Synthesis of 6-methylbenzo-[b]pyrido[3,2-f][1,6]naphthyridines from 4-chloro-2-methylquinoline

Article abstract of DOI:10.1007/s10593-005-0220-6

4-Chloro-2-methylquinolines in reaction with 3-aminopyridine yielded 4-quinolinamines, which upon cyclisation under Vilsmeier-Haak conditions afforded the title compounds. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0220-6

Chemistry of Heterocyclic Compounds, Vol. 41, No. 6, 2005
SYNTHESIS OF 6-METHYLBENZO-
[b]PYRIDO[3,2-f][1,6]NAPHTHYRIDINES
FROM 4-CHLORO-2-METHYLQUINOLINE
T. Suresh, R. Nandha Kumar, and P. S. Mohan
4-Chloro-2-methylquinolines in reaction with 3-aminopyridine yielded 4-quinolinamines, which upon
cyclisation under Vilsmeier–Haak conditions afforded the title compounds.
Keywords: 3-aminopyridine, 4-chloro-2-methylquinoline, 1,6-naphthyridine, 4-quinolinamine,
Vilsmeier–Haak conditions.
Among heterocyclic compounds 1,6-naphthyridines have received much interest and attention especially
due to their pharmacological activities [1-4]. A recent investigation indicated that 1,6-naphthyridines possess
properties of human cytomegalovirus inhibitors [5]. A number of heterocyclic compounds has been synthesized
using Vilsmeier reagent for cyclization purposes [6-12].
In present work the coupling of 4-haloquinolines with 3-aminopyridine by nucleophilic subsitution
resulted in quinolinamines. The latter were further cyclized by Vilsmeier–Haak reagent.
Cl
N
N
R2
H
N
N
H2N
DMF/POCl3
EtOH
–HCl
R2
R2
+
N
Me
N
R 1
N
N
Me
Me
1
R 1
R 1
2
3
1-3 a R1 = R2 = H; b R1 = Me, R2 = H; c R1 = H, R2 = Me; d R1 = OMe, R2 = H;
e R1 = H, R2 = OMe; f R1 = H, R2 = NO2
The reaction between equimolar amount of 4-chloro-2-methylquinoline and 3-aminopyridine in
anhydrous ethanol for 6.5 h afforded the product 2a (Table 1). Its IR spectrum showed strong absorption bands
1
at 3413 cm-1 due to NH group.The H NMR spectrum revealed a single proton broad singlet at δ 10.9,
accountable for NH proton and a singlet at δ 6.7 was accountable for H(3) proton in quinoline ring. The protons
of methyl group were observed at δ 2.4 as a singlet.
A multiplet in the region δ 7.4-7.9 (9H) accounted for the absorption of aromatic protons. The mass
spectrum and elemental analysis further supported the existing compound 2a. The series of the sequence was
also carried out (Table 2).
__________________________________________________________________________________________
Department of Chemistry, Bharathiar University, Coimbatore-641046, TamilNadu, India; e-mail:
ps_mohanin@yahoo.com, suresh@yahoo.com, rajunandha@rediffmail.com. Published in Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, 901-904, June, 2005. Original article submitted September 20, 2002.
778
0009-3122/05/4106-0778©2005 Springer Science+Business Media, Inc.

TABLE 1. Characteristics of the Synthesized Compounds 2a-f and 3a-f
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
2a
2b
2c
2d
2e
2f
C15H15N3
73.50
75.92
77.12
76.46
77.23
76.46
71.65
71.89
71.44
71.89
62.77
63.82
78.67
78.35
78.34
78.74
79.33
78.74
75.31
74.14
74.56
74.14
65.72
66.20
6.43
6.37
6.93
6.82
6.99
6.82
6.45
6.41
5.76
6.41
5.65
5.00
5.17
4.52.
5.33
4.52
4.97
4.52
5.33
4.76
6.13
4.76
17.81
17.71
16.84
16.72
16.56
16.72
15.33
15.72
16.33
15.72
19.76
19.85
17.76
17.13
16.64
16.20
16.93
16.20
16.27
15.26
15.87
15.26
18.76
19.30
197
>300
163
188
218
120
185
210
193
160
197
183
92
86
82
73
65
55
81
73
65
67
62
58
C16H17N3
C16H17N3
C16H17N3O
C16H17N3O
C15H14N4O2
C16H11N3
3a
3b
3c
3d
3e
3f
C17H13N3
C17H13N3
C17H13N3O
C17H13N3O
C16H10N4O2
3.98
3.47
TABLE 2. IR and 1H NMR spectra of the compounds 2a-f and 3a-f
IR spectrum,
Com-
pound
1H NMR spectrum, δ, ppm
ν, cm-1
2a
2b
2c
2d
2e
2f
3413 (NH),
1699 (C=N)
2.4 (3H, s, CH3); 6.7 (1H, s, C3H); 7.4-7.9 (8H, m, Ar−H);
10.9 (1H, br. s, H)
3320 (NH),
1637 (C=N)
2.4 (6H, s, 2CH3); 6.5 (1H, s, C3H); 7.4-7.9 (8H, m, Ar−H);
10.7 (1H, br. s, NH)
3125 (NH),
1620 (C=N)
2.8 (6H, s, 2CH3); 6.8 (1H, s, C3H); 7.2-7.7 (7H, m, Ar−H);
11.0 (1H, br. s, NH)
3220 (NH),
1690 (C=N)
2.5 (3H, s, CH3); 3.9 (3H, s, OCH3); 6.2 (1H, s, C3H);
7.2-7.6 (7H, m, Ar−H); 10.5 (1H, br. s, NH)
2.2 (3H, s, CH3); 3.5 (3H, s, OCH3); 6.7 (1H, s, C3H);
7.6-8.1 (7H, m, Ar−H); 11.1 (1H, br. s, NH)
2.3 (3H, s, CH3); 5.9 (1H, s, C3H); 6.8-7.5 (7H, m, Ar−H);
9.2 (1H, br. s, NH)
3300 (NH),
1619 (C=N)
3130 (NH),
1576 (C=N)
3a
3b
3c
3d
3e
3f
1680 (C=N),
1620 (C=N)
2.4 (3H, s, CH3); 6.8-7.4 (8H, m, Ar−H)
1613 (C=N),
1588 (C=N)
2.3 (6H, s, 2CH3); 6.5-7.5 (7H, m, Ar−H)
1690 (C=N),
1637 (C=N)
2.1 (6H, s, 2CH3); 7.2-8.1 (7H, m, Ar−H)
1620 (C=N),
1590 (C=N)
2.4 (3H, s, CH3); 3.7 (3H, s, OCH3); 7.2-7.7 (7H, m, Ar−H)
2.4 (3H, s, CH3); 3.9 (3H, s, OCH3); 6.8-7.3 (7H, m, Ar−H)
2.2 (3H, s, CH3); 7.0-7.6 (7H, m, Ar−H)
1630 (C=N),
1648 (C=N)
1678 (C=N),
1565 (C=N)
779

When quinolinamine 2a was treated with Vilsmeier–Haak reagent (phosphoryl chloride and
1
dimethylformamide) the desired product 3a was obtained. The H NMR spectrum indicated the disappearance of
singlet at δ 6.7, thereby proving the loss of H(3) proton due to cyclization. A sharp singlet at δ 2.4 is due to methyl
protons. All the other nine aromatic proton resonances exhibited their absorptions between δ 6.8 and 7.4 as an
unresolved multiplet. The mass spectrum showed the molecular ion peak at m/z 245. The spectral and analytical
data supported the structure of 3a as 6-methylbenzo[b]pyrido[3,2-f][1,6]-naphthyridines.This reaction sequence
leading to 3b-f was confirmed by their spectral and analytical data (Table 1, 2).
EXPERIMENTAL
Thin layer chromatography was used to assess the reactions and the purity of products. Melting points
were determined on a Boetius Microheating Table and Mettler-FP5 Melting apparatus and are uncorrected.
IR spectra were recorded in Shimadzu-820IFT instrument in KBr disc and only noteworthy absorption levels
1
(reciprocal centimeter) are listed. H NMR spectra were recorded in an AMX-400 (400 MHz) spectrometer in
CDCl3 solution; chemical shifts are expressed in ppm (δ) relative TMS, coupling constants (J) in Hz and signal
multiplicities are represented by s (singlet), and m (multiplet). Mass spectra were recorded on a Jeol-D-300 mass
spectrometer. CHN analyses were carried out on a Carlo Erba 106 and Perkin–Elmer 240 analysers.
4-Chloro-2-methylquinolines
1
were prepared by treatment of respective 4-hydroxy-2-
methylquinolines with POCl3 (for the synthesis of 4-hydroxy-2-methylquinolines see [14]).
Synthesis of 4-Quinolinamines. Respective 4-chloro-2-methylquinolines 1a-f (0.002 mol) and
3-aminopyridine (0.002 mol) in anhydrous ethanol (20 ml) were refluxed for about a 6.5 h. After the completion
of reaction, inferred through TLC, the reaction mixture was reduced to about half of its volume and allowed to
cool. The solid separated was collected and recrystallized from CHCl3–MeOH, 1:1, 2a-f.
Synthesis of 1,6-Naphthyridines. To an ice-cooled magnetically stirred solution of quinolinamines 2a-f
(0.001 mol) in DMF (0.003 mol), POCl3 (0.007 mol) was added dropwise. The reaction mixture was heated on a
water bath for 16 h. Then it was poured into crushed ice (200 gm) and neutralized with sodium hydroxide
solution. The solid obtained was filtered off and purified by column chromatography over silica gel using
petroleum ether–ethyl acetate, 80:20 as an eluent to give 3a-f.
The authors thank CSIR, New Delhi for the award of Senior Research Fellowship (R.N.K.) and
Bharathiar University for the award of University Research Fellowship (T. S.). SIF, Indian Institute of Science,
Bangalore and Indian Institute of Chemical Technology, Hyderabad supported the spectral details.
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