concentrated (end-volume 2.7 mL per g 4) by distillation
under reduced pressure at 40-50 °C. After cooling to 20-
25 °C sodium hydrogen carbonate (0.08 equiv) was added
to adjust pH to 6-8. Glyoxal, 40% (1.07 equiv) was diluted
with water (2.76 g per g of glyoxal, 40%) and added during
75 min to the ethanol solution containing the phenylenedi-
amine 5, at a rate so that 25 °C was maintained. After 1 h
the reaction was complete as judged by TLC, and the
suspension was heated to 50 °C for another 30 min and
gradually cooled to 0-5 °C. The solids were collected by
filtration, washed with ethanol 40% (1.93 mL per g 4), and
dried under reduced pressure at 40 °C.
8-Methylquinoxaline, 3a.18 Following the procedure
described above with 4a (0.1 mol) via 5a, yielded, after
extraction with toluene and removal of solvent, 3a (12.9 g,
90%) as a brown viscous oil. HPLC purity > 95%. 1H NMR
(300 MHz; CDCl3): δ ) 2.94 (s, 3H), 7.72-7.81 (m, 2H),
8.08 (br d, J ) 8.3 Hz, 1H), 8.97 (dd, J ) 4.6 Hz, J ) 1.8
Hz, 2H).
45-60 min to a a well-stirred solution of sulfaminic acid
(0.5-0.8 equiv) in water (10 mL per g of 3) of 5 °C, and
ethyl acetate (1 mL per g of 3), at a rate so that 20 °C was
not exceeded and the gas evolution accompanied by by-
product precipitation could be conveniently controlled.
[Caution: A pressure rise with heaVy emission of nitrous
gases may occur if the rate of addition in this strongly
exothermic hydrolysis is not obserVed]. After completed
addition the suspension was kept at 25 °C for another 1-3
h. The solids were collected by filtration at 5 °C, washed
with water (3.5 mL per g of 3) and dried under reduced
pressure at 50 °C. The crude product was dissolved in ethanol
95% (5-7 mL per g 3) at 60 °C, crystallized during cooling
to 5 °C. The solids were collected by filtration, washed with
cold ethanol 80% (1.5 mL per g of 3) and dried under
reduced pressure at 50 °C. [Alternatively, the nitration
products were isolated by extraction of the hydrolyzed
reaction mixture with ethyl acetate (ca. 10-15 mL per g of
3). The ethyl acetate layer was washed with brine and
concentrated under reduced pressure, and the residue was
recrystallized from ethanol 95%, or alternatively, separated
by chromatography on silica gel (hexane/ethyl acetate).]
8-Methyl-5-nitroquinoxaline, 1a. The nitration procedure
above with 3a (0.012 mol) gave, after extractive work up
and recrystallization from ethanol, 1a (1.76 g, 77%) as
6-Chloro-8-methylquinoxaline, 3b. Following the pro-
cedure described above with 4b (0.08 mol) via 5b, yielded
3b (13.1 g, 92%) as red-brown crystals, mp 81-83 °C.
1
HPLC purity > 97%; Ni < 300 ppm. H NMR (300 MHz;
CDCl3): δ ) 2.62 (s, 3H), 7.41 (br s, 1H), 7.78 (br s, 1H),
8.67 (br s, 2H). Anal. Calcd for C9H7N2Cl: C 60.52; H 3.95;
N 15.68; Cl 19.85. Found: C 60.39; H 3.80; N 15.64; Cl
19.63.
1
slightly yellow crystals, mp 134-136 °C. H NMR (300
MHz; CDCl3): δ ) 2.97 (s, 3H), 7.79 (AB, 1H, J ) 7.7
Hz), 8.22 (AB, 1H, J ) 7.7 Hz), 9.07 (br s, 1H), 9.12 (br s,
1H). MS (EI): m/z (%) 189 (M+, 100), 159 (52), 143 (62),
116 (37), 77, 63. (Note: The crude sample of 1a contained
traces of a dinitro impurity (m/z: 234).)
6-Bromo-8-methylquinoxaline, 3c. Following the pro-
cedure described above, 4c (0.10 mol) via 5c, yielded 3c
(20.6 g, 92%) as slightly brown crystals, mp 89-91 °C.
1
HPLC purity > 98%. H NMR (300 MHz; CDCl3): δ )
2.80 (s, 3H), 7.74 (br s, 1H), 8.15 (br s, 1H), 8.85 (br s,
1H), 8.86 (br s, 1H). MS (EI): m/z (%) 222 (M+, 100), 168
(13), 143 (84), 116, 89, 63. Anal. Calcd for C9H7N2Br: C
48.46; H 3.16; N 12.56; Br 35.82. Found: C 48.26; H 3.16;
N 12.53; Br 35.58.
6-Iodo-8-methylquinoxaline, 3d. Following the proce-
dure described above, 4d (0.028 mol) via 5d, yielded 3d
(6.7 g, 88%) as slightly brown crystals. HPLC purity > 99%.
%. 1H NMR (300 MHz; CDCl3): δ ) 2.78 (s, 3H), 7.92 (s,
1H), 8.40 (s, 1H), 8.63 (s, 1H), 8.87 (s, 1H).
General Procedure for the Mixed Acid Nitration of
Quinoxalines 3. The quinoxaline 3 (1 equiv) was added in
portions to concentrated sulfuric acid (7.4 equiv; density:
1.83) at 25 °C and heated to 50 °C. Cold mixed acid, freshly
prepared at -15 °C from concentrated sulfuric acid (7.4
equiv) and nitric acid, ca. 65% (1.8 equiv; density: 1.39),
was gradually added over 3 h (2/3 in 60 min and 1/3 in 120
min) to the solution of 3 at 50 °C. [Caution: AboVe 60 °C
the decomposition of mixed acid producing brown nitrous
gases is obVious. Throughout the reaction with a weak
nitrogen stream the process Vapors were washed into a series
of gas scrubbers (water/sodium hydroxide) to aVoid emission
of highly toxic and corrosiVe reaction gases.] The reaction
was kept at 50 °C until HPLC or TLC analysis (or both)
indicated complete conversion (1-21 h). The reaction
mixture was cooled to 20 °C and transferred slowly over
6-Chloro-8-methyl-5-nitroquinoxaline, 1b. The general
nitration procedure above with 3b (0.1 mol) gave, after
filtration and recrystallization from ethanol, 1b (18.7 g, 82%)
as slightly yellow crystals, mp 122-123 °C (lit.2 119.5-
120.5 °C). HPLC purity > 99%; Ni < 1 ppm. 1H NMR (300
MHz; CDCl3): δ ) 2.91 (s, 3H), 7.76 (s, 1H), 9.01 (br s,
1H) 9.03 (br s, 1H). MS (EI): m/z (%) 223 (M+, 69), 193
(100), 177 (26), 165 (35), 142 (84), 114, 87, 63. Anal. Calcd
for C9H6N3O2Cl: C 48.34; H 2.70; N 18.79; Cl 15.85; O
14.31. Found: C 48.13; H 2.47; N 18.74; Cl 15.70; O 14.63.
From the mother liquor of 1b by chromatography 6-hy-
droxy-8-methyl-5-nitroquinoxaline, 6, (0.26 g; ca. 1%) was
isolated as a brownish solid, mp 153-154 °C dec. 1H NMR
(400 MHz; DMSO-d6): δ ) 2.73 (s, 3H), 7.99 (s, 1H); 9.09
(br s, 1H), 9.12 (br s, 1H). MS (EI): m/z (%) 212 (M+, 100),
177 (75), 148, 123, 89, 63. (Note: The main amount of 6 is
found in the aqueous filtrate after hydrolysis of the nitration
mixture and is removed, e.g., by extraction with n-butanol).
As a further by-product 5,6-dichloro-8-methylquinoxa-
line, 7b, (0.16 g, ca. 0.2%) was isolated from the mother
1
liquor of a 0.6 mol nitration batch by chromatography. H
NMR (300 MHz; CDCl3): δ ) 2.81 (s, 3H), 7.44 (s, 1H);
8.82 (br s, 1H), 9.00 (br s, 1H), 11.42 (b, 1H). MS (EI):
m/z (%) 205 (M+, 100), 175 (34), 147 (67), 131 (39), 103,
76. (Note: The sample of compound 7b contained as a trace
impurity 5,7-dichloro-8-methyl-5-nitroquinoxaline (8b; m/z
) 257).)
(18) Landquist, J. K. J. Chem. Soc. 1953, 2816-2819.
322
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Vol. 7, No. 3, 2003 / Organic Process Research & Development