7
40
V. Stockmann, S. Primpke, and A. Fiksdahl
˚
Vol 48
apparatus. Flash column chromatography; SiO
0–63 lm.
Pyrido[3,4-c]pyridazin-4(1H)-one (2). To a solution of 5
2
SDS, 60 A,
4-Acetyl-3-iodopyridine (6). The title compound 6 was pre-
pared by a method described in literature [22]. In a mortar, to
amine 5 (100 mg, 0.734 mmol) and water (150 lL) was added
4
(
mL) at 0 C, an ice-cold solution of NaNO (70 mg, 1.01
106 mg, 0.779 mmol) in ethanol (4 mL) and HCl (conc, 2
ꢀ
p-TsOHꢄH O (560 mg, 2.94 mmol). The mixture was ground
2
2
for 2 min before NaNO (152 mg, 2.20 mmol) was added in
2
two portions. The reaction was ground regularly over 10 min
mmol) in water (1 mL) was added dropwise within 20 min.
ꢀ
The reaction mixture was stirred for 1 h and cooled to ꢁ10 C.
with a pestle until TLC showed full conversion of the amine.
KI (366 mg, 2.20 mmol) was added, and the grinding was con-
tinued for 5 min before minor amounts of water (10 ꢃ 100
lL) was added during the next 10 min. Water (3 mL) and then
From an ice-cold solution of NaOH (1.08 g, 27 mmol) in H O
2
(
NaOH) was added drop-wise over 1 h to give pH 8. The reac-
5 mL)/EtOH (10 mL), the required amount (ꢂ24 mmol
ꢀ
tion was kept stirring for 2 h at ꢁ10 C, keeping pH 8–10 by
Na SO3 (10%, 10 mL) were added before extraction with
EtOAc (3 ꢃ 20 mL). The combined extracts were dried over
2
adding additional NaOH/H O/EtOH solution. The remaining
2
NaOH/EtOH/H
reaction was allowed to heat to room temperature before water
15 mL) was added. The aqueous solution was washed with
ether (10 mL) and acidified with HCl (1M) to give pH 4–6.
Extraction with EtOAc (6 ꢃ 20 mL), drying over Na SO
evaporation of solvent and flash chromatography (gradient: 5–
0% MeOH/CH Cl ) afforded 43 mg (38%) of the title com-
2
O solution was added to give pH 14, and the
Na SO and concentrated under reduced pressure to give 140
2
4
mg of brown oil. The crude product was purified by flash
chromatography (EtOAc/pentane (1:1)) to give 130 mg (72%)
of the title compound 6, as an yellow oil, pure by NMR; R
(
f
2
4
,
0
8
.40 (EtOAc/pentane (1:1)); IR 1700, 1393, 1356, 1249, 1010,
1
ꢁ
1
29, 680, 604, 590 cm
; H NMR (400 MHz, CDCl ): d
3
H
1
2
2
9.03 (s, 1H, py-H2), 8.63 (d, J ¼ 4.8 Hz, 1H, py-H6), 7.32 (d,
3
ꢀ
13
); C NMR
pound 2 as a light orange solid, mp 263–264 C, pure by
NMR: R 0.37 (10% MeOH/CH Cl ); IR: 2827, 1601, 1561,
445, 1314, 1081, 881, 853 cm
DMSO-d ): d 13.93 (br s, 1H, NH), 9.10 (d, J ¼ 0.8 Hz, 1H,
J ¼ 4.8 Hz, 1H, py-H5), 2.62 (s, 3H, CH
f
2
2
(
(
100MHz, CDCl ): d 200.5 (C ¼¼ O), 158.9 (py-C2), 151.0
3
C
ꢁ
1
1
1
;
H NMR (400 MHz,
py-C4), 149.3 (py-C6), 121.9 (py-C5), 89.4 (py-C3), 29.4
6
H
3
(CH ); NMR assignments are based on HMBC and HSQC
H8), 8.53 (d, J ¼ 5.6 Hz, 1H, H6), 7.89 (s, 1H, H3), 7.86 (dd,
H
experiments; ESI-HRMS: calcd for [MþH]þ
7 7
C H INO:
1
J ¼ 5.6, 0.8 Hz, 1H, H5); H NMR (400 MHz, CD
3
OD): d
2
47.9567; obsd 247.9581.
9
5
.08 (s, 1H, H8), 8.52 (d, J ¼ 5.2 Hz, 1H, H6), 7.97 (dd, J ¼
1
.2, 1.2 Hz, 1H, H5), 7.92 (s, 1H, H3); H NMR (400 MHz,
D
2
O): d
H
9.16 (s, 1H, H8), 8.53 (d, J ¼ 6.0 Hz, 1H, H6), 8.05
Acknowledgment. Trygve Andreassen, Ph.D., at the NT-faculty
NMR centre at NTNU is acknowledged for his NMR technical
assistance.
13
(
s, 1H, H3), 7.95 (dd, J ¼ 6.0, 0.8 Hz, 1H, H5); C NMR
(
(
100 MHz, DMSO-d ): d 169.7 (C ¼¼ O), 143.0 (py-C6), 142.0
6
C
py-C2), 141.5 (CH ¼¼ N), 136.1 (py-C3), 125.7 (py-C4), 115.7
13
(
1
py-C5); C NMR (100 MHz, CD
3 C
OD): d
174.0, 145.8,
44.8, 144.6, 139.8, 129.2, 119.2; C NMR (100 MHz, D O):
1
3
2
1
5
REFERENCES AND NOTES
dC 174.6, 145.4, 145.2, 143.9, 139.2, 128.8, 118.9; N chemi-
cal shifts were obtained from H- N HMBC experiments (600
MHz, DMSO-d ): d 341.9 (N2), 331.0 (N7), 172.3 (N1);
1
15
[
1] Bakke, J. M.; Hegbom, I.; Øvreeide, K.; Aaby, K. Acta
Chem Scand 1994, 48, 1001.
2] Bakke, J. M.; Ranes, E. Synthesis 1997, 281.
[3] Stockmann, V.; Fiksdahl, A. Tetrahedron 2008, 64, 7626.
4] Stockmann, V.; Eriksen, K. L.; Fiksdahl, A. Tetrahedron
2008, 64, 11180.
[5] Wathen, M. W.; Wathen, L. K. Pat. WO 2004019933,
6
N
NMR assignments are based on HMBC, HSQC, and NOESY
þ
[
experiments; ESI-HRMS: calcd for [MþH]
C H N O:
7 6 3
þ
1
1
48.0505; obsd 148.0505; calcd for [MþNa]
7 5 3
C H N NaO:
[
70.0325; obsd 170.0321.
4
from 4-acetylpyridine (3) as described elsewhere [18], except
-Acetyl-3-nitropyridine (4). Nitropyridine 4 was prepared
2004; Chem Abstr 2004, 140, 229445.
for minor modifications. Dinitrogen pentoxide (DNP) was pre-
pared from dinitrogen tetroxide and ozone [25]. DNP (10.0 g,
[6] Bundy, G. L.; Ciske, F. L.; Genin, M. J.; Heasley, S. E.;
Larsen, S. D.; Lee, B. H.; May, P. D.; Palmer, J. R.; Schnute, M. E.;
Vaillancourt, V. A.; Thorarensen, A.; Wolf, A. J.; Wicnienski, N. A.;
Wilhite, D. Pat. WO 2002004444, 2002; Chem Abstr 2002, 136,
ꢀ
9
added. The solution was placed on an ice bath, and acetylpyri-
2
2.6 mmol) was kept at ꢁ78 C and MeNO (100 mL) was
1
18476.
[7] Lewgowd, W.; Stanczak, A. Arch Pharm (Weinheim Ger)
007, 340, 65.
8] Fischer, J.; Jahn, U.; Schatz, F.; Stammbach, C.; Thiele, K.;
dine 3 (5.60 g, 46.2 mmol) was added drop-wise over 10 min
ꢀ
while stirring. The reaction was stirred for 20 min at 0 C
before an ice-cold solution of NaHSO (14.5 g, 139 mmol) in
2
3
[
H
2
O (100 mL)/MeOH (300 mL) was added. The reaction was
allowed to heat to room temperature and kept stirring over-
night. MeOH was removed under reduced pressure, H O (50
Wagner-Jauregg, T. W.; Zirngibl, L. Pat. US 4204998, 1980; Chem
Abstr 1980, 93, 186162.
2
[
9] White, W. A. Pat. DE 2065719, 1975; Chem Abstr 1975,
mL) was added, and the aqueous solution was extracted with
CH Cl2 (3 ꢃ 80 mL). The combined organic extracts were
83, 58860.
2
[
10] Entwistle, I. D.; Gilkerson, T.; Barton, J. W. Pat. GB
3
washed with HCl (1M, 50 mL), NaHCO (sat, 100 mL), and
2059263, 1981; Chem Abstr 1981, 95, 182265.
water (50 mL), dried over Na
reduced pressure to yield 5.64 g (73%) of the title compound
as a slightly yellow solid, pure by NMR.
-Amino-4-acetylpyridine (5). The title compound 5 was
prepared as described in literature [20] from nitropyridine 4
2 4
SO , and concentrated under
[
11] Leary, J. A.; Lafleur, A. L.; Liber, H. L.; Biemann, K. Anal
Chem 1983, 55, 758.
12] Zhao, X.; Wang, X.; Niu, J.; Wang, J. Huanjing Kexue
4
[
3
Xuebao 2001, 21, 444.
[13] Barton, J. W.; Walker, R. B. Tetrahedron Lett 1975, 569.
[14] Mirsch, B.; Adamek, M.; Schulz, S.; Poskocil, J. Pat. DD
258809, 1988; Chem Abstr 1989, 111, 39382.
1
and Na
mp 91–92 C (lit. [20], 89–91 C).
2
S
2
ꢀ
O
4
in EtOH to afford 69% yield, pure by H NMR;
ꢀ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet