Mar-Apr 2006
Methylamination of Some 3-Nitro-1,5-Naphthyridines
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J6,8 = 1,46 Hz, J7,8 = 8.18 Hz, JCH3,NH = 5.0 Hz; ir: 3208 (ꢂꢃ),
1497 (NO2, as), 1329 (NO2, s) cm-1.
EXPERIMENTAL
Anal. Calcd. for C9H8N4O2 (204.19): C, 52.94, H, 3,95, N,
27.44. Found: C, 52.66, H, 3.84, N, 27.15.
Melting points (uncorrected) were determined on a Boetius
1
apparatus. The H nmr spectra were recorded on Tesla BS-587A
Amination of 3-Nitro-1,5-naphthyridines (1a-f) with Methylamine/
Potassium Permanganate.
(80 MHz) and on a Varian Mercury 300 (300 MHz) spectrometers
using TMS as an internal standard; the chemical shifts are given in
ppm (ꢀ); and coupling constants are taken from the expanded
spectra. The infrared spectra were recorded on Bio-Rad FTS-175C
spectrophotometer (in potassium bromide pellets). The mass
spectra (EI) were recorded on LKB GC/MS 9000 spectrometer at
70 eV. The reaction products were monitored by TLC on Merck
Silica gel 60 PF 254. Silica gel (Merck, 230-400 mesh) was used
for column chromatography; preparative thin-layer chroma-
tography (PTLC) was carried out on standard plate (20 x 40).
Quantum-chemical calculations were carried out with PM3
method using MOPAC program (version 6.00).
General Procedure.
To 25 - 30 mL of liquid methylamine 0.1 g (0.46-0.57 mmol)
of 3-nitro-1,5-naphthyridines (1a-f) and 0.2 g of potassium
permanganate were added and the resulting mixture was stirred
at -7 °C for 0.5 -1 h. After evaporation of methylamine ca. 30
mL of water was added to the residue and the mixture was
extracted continuously with chloroform for 20 h. The residue
obtained after evaporation of the solvent from the extract was
worked up in the manner described below.
Methylamination of 3-Nitro-1,5-naphthyridine (1a).
Synthesis of Starting and Reference Compounds.
Compound 1a (0.1 g, 0.57 mmol) was treated according to the
general procedure. The residue was crystallized from methanol
3-Nitro- (1a) [8], 2-deuterio-3-nitro- (1aꢁ) [1], 2-amino-3-
nitro- (1b) [1], 2-chloro-3-nitro- (1c) [1], 2-methylamino-3-
nitro- (1d) [11], 2-ethoxy-3-nitro-1,5-naphthyridine (1e) [12]
were prepared according literature procedures.
to give 0.087
naphthyridine (3a) as orange needles with mp 207-208 °C. The
g (75%) of 4-(methylamino)-3-nitro-1,5-
1
compound showed the identical properties (mp, ir and H nmr)
to those of reference sample.
Synthesis of 2-Hydroxy-3-nitro-1,5- naphthyridine (1f).
Methylamination of 2-Amino- 3-nitro-1,5-naphthyridine (1b).
A solution of 2-amino-1,5-naphthyridine (2.0 g, 13.8 mmol)
in 20 mL acetic anhydride and 20 mL glacial acetic acid was
refluxed for 2 h. A resulting brown solution was cooled and
slowly poured onto ca. 50 g of ice with a small volume of water.
The precipitate was collected by filtration and dried to give 2.37
g (80%) as a light-brown solid. Recrystallization from methanol
afforded 2.12 g (72%) of 2-acetamido-1,5-naphthyridine, cream-
colored crystals mp 210 °C; - ms: m/z (%): 187 (M +, 100), 172
Compound 1b (0.1 g, 0.53 mmol) was treated according to the
general procedure. The residue was crystallized from methanol to
give 0.081
g (70%) of 2-amino-4-methylamino-3-nitro-1,5-
naphthyridine (3b) as orange needles with mp 222-223 °C; ms:
1
m/z (%): 219 (M+, 38), 202 (M+-OH, 100); H nmr (CDCl3): ꢀ
8.44 (dd, 6H), 7.73 (dd, 8H), 7.45 (q, 7H), 6.41 (br.s, NH2), 3.49
(s, CH3, NH), J6,7 = 3.91 Hz, J6,8 = 1,46 Hz, J7,8 = 8.54 Hz; ir: 3433,
3126 (NH2), 3271 (ꢂꢃ), 1527 (NO2,as), 1326 (NO2, s) cm-1.
Anal. Calcd. for C9H9N5O2 (219.19): C, 49.32, H, 4.14, N,
31.95. Found: C, 48.95, H, 3.97, N, 31.57.
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(M+-CH3), 145 (M+-COCH3); H nmr (DMSO-d6): ꢀ 10.97 (s,
NH), 8.88 (dd, 6H), 8.60 - 8.17 (m, 3H, 4H, 8H), 7.74 (q, 7H),
2.19 (s, CH3). J6,8 = 1.46 Hz, J6,7 = 4.15 Hz, J7,8 = 8.54 Hz; ir:
3243 (ꢂꢃ), 3100-3500 (br., H2O), 1675 (C=O) cm-1.
Anal. Calcd. for C10H9N3O•1.5H2O (214.21): C, 56.07, H,
5.65, N, 19.62. Found: C, 56.16, H, 5.66, N, 19.56.
Methylamination of 2-Chloro-3-nitro-1,5-naphthyridine (1c).
Compound 1c (0.1 g, 0.48 mmol) was treated according to the
general procedure. The residue was separated by PTLC using
chlorofom as the eluent. The band obtained was extracted with
chloroform in a Soxhlett apparatus for 4 h. From the first band
(the highest Rf), 0.084 g (76%) of 2,4-bis(methylamino)-3-nitro-
1,5-naphthyridine (3c) was obtained, after the crystallization from
octane as orange needles with mp 182-183 °C; ms: m/z (%): 233
(M+, 46), 216 (M+-OH, 100); 1H nmr (DMSO): ꢀ 8.86 (br.s, NH),
8.43 (dd, 6H), 7.78 (dd, 8H), 7.57 (q, 7H), 7.45 (br.s, NH), 2.94
(d, CH3, NH), 2.88 (d, CH3, NH), J6,7 = 4.10 Hz, J6,8 = 1,54 Hz, J7,8
= 8.46 Hz, JCH3,NH = 5.64 Hz, JCH3,NH = 4.36 Hz; ir: 3392, 3203
(NH), 1528 (NO2, as), 1335 (NO2, s) cm-1.
Anal. Calcd. for C10H11N5O2 (233.2): C, 51.49, H, 4.75, N,
30.03. Found: C, 51.22, H, 4.65, N, 29.93.
The residue from the extracts of the second band (the lowest
Rf) was washed with diethyl ether to give 0.010 g (10%) of 2-
methylamino-3-nitro-1,5-naphthyridine (1d) [11].
A
solution of 2.0 g, (9.3 mmol) of 2-acetamido-1,5-
naphthyridine in 18 mL of fuming nitric acid (d 1.51) and 18 mL
of 35% oleum (sulfuric acid) was heated on a water bath for 4 h.
Pouring the cooled solution onto ca. 120 g of ice gave yellow-
orange crystals. The precipitate was collected by filtration,
washed with cold water and dried. Crystallization from aqueous
methanol (1:1) gave 1.64 g (92%) of 2-hydroxy-3-nitro-1,5-
naphthyridine (1f), yellow needles, mp 273 -275 °C (lit. 272-
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274 °C [7]). The compound proved to be identical (mp, ir, H
nmr) as prepared according to literature procedures [7].
Synthesis of 4-Methylamino-3-nitro-1,5-naphthyridine (3a).
4-Chloro-3-nitro-1,5-naphthyridine (1g) [8] (0.1 g, 0.48
mmol) was dissolved in 20 mL of methanol saturated at 0 °C,
with gaseous methylamine. The solution was kept at room
temp. for 24 h. After cooling, the yellow crystalline
precipitate was collected by filtration, washed with cold
methanol, dried to give 76 mg (78%) of 3a as orange needles
Methylamination of 2-Methylamino-3-nitro-1,5-naphthyridine
(1d).
+
with mp 208-210 °C; ms; m/z (%): 204 (M , 15), 187 (M+-
1
OH, 40); H nmr (DMSO-d6): ꢀ 9,08 (s, 2H), 8,89 (dd, 6H),
Compound 1d (0.1 g, 0.5 mmol) was treated according to the
general procedure. The residue was crystallized from octane to
8.28 (dd, 8H), 7.84 (q, 7H), 3.42 (d, CH3, NH), J6,7 = 3.78 Hz,