzed by BiCl3. The simplicity of this
elegant protocol and accessibility of the starting materials allowed us to
prepare these new benzo[b]1,8-naphthyridines derivatives that should
have wide applicability in heterocyclic and medicinal chemistry.



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*Source: 594826-2008-12-28.xml*