Synthesis of alkyl or aryl pyridazinyl ethers

Article abstract of DOI:10.1002/jhet.5570420425

This paper presents the synthesis of some alkyl or aryl pyridazinyl ethers from 2-alkyl-4-halo-5-hydroxy-and 2-alkyl-4,5-dichloropyridazin-3(2H)-ones or 3,6-dichloropyridazine. Reaction of 2-alkyl-4-halo-5-hydroxypyridazin-3(2H)-ones 1 with 1,2-dibromoeth

Full text of DOI:10.1002/jhet.5570420425

May-Jun 2005
Synthesis of Alkyl or Aryl Pyridazinyl Ethers
639
1
1
1
1
Hyun-A Chung, Jeum-Jong Kim, Ho-Kyun Kim, Deok-Heon Kweon, Su-Dong
2
1
1
Cho, Sang-Gyeong Lee, * and Yong-Jin Yoon *
1Department of Chemistry and Research Institute of Natural Sciences, Gyeongsang National University, Chinju
6
60-701, Korea
2
Research Institute of Basic Science Changwon National University, Changwon 641-773, Korea
Received December 21, 2004
This paper presents the synthesis of some alkyl or aryl pyridazinyl ethers from 2-alkyl-4-halo-5-hydroxy-
and 2-alkyl-4,5-dichloropyridazin-3(2H)-ones or 3,6-dichloropyridazine. Reaction of 2-alkyl-4-halo-5-
hydroxypyridazin-3(2H)-ones 1 with 1,2-dibromoethane or 1,3-dibromopropane gave the corresponding
monopyridazin-5-yl ethers 2 and α,ω-[di(pyridazin-5-oxy)]alkanes 3. Treatment of 4 with 4-substituted-
phenol afforded 5-(4-substituted-phenoxy)-2-(4-substituted-phenoxymethyl) derivatives 5. Reaction of 2-
alkyl-4,5-dichloro derivatives 7 with 1 gave the corresponding di(pyridazin-5-yl) ethers 8 in good yields.
Compound 10 was reacted with catechol to give monopyridazin-3-yl ether 11 and/or di(pyridazin-3-yl) ether
1
3
2. Also we described the results for the reaction of 2-alkyl-4-chloro-5-(4-substituted-phenoxy)pyridazin-
(2H)-ones with nucleophiles.
J. Heterocyclic Chem., 42, 639 (2005).
As part of our research program for the development of
novel pyridazin-3(2H)-one derivatives as potential agro-
chemicals, we synthesized some new alkyl or aryl pyri-
dazinyl ethers containing a halogen atom at C-4 position of
pyridazinone ring.
ratio; 1/Br(CH ) )Br/K CO = 1:1:1) gave compounds 2
2 n 2 3
as the main product and 3. The results are summarized in
Table 1. Whereas, treatment of 1a with 1,2-dibromoethane
or 1,3-dibromopropane in the presence of potassium car-
bonate (mole ratio; 1/Br(CH ) )Br/K CO = 2:1:2) also
2
n
2
3
Although some methods for direct synthesis of 4,5-
dialkoxy, and 4(or 5)-monoalkoxypyridazin-3(2H)-one
derivatives from the corresponding 4,5-dihalo derivatives
have been reported, [1-4] they are nonselective for the
alkoxylation of 4,5-dichloropyridazin-3(2H)-ones [4].
Therefore, we selected 5-hydroxy-4-halopyridazin-3(2H)-
ones 1 and 2-chloromethyl-4,5-dichloropyridazin-3(2H)-
one (4) as starting materials for the synthesis of 4-halo-5-
alkoxy derivatives. Compounds 1 [5] and 4 [6] were pre-
pared by literature methods.
gave 3 as the main product. The structures of 2 and 3 were
established by ir, nmr and elemental analyses. The proton
magnetic resonance spectra of 2 showed proton signals of
CH Br (δ 3.59-3.68 ppm range) and CH O (δ 4.35-4.54
2
2
ppm range) involving other proton signals of the proposed
structures, while the proton magnetic resonance spectra of
3 showed proton signals of two CH O (δ 4.11-4.75 ppm
2
range) involving other proton signals of the proposed
structures.
According to the literature [6b], the reaction of 4 with
-
-
Reaction of 1 with 1,2-dibromoethane or 1,3-dibromo-
propane in the presence of potassium carbonate (mole
nucleophiles such as CH O and N selectively afford the
3 3
corresponding 4-chloro-5-substituted-2-methoxy(or

6
40
H.-A Chung, J.-J. Kim, H.-K. Kim, D.-H. Kweon, S.-D. Cho, S.-G. Lee, and Y.-J. Yoon
Vol. 42
Table 1
Yields, Melting Points and Infrared Spectral Data for 2, 3, 5, 8, 11, 12, 14 and 17
-1
Compound
No
Isolated
Yield(%)
Mp (°C)
(Lit. mp)
IR (potassium bromide, cm )
2a
47 [a]
116-117
3110, 3070, 3000, 2890, 1642, 1605, 1450, 1420, 1330, 1299, 1200, 1100, 955, 850, 745
0
.3 [b]
2
b
11 [a]
26 [a]
15 [a]
18 [a]
52 [a]
10 [a]
79-80
118-120
78-80
70-71
82-84
3130, 3100, 3000, 2900, 1660, 1620, 1460, 1430, 1340, 1300, 1218, 1120, 1000, 880, 780
3070, 2980, 2900, 1650, 1605, 1420, 1320, 1300, 1200, 1100, 840
3120, 3060, 2960, 1645, 1610, 1398, 1330, 1305, 1215, 1102, 1000, 880
3075, 2999, 1650, 1420, 1358, 1320, 1282, 1200, 1105, 990, 890, 850
3100, 3060, 3000, 2930, 1660, 1618, 1420, 1400, 1330, 1285, 1220, 1100, 880, 738
3090, 3000, 2955, 2890, 1640, 1610, 1420, 1365, 1320, 1282, 1195, 1102, 905, 860, 760
2
c
2d
2
e
2
f
3
a
145-146
4
0 [b]
3
b
27 [a]
17 [a]
13 [a]
11 [a]
108-109
157-158
188-190
225-228
3140, 3080, 2950, 2880, 1650, 1600, 1410, 1370, 1315, 1280, 1190, 1100, 1030, 890, 860
2998, 2900, 1660, 1610, 1480, 1420, 1350, 1320, 1280, 1200, 1100, 999, 858, 780, 760
3130, 3100, 2999, 2930, 1655, 1610, 1403, 1340, 1300, 1218, 1110, 1030, 880
3070, 3000, 2970, 1640, 1618, 1505, 1400, 1380, 1200, 1090, 860
3
c
3d
3
e
6
7 [b]
3
f
20 [a]
98
81
81
77
198-200
76-78
155-156
133-135
177-179
3150, 3100, 2999, 1660, 1620, 1420, 1310, 1198, 1100, 1038, 878, 680
5a
3090, 3000, 1689, 1605, 1507, 1400, 1290, 1235, 1180, 1170, 1085, 1050, 1030, 760
3100, 3070, 2980, 2930, 1670, 1605, 1495, 1380, 1278, 1232, 1220, 1090, 1040, 840, 820
3060, 3000, 2250, 1680, 1500, 1460, 1420, 1385, 1280, 1230, 1180, 1030, 850
3140, 3100, 2950, 2900, 1690, 1630, 1605, 1540, 1520, 1368, 1330, 1290, 1240, 1122,
5b
5c
5d
1
030, 880
5
e
88
72
82
83
87 [a]
10 [a]
73-75
3100, 3045, 3000, 2940, 2870, 1665, 1525, 1402, 1300, 1265, 1222, 1050, 860, 802, 765
3070, 3002, 2952, 1662, 1610, 1405, 1303, 1270, 1190, 1100, 860
3070, 2960, 2870, 1655, 1600, 1380, 1310, 1265, 1190, 1095
3070, 3050, 2975, 1665, 1630, 1600, 1405, 1310, 1260, 1090, 880
3500-2900(br), 1620, 1600, 1520, 1445, 1300, 1240, 1160, 1110, 1100, 860, 760
3150, 3075, 1585, 1500, 1419, 1300, 1190, 1150, 860, 760
8a
148-149
133-134
177-179
148-150
166-168
8b
8c
1
1
1
2
8
8 [b]
86 [c]
6 [d]
4 [e]
89 [f]
4 [g]
1
1
4a
4b
154-155
(154-155)
[8]
99-100
(99-100)
3125, 3070, 3020, 2990, 1645, 1610, 1400, 1332, 1300, 1221, 1105, 962, 880
8
9
3140, 3090, 3025, 2990, 1658, 1620, 1489, 1465, 1428, 1340, 1300, 1200, 1120, 970, 870
2
[5a]
1
4c
52 [h]
74
109-110
3100, 3060, 3000, 2955, 2900, 1650, 1605, 1468, 1440, 1365, 1275, 1210, 1210, 1180,
1100, 959, 820
(
[
109-110)
5a]
1
7
84-85
3100, 3045, 3000, 2900, 2140, 1639, 1415, 1362, 1320, 1300, 1225, 1140, 1015, 980, 855
[
[
a] Method A in Scheme 4; [b] Method B in Scheme 4; [c] From compound 13a; [d] From compound 13b; [e] From compound 13c.
f] From compound 13d; [g] From compound 17; [h] From compound 13e.
azido)methyl derivatives. Therefore, we attempted the syn-
thesis of 4-chloro-5-phenoxy-2-phenoxymethylpyridazin-
gave only compounds 5 in good yield instead of 4,5-di(4-
substituted-phenyl)-2-chloromethyl derivatives 6.
3
(2H)-one 5 from 4. Reaction of 4 with p-substituted-phe-
The structures of 5 were established by ir, nmr and ele-
mental analyses. The proton magnetic resonance spectra of
nol in the presence of potassium carbonate in acetonitrile

May-Jun 2005
Synthesis of Alkyl or Aryl Pyridazinyl Ethers
641
5
showed protons signals of CH O at the N-2 position in
Reaction of 3,6-dichloropyridazine (10) [7] with catechol
2
the δ 5.95-6.17 ppm range as singlet, as well as other
proton signals corresponding to the proposed structures.
Condensation of 1 with 7 in the presence of potassium
carbonate in dimethylsulfoxide furnished the correspond-
ing dipyridazinyl ethers 8 in good yields. The formation of
in the presence of potassium carbonate in acetonitrile (mole
ratio; 10/catechol/K CO = 1:1:1) also afforded 11 in 87%
2
3
yield and 12 in 10% yield. Whereas, treatment of 10 with
catechol in the presence of potassium carbonate in acetoni-
trile (mole ratio; 10/catechol/K CO = 2:1:2) afforded only
2
3
9
by the intermolecular reaction of 1, however, was not
12 in 88% yield. The structures of 11 and 12 were estab-
lished by ir, nmr and elemental analyses. The infrared spec-
trum of 11 showed an absorption band of OH (3500-2900
cm ), whereas that of 12 did not show the absorption band
of OH. The proton magnetic resonance spectrum of 11
showed the proton signal of OH at δ 9.55 ppm.
We also attempted the synthesis of 4-methoxy-5-(4-sub-
stituted-phenyl) derivatives 15 from 13. Methoxylation of
13 [8] with potassium carbonate/methanol system gave
only the corresponding 4-chloro-5-methoxy derivatives 14
detected under the same condition. The structures of 8
were established by ir, nmr and elemental analyses. The
proton magnetic resonance spectra of 8 revealed the proton
signal of C-6 in the δ 7.60-7.66 ppm range, as well as other
protons signals corresponding to the proposed structures.
The carbon-13 magnetic resonance spectra of 8 showed
carbon signals of the carbonyl at C-3 (for 8a: δ 158.1; for
-1
8
b: δ 181.3; for 8c: δ 157.8 ppm), as well as other carbons
signals corresponding to the proposed structures.
Table 2
1H Nmr Spectral Data for 2, 3, 5, 8, 11, 12, 14 and 17
Compound
No
Solvent [a]
1H Nmr (δ, ppm) [b]
2
2
2
2
2
2
3
3
3
3
3
3
5
5
5
5
5
8
8
8
a
b
c
d
e
f
a
b
c
d
e
f
a
b
c
d
e
a
b
c
C
C
C
C
C
C
C
C
D
D
D
D
C
C
C
C+D
C
C
1.30(t, 3H, J = 7.2), 3.60 (t, 2H, J = 6.2), 4.17 (q, 2H, J = 7.2), 4.47(t, 2H, J = 6.2), 7.70(s, 1H)
0.95(t, 3H, J = 7.5), 1.82(m, 2H), 3.68(t, 2H, J = 6.6), 4.15(t, 2H, J = 7.5), 4.55(t, 2H, J = 6.6), 7.77(s, 1H)
0.95(t, 3H, J = 7.5), 1.82(q, 2H, J = 7.5), 3.68(t, 2H, J = 6.3), 4.16 (t, 2H, J = 7.5), 4.54(t, 2H, J = 6.3), 7.67(s, 1H)
2.29(m, 2H), 3.65(t, 2H, J = 6.5), 3.69(s, 3H), 4.45(t, 2H, J = 6.5), 8.23(s, 1H)
1.37(t, 3H, J = 7.2), 2.38(t, 2H, J = 6.0), 3.63(t, 2H, J = 6.0), 4.25(q, 2H, J = 7.2), 4.39(t, 2H, J = 6.0), 7.8(s, 1H)
2.34(m, 2H), 3.59(t, 2H, J = 7.2), 4.35(t, 2H, J = 7.2), 5.33(s, 2H), 7.35(m, 5H), 7.80(s, 1H)
1.37(t, 6H, J = 7.2), 4.24(q, 4H, J = 7.2), 4.66(s, 4H), 7.90(s, 2H)
0.94(t, 6H, J = 7.5, 7.0), 1.82(m, 4H), 4.15(t, 2H, J = 7.5, 7.0), 4.66(s, 4H), 7.89(s, 2H)
0.86(t, 6H, J = 7.5), 1.71(m, 4H), 4.06(t, 2H, J= 7.5), 4.75(s, 4H), 8.18(s, 2H)
2.24(m, 2H), 3.68(s, 6H), 4.49(t, 4H, J = 6.2), 8.21(s, 2H)
1.25(t, 6H, J = 7.1), 2.25(t, 2H, J = 6.0), 4.11(m, 4H), 4.51(t, 4H, J = 7.1), 8.26(s, 2H)
2.24(m, 2H), 4.50(t, 4H, J = 6.0), 5.28(s, 4H), 7.30(m, 10H), 8.29(s, 2H)
6.05(s, 2H), 7.44(m, 10H), 8.25(s, 1H)
6.01(s, 2H), 7.22(m, 8H), 7.52(s, 1H)
6.11(s, 2H), 7.20(m, 4H), 7.61(t, 2H, J = 1.9), 7.62(s, 1H), 7.76(t, 2H, J = 1.9)
6.17(s, 2H), 7.26(m, 4H), 7.74(s, 1H), 8.21(s, 2H, J = 9.2), 8.33(d, 2H, J = 9.2)
3.75(s, 3H), 3.82(s, 3H), 5.95(s, 2H), 6.92(m, 8H), 7.47(s, 1H)
1.41(t, 6H, J = 7.0), 4.29(m, 4H), 7.66(s, 2H)
0.86(t, 6H, J = 7.2), 1.72(m, 4H), 4.06(t, 4H, J = 7.2), 8.19 (s, 2H)
5.35(s, 4H), 7.38(m, 10H), 7.60(s, 2H)
D
C
1
1
2
4a
4b
4c
7
D
C
C
D
D
C
6.69(m, 4H), 7.32(d, 1H, J = 9.5), 7.71(d, 1H, J = 9.5), 9.55(bs, 1H)
7.01(d, 2H, J = 9.0), 7.23(m, 4H), 7.36(d, 2H, J = 9.0)
3.84(s, 3H), 4.09(s, 3H), 7.80(s, 1H)
1.40(t, 3H, J = 7.2), 4.10(s, 3H), 4.20(q, 2H, J = 7.2), 7.80(s, 1H)
1.28(d, 6H, J = 6.0), 4.08(s, 3H), 5.14(m, 1H), 8.31(s, 1H)
1.37(t, 3H, J = 7.2), 4.23(q, 2H, J = 7.2), 7.62(s, 1H)
1
1
1
1
1
[
a] Solvent: C=CDCl , D=DMSO-d ; [b] Abbreviations used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, J = Hz unit.
3 6

642
H.-A Chung, J.-J. Kim, H.-K. Kim, D.-H. Kweon, S.-D. Cho, S.-G. Lee, and Y.-J. Yoon
Vol. 42
instead of compound 15. The alkyl groups at the N-2 posi-
tion of pyridazin-3(2H)-one has an effect on the methoxyla-
tion of 13 based on our results. Compound 16 [8] was also
Further work is under way in our laboratory including
the biological characterization, other chemical transfor-
mation of new derivatives and the regioselective function-
alization using 5-azido or 5-phenoxy derivatives.
treated with NaN /NH Cl in dimethylformamide to give 5-
3
4
azido-4-chloro derivative 17 instead of the 4-azido-5-(4-
cyanophenyl) derivative. Treatment of 17 with potassium
carbonate/methanol also gave the corresponding 4-chloro-
EXPERIMENTAL
5
-methoxy derivative 14b instead of the 4-methoxy-5-
TLC was performed on silica gel (60 F2 Merck). The
spots were located by UV light. Open-bed chromatography
was carried out on silica gel (70 ~ 230 mesh, Merck) using
gravity flow. The column was packed as slurries with the
54
azido derivative. The structures of 14 and 17 were estab-
lished by ir, nmr and elemental analyses. And compounds
14 and 17 were also identical to authentic compounds.
Finally, 2-Alkyl-4-halo-5-hydroxypyridazin-3(2H)-
ones 1 proved to be useful precursors for the synthesis
-halo-5-alkoxy or aryloxypyridazin-3(2H)-ones. The
conversion of 5-phenoxy or azido derivatives to 5-azido
or methoxy derivatives may also be useful for the
regioselective functionalization.
elution solvent. Melting points were determined with a capil-
1
13
lary apparatus and uncorrected. H and C NMR spectra
were recorded on a 300 MHz spectrometer with chemical
shift values reported in δ units (ppm) relative to an internal
standard (TMS). IR spectra were obtained on an IR spec-
trophotometer. Elemental analyses were performed with a
Perkin Elmer 240C.
4

May-Jun 2005
Synthesis of Alkyl or Aryl Pyridazinyl Ethers
643
Table 3
13
C Nmr Spectral Data for 2, 3, 5, 8, 11, 12, 14 and 17
Compound
No
Solvent [a]
1H Nmr (δ, ppm)
2
2
2
2
2
2
3
3
3
3
3
3
5
5
5
5
5
8
8
8
a
b
c
d
e
f
a
b
c
d
e
f
a
b
c
d
e
a
b
c
C
C
C
C
C
C
C
C
D
D
D
D
C
C
C
C+D
C
C
13.9, 28.3, 48.4, 70.5, 118.5, 127.7, 154.2, 158.7
11.4, 22.0, 28.3, 54.6, 70.5, 118.5, 127.5, 154.1, 158.9
11.1, 21.7, 27.8, 54.4, 70.1, 109.6, 126.6, 155.7, 158.8
30.3, 31.7, 68.4, 114.6, 127.4, 127.7, 154.4, 157.6
13.5, 29.0, 32.0, 47.9, 67.9, 117.4, 126.8, 154.2, 158.4
28.9, 32.0, 55.9, 68.0, 117.6, 127.2, 128.1, 128.6, 129.0, 135.7, 154.2, 158.5
13.5, 47.9, 69.0, 118.1, 127.3, 154.0, 158.2
11.4, 22.0, 54.6, 69.3, 118.4, 127.5, 154.3, 158.8
10.8, 21.2, 53.2, 69.0, 107.0, 127.9, 156.2, 157.8
29.5, 41.2, 66.5, 117.6, 126.9, 154.7, 159.1
13.3, 28.5, 46.8, 66.9, 114.7, 127.9, 154.3, 157.1
29.0, 55.2, 67.5, 99.4, 115.2, 128.0, 128.3, 128.9, 136.8, 154.9, 157.9
78.2, 116.7, 120.4, 120.7, 123.2, 126.9, 130.3, 131.0, 131.2, 154.0, 154.3, 157.2, 159.3
77.9, 117.6, 120.8, 120.9, 127.7, 129.6, 130.4, 130.7, 131.7, 152.0, 153.2, 155.2, 158.6
77.3, 106.1, 109.7, 116.5, 117.7, 118.7, 119.3, 123.4, 131.6, 134.2, 134.8, 152.1, 156.9, 158.4, 159.8
77.9, 116.1, 116.3, 119.1, 123.8, 126.2, 126.7, 132.2, 142.9, 145.2, 152.3, 158.6, 161.8
55.6, 55.7, 78.8, 114.7, 115.6, 117.7, 118.9, 121.2, 129.8, 146.7, 150.6, 154.2, 155.2, 157.8, 158.7
13.7, 48.8, 123.1, 129.8, 150.7, 158.1
D
C
D
C
34.4, 44.6, 77.3, 144.8, 154.0, 174.3, 181.3
56.5, 123.0, 128.5, 129.0, 129.3, 129.6, 135.0, 150.3, 157.8
117.5, 119.9, 120.8, 123.1, 127.0, 132.4, 140.8, 149.2, 151.7, 165.2
119.9, 123.6, 127.5, 132.0, 145.2, 152.9, 164.9
41.2, 58.0, 117.0, 126.3, 155.4, 159.2
13.5, 47.8, 57.6, 116.7, 126.1, 154.9, 158.4
1
1
1
1
1
1
1
2
4a
4b
4c
7
C
D
D
C
21.0, 50.7, 57.5, 116.4, 125.9, 154.4, 158.4
13.4, 48.1, 122.7, 129.3, 139.1, 156.9
[
a] Solvent: C=CDCl , D=DMSO-d .
3 6
Table 4
Elemental Analysis of 2, 3, 5, 8, 11, 12, 14 and 17.
Table 4 (continued)
Compound
No
Molecular
Formula
Calcd./Found(%)
H
Compound
No
Molecular
Formula
Calcd./Found(%)
H
C
N
C
N
5
b
C
C
C
C
C
C
C
C
C
C
C
C
C
17
19
17
H
H
H
H
H
H
H
H
H
11
11
11
N
N
N
N
N
N
N
2
4
4
O
O
O
O
O
O
O
3
3
7
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3
51.35
1.46
60.25
0.29
48.76
8.97
2.79
2.82
2.93
2.99
2.65
2.69
4.41
4.48
3.65
3.69
4.49
4.53
3.54
3.61
3.17
3.21
2.41
2.45
4.04
4.12
4.81
4.90
2.92
2.99
3.03
3.11
7.04
7.20
2
a
C
C
C
C
C
C
C
C
C
C
C
C
C
8
9
9
8
9
H
H
H
H
H
10
12
12
10
12
N
N
N
N
N
2
2
2
2
2
O
O
O
O
O
2
2
2
2
2
BrCl
BrCl
34.13
4.08
36.57
6.44
31.79
2.00
34.13
4.01
36.57
6.50
47.02
7.12
44.82
4.88
47.65
7.70
39.05
9.09
43.23
3.31
46.29
6.12
58.49
8.51
62.11
2.17
3.58
3.51
4.09
4.01
3.56
3.68
3.58
3.66
4.09
4.19
3.95
4.01
4.30
4.33
5.00
5.01
4.10
4.13
3.91
4.01
4.66
4.43
4.32
4.39
3.99
4.02
9.95
9.89
9.48
9.37
8.24
8.22
9.95
10.01
9.48
9.29
5
3
5c
14.79
14.81
13.38
13.43
7.21
2b
6
3
5d
2
c
Br
2
4
3
2d
BrCl
BrCl
5e
8a
19
12
14
22
10
17
12
16
16
2
4
4
4
5
3
3
3
58.69
58.72
43.52
43.66
46.81
46.90
58.04
58.11
53.95
53.98
50.17
50.21
41.28
41.31
44.58
44.61
41.76
41.82
36.10
36.33
3
7.28
2
e
2
2
2
16.92
16.97
15.60
15.63
12.31
12.44
12.58
12.64
16.72
16.80
16.05
16.12
14.85
14.92
16.23
16.31
35.09
35.13
3
2
f
14
14
16
16
13
15
25
17
H
14
16
20
20
14
18
22
13
N
N
N
N
N
N
N
N
2
4
4
4
4
4
4
2
O
O
O
O
O
O
O
O
2
4
4
4
4
4
4
3
BrCl
7.83
7.79
8b
4
3a
H
H
H
H
H
H
H
Cl
2
2
14.93
14.79
13.89
13.90
11.38
11.39
15.51
15.55
14.39
14.16
10.91
10.98
8.52
8c
4
3b
Cl
11
7
N
2
O
O
2
2
Cl
Cl
4
3
c
Br
2
12
14
8
N
4
2
3
3d
Cl
2
Cl
2
Cl
2
Cl
14a
14b
14c
17
6
7
6
6
H
7
N
2
2
2
5
O
O
O
2
2
2
Cl
Cl
Cl
4
3
e
H
9
5
6
N
N
N
4
3
f
H
H
5
5a
OCl
6
8.60

644
H.-A Chung, J.-J. Kim, H.-K. Kim, D.-H. Kweon, S.-D. Cho, S.-G. Lee, and Y.-J. Yoon
Vol. 42
4
-Chloro-2-ethyl-5-(2-bromoethoxy)pyridazin-3(2H)-one (2a)
and 1,2-Bis[4-chloro-2-ethyl-3-oxopyridazin-5-yl]oxy]ethane
3a).
rated under reduced pressure to give 3b in 27% yield (1.7 g,
recrystallization solvent: diethyl ether/n-hexane = 1:2, v/v).
(
4
-Bromo-2-propyl-5-(2-bromoethoxy)pyridazin-3(2H)-one (2c)
and 1,2-Bis[4-bromo-2-propyl-3-oxopyridazin-5-yl]oxy]ethane
3c).
Method A.
(
A mixture of 1a (2.1 g, 12 mmoles), 1,2-dibromoethane (2.16
g, 12 mmoles), potassium carbonate (1.66 g, 12 mmoles) and
dimethylformamide (50 mL) was stirred at room temperature for
Method A.
A mixture of 1c (2.88 g, 12 mmoles), 1,2-dibromoethane (2.16
g, 12 mmoles), potassium carbonate (1.66 g, 12 mmoles) and
dimethylformamide (20 mL) was stirred for 54 hours at 35-40
2
4 hours. The mixture was poured into water (200 mL) with stir-
ring. After extracting with chloroform (150 mL) the products,
chloroform solution was washed with water (200 mL x 5) and
dried over anhydrous magnesium sulfate. After evaporating the
solvent under reduced pressure, the resulting residue was applied
to the top of an open-bed silica gel column (2.4 x 5 cm). The col-
°
C. After cooling to room temperature, the mixture was poured
into water (200 mL) with stirring. After extracting with chloro-
form (50 mL) the products, chloroform solution was washed with
water (200 mL x 5) and dried over anhydrous magnesium sulfate.
After co-evaporating silica gel (4 g) under reduced pressure, the
resulting residue was applied to the top of an open-bed silica gel
column (2.4 x 10 cm). The column was eluted with chloroform.
umn was eluted with chloroform. Fractions containing 2a (R =
f
0
.3 CHCl /diethyl ether = 9.5:0.5, v/v) were combined and evap-
3
orated under reduced pressure to give 2a in 47% yield (3 g,
recrystallization solvent: diethyl ether/n-hexane = 1:3, v/v).
Fractions containing 3a (R = 0.05 CHCl /diethyl ether = 9.5:0.5,
v/v) were combined and evaporated under reduced pressure to
give 3a in 10% yield (0.9 g, recrystallization solvent: diethyl
ether).
Fractions containing 2c (R = 0.54 CHCl /diethyl ether = 9.5:0.5,
f
3
f
3
v/v) were combined and evaporated under reduced pressure to
give 2c in 26% yield (1.1 g, recrystallization solvent: n-hexane).
Fractions containing 3c (R = 0.18 CHCl /diethyl ether = 9.5:0.5,
f
3
v/v) were combined and evaporated under reduced pressure to
Method B.
give 3c in 17% yield (1.1 g).
A mixture of 1a (1 g, 5.75 mmoles), 1,2-dibromoethane (0.25
g, 2.87 mmoles), potassium carbonate (0.79 g, 5.75 mmoles) and
dimethylformamide (15 mL) was stirred at room temperature for
4-Chloro-2-methyl-5-(3-bromopropyloxy)pyridazin-3(2H)-one
(2d) and 1,3-Bis[4-chloro-2-methyl-3-oxopyridazin-5-yl]oxy]-
propane (3d).
4
5 hours. The mixture was poured into water (200 mL) with stir-
Method A.
ring. After extracting with chloroform (50 mL) the products,
chloroform solution was washed with water (100 mL x 5) and
dried over anhydrous magnesium sulfate. After evaporating the
solvent under reduced pressure, the resulting residue was applied
to the top of an open-bed silica gel column (2.4 x 5 cm). The col-
A mixture of 1d (3 g, 19 mmoles), 1,3-dibromopropane (3.8 g,
19 mmoles), potassium carbonate (2.63 g, 19 mmoles) and
dimethylformamide (20 mL) was stirred for 77 hours at 40-50
°C. After cooling to room temperature, the mixture was poured
into water (150 mL) with stirring. After extracting with chloro-
form (50 mL x 3) the products, chloroform solution was washed
with water (200 mL x 5) and dried over anhydrous magnesium
sulfate. After evaporating the solvent under reduced pressure, the
resulting residue was applied to the top of an open-bed silica gel
column (2.4 x 10 cm). The column was eluted with chloroform.
umn was eluted with chloroform. Fractions containing 2a (R =
f
0
.3 CHCl /diethyl ether = 9.5:0.5, v/v) were combined and evap-
3
orated under reduced pressure to give 2a in 0.3% yield (0.01 g,
recrystallization solvent: diethyl ether/n-hexane = 1:3, v/v).
Fractions containing 3a (Rf = 0.05 CHCl /diethyl ether =
3
9
.5:0.5, v/v) were combined and evaporated under reduced pres-
sure to give 3a in 40% yield (0.9 g, recrystallization solvent:
Fractions containing 2d (R = 0.53 CHCl /diethyl ether = 9.5:0.5,
f 3
diethyl ether).
v/v) were combined and evaporated under reduced pressure to
give 2d in 15% yield (1.5 g, recrystallization solvent: chloro-
4
-Chloro-2-propyl-5-(2-bromoethoxy)pyridazin-3(2H)-one (2b)
and 1,2-Bis[4-chloro-2-propyl-3-oxopyridazin-5-yl]oxy]ethane
3b).
form/n-hexane = 1:5, v/v). Fractions containing 3d (R = 0.14
f
CHCl /diethyl ether = 9.5:0.5, v/v) were combined and evapo-
3
(
rated under reduced pressure to give 3d in 13% yield (1.8 g).
Method C.
4
-Chloro-2-ethyl-5-(3-bromopropyloxy)pyridazin-3(2H)-one
A mixture of 1b (1.13 g, 6 mmoles), 1,2-dibromoethane (2.16
g, 12 mmoles), potassium carbonate (1.66 g, 12 mmoles) and
dimethylformamide (20 mL) was stirred for 6 days at 50-60 °C.
After cooling to room temperature, the mixture was poured into
water (100 mL) with stirring. After extracting with chloroform
(2e) and 1,3-Bis[4-chloro-2-ethyl-3-oxopyridazin-5-yl]oxy]-
propane (3e).
Method A.
A mixture of 1a (5 g, 29 mmoles), 1,3-dibromopropane (7 g,
29 mmoles), potassium carbonate (4.01 g, 29 mmoles) and ace-
tonitrile (120 mL) was refluxed for 24 hours. After cooling to
room temperature, the mixture was filtered. After evaporating the
solvent under reduced pressure, the resulting residue was applied
to the top of an open-bed silica gel column (2.4 x 20cm). The col-
(
100 mL) the products, chloroform solution was washed with
water (200 mL x 5) and dried over anhydrous magnesium sulfate.
After evaporating the solvent under reduced pressure, the result-
ing residue was applied to the top of an open-bed silica gel col-
umn (2.4 x 12 cm). The column was eluted with chloroform.
Fractions containing 2b (R = 0.53 CHCl /diethyl ether = 9.5:0.5,
umn was eluted with chloroform. Fractions containing 2a (R =
f
3
f
v/v) were combined and evaporated under reduced pressure to
0.54 CHCl /diethyl ether = 9.5:0.5, v/v) were combined and
3
give 2b in 11% yield (0.5 g, recrystallization solvent: diethyl
evaporated under reduced pressure to give 2e in 18% yield (1.5 g,
recrystallization solvent: n-hexane). Fractions containing 3e (Rf
ether/n-hexane = 1:2, v/v). Fractions containing 3b (R = 0.17
f
CHCl /diethyl ether = 9.5:0.5, v/v) were combined and evapo-
= 0.16 CHCl /diethyl ether = 9.5:0.5, v/v) were combined and
3
3

May-Jun 2005
Synthesis of Alkyl or Aryl Pyridazinyl Ethers
645
evaporated under reduced pressure to give 3e in 11% yield (2.5 g,
recrystallization solvent: diethyl ether).
present by tlc monitoring (8a for 58 hours at 60-70 °C, 8b for 8
hours at room temperature, 8c for 8 days at 80-90 °C). After cool-
ing to room temperature, chloroform (100 mL) and water (200
mL) were added to the mixture with stirring. After separating, the
organic layer was washed with excess water and dried over anhy-
drous magnesium sulfate. After evaporating the solvent under
reduced pressure, the resulting residue was applied to the top of
an open-bed silica gel column (2.4 x 8 cm). The column was
eluted with chloroform/diethyl ether (9.5:0.5, v/v, for 8a) or chlo-
Method B.
A mixture of 1a (1 g, 5.74 mmoles), 1,3-dibromopropane (0.58
g, 2.87 mmoles), potassium carbonate (0.79 g, 5.75 mmoles) and
dimethylformamide (15 mL) was refluxed for 79 hours. After
cooling to room temperature, the mixture was filtered. After
evaporating the solvent under reduced pressure, the resulting
residue was applied to the top of an open-bed silica gel column (2
x 20 cm). The column was eluted with chloroform. Fractions
roform (for 8b and 8c). Fractions containing 8 (8a R = 0.18, 8b
f
R =0.20, 8c R = 0.21; CHCl /diethyl ether = 9.5:0.5, v/v) were
f
f
3
containing 3e (Rf = 0.16 CHCl /diethyl ether = 9.5:0.5, v/v)
were combined and evaporated under reduced pressure to give 3e
in 67% yield (1.4 g, recrystallization solvent: diethyl ether).
combined and evaporated under reduced pressure to give 8 (8a in
72% yield, 8b in 82% yield, 8c in 83% yield; recrystallization
solvent: diethyl ether/n-hexane = 1:2, v/v).
3
2
-Benzyl-4-Chloro-5-(3-bromopropyloxy)pyridazin-3(2H)-one
6-Chloropyridazin-3-yl-2-hydroxyphenyl ether (11) and 1,2-
Bis[6-chloropyridazin-3-yl]oxy]benzene (12).
(
2f) and 1,3-Bis[2-benzyl-4-chloro-3-oxopyridazin-5-
yl]oxy]propane (3f).
A solution of 3,6-dichloropyridazine (10, 1 g, 7.61 mmoles),
catechol (1.43 g, 13 mmoles), potassium carbonate (1.9 g, 13
mmoles) and acetonitrile (30 mL) was refluxed for 25 hours.
After cooling to room temperature, the mixture was filtered and
washed with methanol (10 mL). The combined filtrate was co-
evaporated with silica gel (4 g) under reduced pressure. The
resulting residue was applied to the top of an open-bed silica gel
column (2.4 x 12 cm). The column was eluted with chloroform.
Method A.
A mixture of 1e (5 g, 20 mmoles), 1,3-dibromopropane (4.24
g, 21 mmoles), potassium carbonate (2.9 g, 21 mmoles) and ace-
tonitrile (120 mL) was refluxed for 22 hours. After cooling to
room temperature, the mixture was filtered. After evaporating the
solvent under reduced pressure, the resulting residue was applied
to the top of an open-bed silica gel column (3 x 20 cm). The col-
Fractions containing 12 (R = 0.32, CHCl /diethyl ether =
f
3
umn was eluted with chloroform. Fractions containing 2f (R =
f
9.5:0.5, v/v) were combined. After evaporating under reduced
pressure, the residue was washed with diethyl ether and dried in
0
.58 CHCl /diethyl ether = 9.5:0.5, v/v) were combined and
3
evaporated under reduced pressure to give 2f in 52% yield (1.8 g,
recrystallization solvent: diethyl ether/n-hexane = 1:2, v/v).
Fractions containing 3f (R = 0.21 CHCl /diethyl ether = 9.5:0.5,
v/v) were combined and evaporated under reduced pressure to
give 3f in 20% yield (1 g).
air to give 12 in 10% (0.4 g) yield. Fractions containing 11 (R =
f
0
.18, CHCl /diethyl ether = 9.5:0.5, v/v) were combined. After
3
f
3
evaporating under reduced pressure, the residue was recrystal-
lized from diethyl ether/n-hexane (1:1.5, v/v) and dried in air to
give 11 in 87% (1.7 g) yield.
4
-Chloro-5-phenoxy-2-phenoxymethylpyridazin-3(2H)-ones 5.
A mixture of 4 (2.99 g, 14 mmoles), phenol (2.64 g, 28
Synthesis of 2-Alkyl-4-chloro-5-methoxypyridazin-3(2H)-ones
1
4 from 13 and 17.
mmoles), potassium carbonate (3.87 g, 28 mmoles) and acetoni-
trile (15 mL) was refluxed until 4 was disappeared (5a for 3
hours, 5b for 1 hour, 5c for 2 hours, 5d for 19 hours, 5e for 8
hours). After cooling to room temperature, the mixture was fil-
tered. The work-up processes were the following: For 5a and 5b:
After evaporating the solvent under reduced pressure, the result-
ing residue was triturated in water (50 mL) with stirring. The
resulting precipitates was filtered, washed with n-hexane and
dried in air to give 5 (5a = 98%, 5b=81%). For 5c and 5d: After
evaporating the solvent under reduced pressure, the resulting
residue was applied to the top of an open-bed silica gel column (2
x 12 cm). The column was eluted with chloroform. Fractions
containing 5 (5c R = 0.33, 5d R =0.36; CHCl /diethyl ether =
A mixture of 2-alkyl-4-chloro-5-(4-substituted-phenoxy)pyri-
dazin-3(2H)-ones 13 or 17 (2.8 mmoles), potassium carbonate
(0.58 g, 4.19 mmoles) and methanol (20 mL) was refluxed until
the 5-phenoxy derivative was no longer present by tlc monitoring
(13a for 2.5 hours, 13b for 2 hours, 13c for 20 hours, 13d, 13e
and 17 for 1 hour). The work-up processes were the followings:
For 13a, 13b, 13d and 17: After evaporating the solvent under
reduced pressure, water (20 mL) was added to the residue with
stirring. The precipitate was collected by filtration and dried in
air to give 14a or 14b. For 13c and 13e: After cooling to room
temperature, the mixture was filtered. The filtrate was co-evapo-
rated with silica gel (2 g) under reduced pressure. The residue
was applied to the top of an open-bed silica gel column (2.4 x 10
cm). The column was eluted with methylene chloride. Fractions
containing 14a (R = 0.56, CHCl /diethyl ether = 9.5:0.5, v/v) or
f
f
3
9
.5:0.5, v/v) were combined and evaporated under reduced pres-
sure to give 5 (5c in 81% yield, 5d in 77% yield; recrystallization
f
3
solvent: CHCl /n-hexane = 1:1, v/v). For 5e: After evaporating
14c(R = 0.60, CHCl /diethyl ether = 9.5:0.5, v/v) were com-
3
f 3
the solvent under reduced pressure, the resulting residue was
recrystallized from water/methanol (5:2, v/v) to give 5e in 88%
yield.
bined and evaporated under reduced pressure to give 14a (recrys-
tallization solvent: diethyl ether) or 14c (recrystallization solvent:
diethyl ether/n-hexane = 1:2, v/v).
Bis(4-chloro-2-alkyl-3-oxopyridazin-5-yl)ethers 8.
5-Azido-4-chloro-2-ethylpyridazin-3(2H)-one (17).
A mixture of 7 (27 mmoles), 1 (27 mmoles), potassium car-
bonate (4.4 g, 30 mmoles) and solvent (for 8a DMSO, 20 mL; for
A mixture of 16 (1.5 g, 5.45 mmoles), sodium azide (0.7 g, 10
mmoles), ammonium chloride (0.54 g, 10 mmoles) and dimethyl-
formamide (20 mL) was stirred for 122 hours at room tempera-
ture. Chloroform (150 mL) and water (100 mL) were added to the
8
b acetonitrile, 20 mL; for 8c DMSO/acetonitrile=15:50 mL)
was stirred at suitable temperature until 7 and 1 were no longer

646
H.-A Chung, J.-J. Kim, H.-K. Kim, D.-H. Kweon, S.-D. Cho, S.-G. Lee, and Y.-J. Yoon
Vol. 42
mixture. The resulting mixture was stirred for an additional 5
hours. The organic layer was separated, washed with excess
water and dried over anhydrous magnesium sulfate. After evap-
orating the solvent under reduced pressure, the resulting residue
was applied to the top of an open-bed silica gel column (2 x 15
cm). The column was eluted with chloroform. Fractions contain-
[3] S. Y. Choi, S. C. Shin, Y. J. Yoon, J. Heterocyclic Chem.,
28, 385(1991).
[4] S. G. Lee, J. J. Kim, H. K. Kim, D. H. Kweon, Y. J. Kang,
S. D. Cho, S. K. Kim
and Y. J. Yoon, Curr. Org. Chem., 8, 1463 (2004).
5a] S. D. Cho, W. Y. Choi and Y. J. Yoon, J. Heterocyclic
Chem., 33, 1579 (1996); [b] S. D. Cho, D. H. Kweon, Y. J. Kang,
H.-A. Chung and Y. J. Yoon, J. Heterocyclic Chem., 35, 601 (1998).
6a] D. H. Kweon, S. D. Cho, S. K. Kim, J. W. Chung and Y. J.
Yoon, J. Heterocyclic Chem., 33, 1915 (1996); [b] H. -A. Chung, Y. J.
Kang and Y. J. Yoon, J. Heterocyclic Chem. 35, 1257 (1998).
[
ing 17 (R = 0.62 CHCl /diethyl ether = 9.5:0.5, v/v) were com-
f
3
bined and evaporated under reduced pressure to give 17 in 74%
yield (0.8 g, recrystallization solvent: n-hexane).
[
REFERENCES AND NOTES
[7] M. S. Shin, Y. J. Kang, H.-A. Chung, J. W. Park, D. H.
Kweon, W. S. Lee and Y. J. Yoon, J. Heterocyclic Chem., 36, 1135
(1999).
[1] K. Dury, Angew. Chem., Int. Ed., 4, 292 (1965).
[
2] R. D. Bryant, F.-A Kuung, M. S. South, J. Heterocyclic
[8] D. H. Kweon, Y. J. Kang, H.-A. Chung and Y. J. Yoon, J.
Heterocyclic Chem., 35, 819 (1998).
Chem., 32, 1473 (1995).