Tri-component reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones: Synthesis of 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-[4,5-b:4,5- e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy) pyrimidine

Article abstract of DOI:10.1016/j.tet.2005.03.071

Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base gave 2,4,5-trisubstituted- pyridazin-3(2H)-ones 4-9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e] -4H-thiopyran-1,6-diones 11 as a novel heterocycle.

Full text of DOI:10.1016/j.tet.2005.03.071

Tetrahedron 61 (2005) 5389–5395
Tri-component reaction of
2-alkyl-4,5-dichloropyridazin-3(2H)-ones: synthesis of
5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-
[4,5-b:4,5-e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy)
pyrimidine
Jung-Won Park,a Jeum-Jong Kim,a Ho-Kyun Kim,a Hyun-A Chung,a Su-Dong Cho,b,
*
Sang Gyeong Lee,a Motoo Shiroc and Yong-Jin Yoona,
*
aDepartment of Chemistry and Environmental Biotechnology, National Core Research Center, Gyeongsang National University,
Chinju 660-701, South Korea
bDepartment of Chemistry, Research Institute of Basic Sciences, Changwon National University, Changwon 641-773, South Korea
cRikagu Corporation, 3-9-12 Matsubara-cho, Akishima-shi, Tokyo 196-8666, Japan
Received 27 January 2005; accepted 7 March 2005
Available online 13 April 2005
Abstract—Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base
gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones 4–9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-
dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-diones 11 as a novel heterocycle.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
In the previous report,1,2 we reported the replacement of
4-cyanophenoxy group of 2-methyl-4-halo-5-(4-cyano-
phenoxy)pyridazin-3(2H)-ones by alkoxy groups such as
methoxy and ethoxy. Therefore, we tried the regioselective
substitution of 4-chloro-2-methyl-5-(4-cyanophenoxy)-
pyridazin-3(2H)-one with 2-mercaptopyrimidine. In this
preliminary experiment, we detected the several products on
the tlc. As part of our research program for the regio-
selective displacement of 4,5-dichloropyridazin-3(2H)-one,
we studied the tri-component reactions of 2-alkyl-4,5-
dichloropyridazin-3(2H)-ones with 4-cyanophenol and
2-mercaptopyrimidine.
Reaction of 1a with 2 and 3 in the presence of triethylamine
in refluxing acetonitrile gave compounds 4a (42%) and 8a
(25%) (entry 1 in Table 1), whereas this reaction was carried
out in the presence of potassium carbonate instead of
triethylamine to afford 6a (22%) and 7a (43%) (entry 2 in
Table 1) (Scheme 1).
Treatment of 1b with 2 and 3 in the presence of potassium
carbonate in refluxing acetonitrile yielded 6b (6%), 7b
(41%) and 8b (26%) (entry 3 in Table 1). On the other hand,
compound 1c was reacted with 2 and 3 in the presence of
potassium carbonate in refluxing acetonitrile afforded 6c
(7%), 7c (32%), 8c (28%) and phenyl pyrimidin-2-yl ether
10 (9%) as a new product (entry 4 in Table 1). Also this
reaction was carried out in the presence of cesium carbonate
instead of potassium carbonate to give 10 (42%) as the main
and 11c (6%) as another new product (entry 5 in Table 1).
Tri-component reaction of 1d with 2 and 3 in the presence of
potassium carbonate in refluxing acetonitrile gave 5d
(15%), 7d (44%) and 8d (19%) (entry 6 in Table 1).
In this paper, we would like to report on the reaction results
and new compounds in the title reaction.
Keywords: Tri-component reaction; 2-Alkyl-4,5-dichloropyridazin-3(2H)-
ones; 5-Cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-
e]-4H-thiopyran-1,6-diones; 2-(4-Cyanophenoxy)pyrimidine.
In order to elucidate the formation pathway of the new
compounds 10 and 11c, we attempted some further
*
Corresponding authors. Tel.: C82 055 751 6019; fax: C82 055 761 0244
(Y.-J.Y.); e-mail: yjyoon@nongae.gsnu.ac.kr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.071

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J.-W. Park et al. / Tetrahedron 61 (2005) 5389–5395
Table 1. Reaction of 1 with 2 and 3 in the presence of bases in refluxing acetonitrile
Entry
1(R)
Base
Reaction
time (h)
Product distribution (isolated yield, %)
4
5
6
7
8
9
10
11
1
2
3
4
5
6
a Me
a Me
b Et
c n-Pr
c n-Pr
d CH2Ph
Et3N
21
44
16
27
115
5
42
—
—
—
—
—
—
—
—
Trace
—
15
—
22
6
—
43
41
32
—
44
25
—
26
28
—
19
—
—
—
—
—
—
—
—
—
—
—
—
6
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
7
9
42
—
—
Trace
—
Scheme 1.
The treatment of 4a with 2 in the presence of potassium
carbonate in refluxing acetonitrile also gave 10 in 72%
yield. These are similar to the previously reported results.3,4
However, 4b and 4d did not form compound 10 under the
same conditions.
Compound 5 was also treated with 3 in the presence of
potassium carbonate in refluxing acetonitrile to form
compounds 6, 7 and 10. This reaction involved the ipso
substitution of 5 by 2-mercaptopyrimidine anion to 4 at C5
(Scheme 2).
Scheme 2.
Reaction of 7c with some other bases such as K2CO3,
Cs2CO3 and Rb2CO3 in refluxing acetonitrile afforded 10
(30–43%) and 4-cyanophenol (2). However, treatment of
compound 6c with these bases did not form compound 10
(Scheme 3).
Thus, it is possible that compound 10 may have been formed
via two pathways. Pathway A: 1/4/7/10. Pathway B:
1/5/4/7/10. Compound 7 is a key intermediate for
the synthesis of 10. The formation of 10 from 7 under our
condition was an unusual reaction.
Scheme 3.
In order to establish the structures of compound 6 and 7, we
attempted methoxylation of 6c and 7c. Compound 6 and 7
were treated with potassium carbonate in methanol to 12
and 13, respectively.5 The substituted position of the
methoxy group for 12 and 13 was established easily by
reactions. First, the reaction of 4c with phenol 2 in the
presence of potassium carbonate in refluxing acetonitrile for
8 days gave 10 in 40% yield, whereas the reaction which
was carried out in the presence of cesium carbonate instead
of potassium carbonate for 4 days, afforded 10 in 44% yield.

J.-W. Park et al. / Tetrahedron 61 (2005) 5389–5395
5391
the NOE (between C5–OMe protons and C6–H proton for
12 in Scheme 4). The structures of 4, 5, 8, 9 and 10 were
established by IR, NMR, and elemental analysis.
On the other hand, we also attempted further reactions in
order to elucidate the formation pathway(mechanism) of the
new type heterocycles 11. Reaction of 7a with cesium
carbonate in refluxing acetonitrile gave 10 (17%), 11a
(12%) and 4-cyanophenol (2, 69%). Compound 1b was
reacted with 3 in the presence of cesium carbonate in
refluxing acetonitrile and it gave 8b (36%) and 11b (13%).
Treatment of 4a with cesium carbonate in refluxing
acetonitrile afforded 11a (55%) and 8a (40%) (Scheme 5).
Scheme 4.
However, compound 5, 6, 8 and 9 did not form 11 under our
condition. Thus, compound 11 may have been formed via
two pathways. Pathway A: 1/4/7/11. Pathway B: 1/
4/11. The synthetic mechanism of 11 under our condition
is also showed in Scheme 6. The structures of 11 were
established by IR, NMR, elemental analysis and X-ray
diffraction for 11a (Fig. 1).6
3. Conclusion
In summary, we report herein the results of the tri-
component reaction of 2-alkyl-4,5-dichloropyridazin-
3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine
to give 2,4,5-trisubstituted-pyridazin-3(2H)-ones (4-9),
2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyri-
midin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]-4H-
thiopyran-1,6-diones 11. The formation of ether 10 and
tricyclic fused heterocycles 11 from 2-alkyl-4,5-dichloro-
pyridazin-3(2H)-ones is a new type of reaction. Also
compound 11 is a novel heterocycle. Further work including
the chemical transformation and application of novel
compounds are under way in our laboratory.
Scheme 5.
Scheme 6. Proposed mechanism for the synthesis of 11.

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J.-W. Park et al. / Tetrahedron 61 (2005) 5389–5395
bromide): n 3030, 2970, 1650, 1549, 1497, 1376, 1313,
1229, 1172, 1018, 954, 873, 797, 769, 748, 707, 628 cmK1
;
1H NMR (deuteriochloroform): d 3.87 (s, 3H), 7.17 (t, 1H,
JZ4.9 Hz), 7.98 (s, 1H), 8.60 (d, 2H, J Z4.9 Hz); 13C NMR
(deuteriochloroform) d 41.4, 119.0, 135.5, 138.6, 138.8,
157.2, 158.5, 168.7. Anal. Calcd for C9H7ClN4OS: C,
42.44; H, 2.77; N, 22.00; S, 12.59. Found: C, 42.15; H, 2.24;
N, 21.97; S, 12.51.
4.2.2. 2-Benzyl-4-chloro-5-(4-cyanophenoxy)pyridazin-
3(2H)-one (5d). Mp 196–197 8C; IR (potassium bromide):
n 3090, 2970, 2950, 2232, 1659, 1608, 1587, 1489, 1395,
1330, 1311, 1260, 1224, 1151, 1100, 1076, 1007, 938, 858,
747, 699, 559 cmK1; 1H NMR (deuteriochloroform): d 5.36
(s, 2H), 7.09–7.15 (m, 2H), 7.30–7.38 (m, 3H), 7.44–7.48
(m, 2H), 7.58 (s, 1H), 7.69–7.73 (m, 2H); 13C NMR
(deuteriochloroform) d 56.4, 109.1, 117.9, 119.0, 123.4,
128.4, 128.7, 129.2, 130.5, 134.7, 135.2, 151.5, 157.3,
158.2. Anal. Calcd for C18H12ClN3O2: C, 64.01; H, 3.58; N,
12.44; Cl, 10.50. Found: C, 64.04; H, 3.61; N, 12.49; Cl,
10.56.
4.2.3. 2-Methyl-4-(pyirimidin-2-ylsulfanyl)-5-(4-cyano-
phenoxy)pyridazin-3(2H)-one (6a). Mp 207–208 8C; IR
(potassium bromide): n 3117, 3072, 2226, 1648, 1586, 1551,
Figure 1. ORTEP plot for X-ray crystal structures of 11a.
1497, 1375, 1267, 1229, 1172, 1069, 840, 769, 543 cmK1
;
1H NMR (deuteriochloroform): d 3.82 (s, 3H), 7.03 (t, 1H,
JZ4.8 Hz), 7.14–7.18 (m, 2H), 7.61 (s, 1H), 7.61–7.67 (m,
2H), 8.46 (d, 2H, JZ4.8 Hz); 13C NMR (deuteriochloro-
form) d 41.0, 108.7, 117.9, 118.0, 119.1, 120.2, 130.2,
134.4, 156.8, 157.6, 158.0, 160.1, 168.9. Anal. Calcd for
C16H11N5O2S: C, 56.96; H, 3.29; N, 20.76; S, 9.50. Found:
C, 57.00; H, 3.32; N, 20.82; S, 9.55.
4. Experimental
4.1. General
Melting points were determined with a Thomas-Hoover
capillary apparatus and were uncorrected. 1H and 13C NMR
spectra were obtained on a Bruker FT NMR-DRX 500 or
Varian Inova 500 spectrometer and with chemical shift
values reported in d units (part per million) relative to an
internal standard (teteramethylsilane). IR spectra were
obtained on a Hitachi 270-50 or Mattson Genesis Series
FT-IR spectrophotometer. Elemental analyses were per-
formed with a Perkin–Elmer 240C. X-ray diffraction data
were obtained with a Rigaku AFC7R diffractometer with
filtered Cu Ka radiation and a rotating anode generator.
TLC was performed on SiO2 (silica gel 60 F254, Merck).
The spots were located by UV light. Column chromato-
graphy was carried out on SiO2 (silica gel 60, 70–230
mesh). Compounds 1 were prepared from 4,5-dichloro-
pyridazin-3(2H)-one by the literature method.7
4.2.4. 2-Ethyl-5-(4-cyanophenoxy)-4-(pyrimidin-2-yl-
sulfanyl)pyridazin-3(2H)-one (6b). Mp 183–184 8C; IR
(potassium bromide): n 3070, 2970, 2250, 1650, 1600, 1550,
1500, 1380, 1320, 1260, 1230, 1170, 1070, 840, 760,
1
540 cmK1; H NMR (deuteriochloroform): d 1.40 (t, 3H,
JZ7.2 Hz), 4.25 (q, 2H, JZ7.2 Hz), 6.99 (t, 1H, JZ
4.9 Hz), 7.13–7.15 (m, 2H), 7.60 (s, 1H), 7.60–7.64 (m, 2H),
8.44 (d, 2H, JZ4.9 Hz); 13C NMR (deuteriochloroform) d
13.4, 48.1, 108.8, 117.8, 118.0, 119.2, 120.7, 130.3, 134.4,
156.5, 157.6, 158.1, 159.7, 169.2. Anal. Calcd for
C17H13N5SO2: C, 58.11; H, 3.73; N, 19.93; S, 9.13.
Found: C, 58.14; H, 3.80; N, 20.00; S, 9.16.
4.2.5. 2-Propyl-4-(pyrimidin-2-ylsulfanyl)-5-(4-cyano-
phenoxy)pyridazin-3(2H)-one (6c). Mp 109–110 8C; IR
(potassium bromide): n 3008, 2969, 2229, 1649, 1590, 1550,
1499, 1375, 1310, 1255, 1225, 1174, 1079, 841, 770,
4.2. Reaction of 1 with 2 and 3
Method A. A mixture of 1 (5.586 mmol), 2 (5.586 mmol), 3
(5.586 mmol), base (5.586 mmol) and acetonitrile (50 mL)
was refluxed until 1 was disappeared. After cooling to room
temperature, the mixture was filtered and washed with
acetonitrile (35 mL!2). The combined filtrate was evap-
orated under reduced pressure. The residue was applied to
the top of an open-bed silica gel column (3!22 cm). The
column was eluted with ethyl acetate/n-hexane (1:1, v/v).
Fractions involving each product were combined and
evaporated under reduced pressure to give the product.
1
750 cmK1; H NMR (deuteriochloroform): d 0.97 (t, 3H,
JZ7.4 Hz), 1.83–1.88 (m, 2H), 4.17 (t, 2H, JZ7.4 Hz),
7.00 (t, 1H, JZ4.9 Hz), 7.13–7.17 (m, 2H), 7.60 (s, 1H),
7.63–7.66 (m, 2H), 8.45 (d, 2H, JZ4.9 Hz); 13C NMR
(deuteriochloroform) d 11.3, 21.7, 53.8, 108.3, 117.9, 118.3,
119.1, 121.2, 130.7, 134.9, 154.3, 157.4, 158.3, 159.9,
168.9. Anal. Calcd for C18H15N5SO2: C, 59.16; H, 4.14; N,
19.17; S, 8.78. Found: C, 59.21; H, 4.20; N, 19.21; S, 8.82.
4.2.6. 2-Methyl-4-(pyirimidin-2-ylsulfanyl)-5-(4-cyano-
phenoxy)pyridazin-3(2H)-one (7a). Mp 160–161 8C; IR
(potassium bromide): n 3100, 3070, 2945, 2226, 1650, 1549,
4.2.1. 2-Methyl-4-chloro-5-(pyirimidin-2-ylsulfanyl)-
pyridazin-3(2H)-one (4a). Mp 134–135 8C; IR (potassium

J.-W. Park et al. / Tetrahedron 61 (2005) 5389–5395
5393
1
1
1501, 1384, 1298, 1240, 951, 826, 765 cmK1; H NMR
630 cmK1; H NMR (deuteriochloroform): d 1.43 (t, 3H,
JZ7.2 Hz), 4.24 (q, 2H, JZ7.2 Hz), 7.02 (t, 1H, JZ
4.9 Hz), 7.12 (t, 1H, JZ5.0 Hz), 8.07 (s, 1H), 8.49 (d, 2H,
JZ4.8 Hz), 8.57 (d, 2H, JZ4.9 Hz); 13C NMR (deuterio-
chloroform) d 13.3, 48.0, 117.8, 118.4, 137.1, 138.2, 141.5,
157.5, 157.8, 158.0, 169.3, 169.6. Anal. Calcd for
C14H12N6OS2: C, 48.82; H, 3.51; N, 24.40; S, 18.62.
Found: C, 48.90; H, 3.61; N, 24.51; S, 18.70.
(deuteriochloroform): d 3.82 (s, 3H), 7.01–7.06 (m, 2H),
7.11 (t, 1H, JZ4.8 Hz), 7.55–7.60 (m, 2H), 8.00 (s, 1H),
8.52 (d, 2H, JZ4.8 Hz); 13C NMR (deuteriochloroform) d
40.2, 107.3, 117.4, 118.4, 118.5, 125.8, 133.8, 139.8, 150.4,
155.8, 158.0, 158.9, 168.7. Anal. Calcd for C16H15N5O2S:
C, 56.96; H, 3.29; N, 20.76; S, 9.50. Found: C, 57.01; H,
3.34; N, 20.80; S, 9.59.
4.2.7. 2-Ethyl-4-(4-cyanophenoxy)-5-(pyrimidin-2-yl-
sulfanyl)pyridazin-3(2H)-one (7b). Mp 110–111 8C; IR
(potassium bromide): n 3080, 3000, 2250, 1660, 1600, 1560,
1500, 1460, 1380, 1310, 1260, 1170, 1020, 960, 840, 780,
750, 630, 550 cmK1; 1H NMR (deuteriochloroform): d 1.41
(t, 3H, JZ7.2 Hz), 4.22 (q, 2H, JZ7.2 Hz), 7.01–7.03 (m,
2H), 7.08 (t, 1H, JZ4.9 Hz), 7.52–7.57 (m, 2H), 8.02 (s,
1H), 8.51 (d, 2H, JZ4.9 Hz); 13C NMR (deuteriochloro-
form) d 13.4, 47.4, 107.4, 117.4, 118.4, 118.5, 125.6, 133.9,
139.7, 150.4, 155.4, 158.0, 159.0, 168.9. Anal. Calcd for
C17H13N5SO2: C, 58.11; H, 3.73; N, 19.93; S, 9.13. Found:
C, 58.15; H, 3.78; N, 20.01; S, 9.18.
4.2.12. 2-Propyl-4,5-di(pyrimidin-2-ylsulfanyl)pyrida-
zin-3(2H)-one (8c). Mp 98–100 8C; IR (potassium
bromide): n 3057, 2963, 2930, 1655, 1548, 1426, 1373,
1300, 1268, 1167, 1056, 945, 805, 768, 745, 625 cmK1; 1H
NMR (deuteriochloroform): d 0.97 (t, 3H, JZ7.4 Hz), 1.84–
1.90 (m, 2H), 4.14 (t, 2H, JZ7.4 Hz), 7.02 (t, 1H, J Z
4.9 Hz), 7.11 (t, 1H, JZ4.9 Hz), 8.05 (s, 1H), 8.48 (d, 2H,
JZ4.9 Hz), 8.56 (d, 2H, JZ4.9 Hz); 13C NMR (deuterio-
chloroform) d 11.5, 22.0, 54.7, 118.2, 118.8, 137.5, 138.4,
141.6, 157.9, 158.3, 158.4, 169.5, 169.8. Anal. Calcd for
C15H14N6OS2: C, 50.26; H, 3.94; N, 23.45; S, 17.89. Found:
C, 50.31; H, 4.02; N, 23.51; S, 17.93.
4.2.8. 2-Propyl-4-(4-cyanophenoxy)-5-(pyrimidin-2-
ylsulfanyl)pyridazin-3(2H)-one (7c). Mp 91–92 8C; IR
(potassium bromide): n 3062, 2962, 2875, 2228, 1650, 1590,
4.2.13. 2-Benzyl-4,5-di(pyrimidin-2-ylsulfanyl)pyrida-
zin-3(2H)-one (8d). Mp 167–168 8C; IR (potassium
bromide): n 3115, 3075, 3028, 1660, 1549, 1454, 1350,
1553, 1496, 1381, 1306, 1248, 1169, 945, 843, 767 cmK1
;
1164, 967, 876, 824, 769, 723, 627 cmK1 1H NMR
;
1H NMR (deuteriochloroform): d 0.97 (t, 3H, JZ7.4 Hz),
1.83–1.88 (m, 2H), 4.13 (t, 2H, JZ7.4 Hz), 7.00–7.04 (m,
2H), 7.09 (t, 1H, JZ4.9 Hz), 7.55–7.59 (m, 2H), 8.02 (s,
1H), 8.51 (d, 2H, JZ4.9 Hz); 13C NMR (deuteriochloro-
form) d 11.1, 21.7, 53.7, 107.3, 117.4, 118.4, 118.5, 125.5,
133.8, 139.6, 150.4, 155.6, 158.0, 158.9, 168.8. Anal. Calcd
for C18H15N5SO2: C, 59.16; H, 4.14; N, 19.17; S, 8.78.
Found: C, 59.22; H, 4.21; N, 19.22; S, 8.84.
(deuteriochloroform): d 5.34 (s, 2H), 7.00 (t, 1H, JZ
4.9 Hz), 7.10 (t, 1H, JZ4.9 Hz), 7.29–7.34 (m, 3H), 7.40–
7.49 (m, 2H), 8.06 (s, 1H), 8.44 (d, 2H, JZ4.6 Hz), 8.55 (d,
2H, JZ4.9 Hz); 13C NMR (deuteriochloroform) d 56.1,
117.8, 118.5, 128.0, 128.6, 128.9, 135.9, 137.2, 138.3,
141.9, 157.5, 157.9, 158.0, 169.0, 169.4. Anal. Calcd for
C19H14N6OS2: C, 56.14; H, 3.47; N, 20.67; S, 15.78. Found:
C, 56.21; H, 3.52 N, 20.71; S, 15.83.
4.2.9. 2-Benzyl-4-(4-cyanophenoxy)-5-(pyrimidin-2-
ylsulfanyl)pyridazin-3(2H)-one (7d). Mp 106–107 8C; IR
(potassium bromide): n 3061, 3000, 2225, 1657, 1590, 1553,
1494, 1379, 1303, 1244, 1165, 951, 835, 760, 736, 700,
4.2.14. 2-(4-Cyanophenoxy)pyrimidine (10). Mp 108–
109 8C; IR (potassium bromide): n 3095, 3059, 2231, 1602,
1568, 1503, 1405, 1289, 1222, 1161, 1017, 901, 862, 820,
1
791, 626 cmK1; H NMR (deuteriochloroform): d 7.12 (t,
1
627 cmK1; H NMR (deuteriochloroform): d 5.32 (s, 2H),
1H, JZ4.8 Hz), 7.32–7.36 (m, 2H), 7.72–7.75 (m, 2H), 8.60
(d, 2H, JZ4.8 Hz); 13C NMR (deuteriochloroform) d 109.2,
117.2, 118.4, 122.6, 133.9, 156.3, 159.9, 164.5. Anal. Calcd
for C11H7N3O: C, 67.00; H, 3.58; N, 21.31. Found: C,
67.03; H, 3.62; N, 21.36.
6.99–7.01 (m, 2H), 7.08 (t, 1H, JZ4.9 Hz), 7.30–7.34 (m,
3H), 7.44–7.45 (m, 2H), 7.55–7.57 (m, 2H), 8.03 (s, 1H),
8.50 (d, 2H, J Z4.9 Hz); 13C NMR (deuteriochloroform) d
55.6, 103.3, 117.3, 118.4, 118.5, 126.0, 128.3, 128.7, 129.1,
133.8, 135.5, 139.9, 150.5, 155.5, 158.0, 158.8, 168.7. Anal.
Calcd for C22H15N5O2S: C, 63.91; H, 3.66; N, 16.94; S,
7.76. Found: C, 64.13; H, 3.72; N, 17.11.
4.2.15. 5-Cyano-5-(pyrimidin-2-yl)-2,7-dipropyl-5H-
dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-dione (11c).
Mp 185–186 8C; IR (potassium bromide): n 3060, 2970,
1
4.2.10. 2-Methyl-4,5-di(pyirimidin-2-ylsulfanyl)pyrida-
zin-3(2H)-one (8a). Mp 125–126 8C; IR (potassium
bromide): n 3064, 2980, 1660, 1554, 1383, 1250, 1167,
2880, 1640, 1610, 1570, 1400 cmK1; H NMR (deuterio-
chloroform): d 0.88 (t, 3H, JZ4.5 Hz), 0.95 (t, 3H, JZ
4.5 Hz), 1.76 (q, 2H, JZ4.5 Hz), 1.82 (q, 2H, JZ4.5 Hz),
4.00–4.06 (m, 4H), 7.26–7.30 (m, 1H), 7.79 (s, 1H), 8.18 (s,
1H), 8.77 (d, 2H, JZ4.9 Hz); 13C NMR (deuteriochloro-
form) d 10.9, 11.1, 21.5, 21.6, 49.2, 53.6, 53.9, 116.9, 120.4,
124.4, 128.4, 131.8, 133.1, 134.9, 135.5, 155.4, 156.3,
158.3, 166.4. Anal. Calcd for C20H19N7O2S: C, 56.99; H,
4.54; N, 23.26; S, 7.61. Found: C, 57.02; H, 4.61; N, 23.32;
S, 7.70.
1024, 947, 865, 806, 769, 745, 625 cmK1 1H NMR
;
(deuteriochloroform): d 3.82 (s, 3H), 7.02–7.16 (m, 2H),
8.05 (s, 1H), 8.47–8.58 (m, 4H); 13C NMR (deuteriochloro-
form) d 40.9, 117.9, 118.5, 136.6, 138.2, 141.9, 157.6,
158.0, 158.2, 168.9, 169.2. Anal. Calcd for C13H10N6OS2:
C, 47.26; H, 3.05; N, 25.44; S, 19.41. Found: C, 47.30; H,
3.12; N, 25.51; S, 19.47.
4.2.11. 2-Ethyl-4,5-di(pyrimidin-2-ylsulfanyl)pyridazin-
3(2H)-one (8b). Mp 121–123 8C; IR (potassium bromide): v
3100, 3050, 3000, 1740, 1650, 1560, 1450, 1430, 1380,
1240, 1170, 1050, 990, 940, 840, 810, 770, 750, 700,
4.3. Synthesis of compound 10
Method B. Reaction of 4a or 4c with 2. A mixture of 4
(0.393 mmol), 2 (47 mg, 0.393 mmol) and base (potassium

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J.-W. Park et al. / Tetrahedron 61 (2005) 5389–5395
carbonate for 4a; cesium carbonate for 4c, 0.393 mmol) and
acetonitrile (20 mL) was refluxed until 4 was disappeared.
After cooling to room temperature, the mixture was filtered
and washed with acetonitrile (35 mL!2). The combined
filtrate was evaporated under reduced pressure. The residue
was applied to the top of an open-bed silica gel column (3!
12 cm). The column was eluted with methylene chloride.
Fractions involving 10 were combined and evaporated
under reduced pressure to give 10 as yellowish crystal in
44% (for 4c) and 72% (for 4a) yield, respectively.
under reduced pressure to give 11b (13%). Fractions
involving 8b were also combined and evaporated to afford
8b (36%).
Method F. A mixture of 4a (50 mg, 0.2 mmol), cesium
carbonate (130 mg, 0.4 mmol) and acetonitrile (30 mL) was
refluxed for 20 hours. After cooling to the room tempera-
ture, the mixture was filtered and evaporated under reduced
pressure. The residue was applied to the top of an open-bed
silica gel column (3!12 cm). The column was eluted with
methylene chloride. Fractions involving 11a were combined
and evaporated under reduced pressure to give 11a (55%).
Fractions involving 8a were also combined and evaporated
to afford 8a (40%).
Method C. Reaction of 7 with base. A mixture of 7
(2.74 mmol) and base such as K2CO3, Cs2CO3 and Rb2CO3
(5.9 mmol) and acetonitrile (50 mL) was refluxed until 7
was disappeared. After cooling to room temperature, the
mixture was filtered and washed with acetonitrile (25 mL!
2). The combined filtrate was evaporated under reduced
pressure. The residue was applied to the top of an open-bed
silica gel column (5!18 cm). The column was eluted with
ethyl acetate/n-hexane (1:2, v/v). Fractions involving 10
were combined and evaporated under reduced pressure to
give 10 in 43% yield. Fractions involving 4-cyanophenol
were combined and evaporated under reduced pressure to
afford 4-cyanophenol (39%).
4.5.1. 5-Cyano-5-(pyrimidin-2-yl)-2,7-dimethyl-5H-
dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-dione (11a).
Mp 186 8C; IR (potassium bromide): n 3080, 3020, 2970,
1
1650, 1580, 1420, 1280, 1250, 1040, 875, 780 cmK1; H
NMR (deuteriochloroform): d 3.72 (s, 3H), 3.78 (s, 3H),
7.29 (t, 1H, JZ4.90 Hz), 7.79 (s, 1H), 8.17 (s, 1H), 8.77 (d,
2H, JZ4.89 Hz); 13C NMR (deuteriochloroform) d 40.20,
40.25, 53.45, 116.79, 120.47, 124.18, 128.63, 131.56,
133.08, 134.90, 135.81, 155.59, 156.56, 158.35, 166.24.
Anal. Calcd for C16H11N7O2S: C, 52.60; H, 3.03; N, 26.84;
S, 8.78. Found: C, 52.66; H, 3.09; N, 26.88; S, 8.90.
4.4. Reaction of 6c or 7c with potassium carbonate/
methanol
4.5.2. 5-Cyano-5-(pyrimidin-2-yl)-2,7-diethyl-5H-dipyri-
dazino[4,5-b:4,5-e]-4H-thiopyran-1,6-dione (11b). Mp
227–228 8C; IR (potassium bromide): n 3080, 3050, 2990,
2950, 2880, 1640, 1600, 1570, 1450, 1410, 1380, 1350,
1310, 1270, 1240, 1220, 1180, 1150, 1090, 1060, 1010,
A mixture of 6c or 7c (1.375 mmol), potassium carbonate
(228 mg, 1.65 mmol) and MeOH (30 mL) was stirred until
6c or 7c was disappeared at room temperature. The mixture
was coevaporated with silica gel (600 mg) under reduced
pressure. The residue was applied to the top of an open-bed
silica gel column (3!12 cm). The column was eluted with
methylene chloride/diethyl ether (30:1, v/v). Fractions
involving 4-cyanophenol were combined and evaporated
under reduced pressure to give 4-cyanophenol. Fractions
involving 12 or 13 were combined and evaporated to afford
12 (74%) or 13 (58%).
1
1000, 960, 880, 850, 830, 760, 740, 700 cmK1; H NMR
(deuteriochloroform): d 1.29–1.41 (m, 6H), 4.08–4.24 (m,
4H), 7.30 (t, 1H, JZ5.0 Hz), 7.83 (s, 1H), 8.18 (s, 1H), 8.78
(d, 2H, JZ5.0 Hz); 13C NMR (deuteriochloroform) d 13.2,
13.3, 47.2, 47.6, 49.1, 116.9, 120.5, 124.3, 128.4, 131.8,
133.2, 135.0, 135.6, 155.1, 156.1, 158.3, 166.3. Anal. Calcd
for C18H15N7O2S: C, 54.95; H, 3.84; N, 24.92; S, 8.15.
Found: C, 55.02; H, 3.90; N, 24.99; S, 8.21.
4.5. Synthesis of 11a and 11b from 7a, 1b and 4a
Method D. A mixture of 7a (0.35 g, 1.04 mmol), cesium
carbonate (0.74 g, 2.28 mmol) and acetonitrile (20 mL) was
refluxed for 24 hours. After cooling to the room tempera-
ture, the mixture was filtered and evaporated under reduced
pressure. The residue was applied to the top of an open-bed
silica gel column (3!12 cm). The column was eluted with
methylene chloride. Fractions involving 10 were combined
and evaporated under reduced pressure to give 10 (17%).
Fractions involving 4-cyanophenol were combined and
evaporated under reduced pressure to give 4-cyanophenol
(2, 69%). Fractions involving 11a were combined and
evaporated to afford 11a (12%).
Acknowledgements
This work was supported by a grant from the Korea Science
and Engineering Foundation (KOSEF) to the Environmental
Biotechnology National Core Research Center (grant #:
R15-2003-012-02001-0).
References and notes
Method E. A mixture of 1b (1 g, 5.19 mmol), 3 (582 mg,
5.19 mmol), cesium carbonate (3.38 g, 10.38 mmol) and
acetonitrile (30 mL) was refluxed for 48 hours. After
cooling to the room temperature, the mixture was filtered
and evaporated under reduced pressure. The residue was
applied to the top of an open-bed silica gel column (3!
12 cm). The column was eluted with methylene chloride.
Fractions involving 11b were combined and evaporated
1. Kweon, D. H.; Kang, Y. J.; Chung, H. A.; Yoon, Y. J.
J. Heterocycl. Chem. 1998, 35, 819.
2. Lee, S. G.; Kim, J. J.; Kim, H. K.; Kweon, D. H.; Kang, Y. J.;
Cho, S. D.; Km, S. G.; Yoon, Y. J. Curr. Org. Chem. 2004, 8,
1463.
3. Font, D.; Heras, M.; Villagordo, J. M. Synthesis 2002, 1833.
4. Ram, V. J.; Singha, U. K.; Guru, P. Y. Eur. J. Med. Chem.,
1990, 25, 533.

J.-W. Park et al. / Tetrahedron 61 (2005) 5389–5395
5395
5. Kang, Y. J.; Chung, H. A.; Kweon, D. H.; Cho, S. D.; Lee, S. G.;
Kim, S. K.; Yoon, Y. J. J. Heterocycl. Chem. 1998, 35, 595.
6. Crystal data for 11a: C36H32N14O5S2, formula weightZ804.86,
Crystal systemZtriclinic, lattice typeZprimitive, lattice par-
160.08, exposure rateZ12.0 s/8, detector positionZ127.40 mm,
pixel sizeZ0.100 mm, 2qmaxZ60.18, no. of reflections
measuredZtotal: 21,521, unique: 10,443 (RintZ0.096), correc-
tions Lorentz-polarizationabsorption (trans. factors: 0.902–
0.989), no. observations (all reflections)Z10,443, reflection/
parameter ratioZ20.28, residuals: R1 (IO2.00s(I))Z0.053,
residuals: R (all reflections)Z0.124, residuals: wR2 (all
reflections)Z0.097, goodness of fit indicatorZ0.924, max
shift/error in final cycleZ0.001, maximum peak in final diff.
˚
˚
˚
ameters aZ9.410(2) A, bZ13.055(3) A, cZ16.915(3) A, aZ
3
˚
103.96(5)8 bZ101.55(3)8, gZ109.33(7)8, VZ1811.7(14) A ,
space group P-1 (#2), Z valueZ2, DcalcZ1.475 g/cm3, F000
Z
836.00, m(Mo Ka) 2.14 cmK1, Data were collected on a Rigaku
RAXIS-RAPID imaging plate diffractometer with graphite
3
˚
˚
monochromated Mo Ka radiation (lZ0.71075 A). Detector
mapZ0.50 e/A , minimum peak in final diff. mapZ
3
˚
apertureZ270 mm!256 mm, Data imagesZ44 exposures, u
oscillation range (cZ45.0, (FZ0.0)Z130.0–190.08, exposure
rateZ12.0 s/8, u oscillation range (cZ45.0, FZ180.0)Z0–
K0.41 e/A .
7. Cho, S. D.; Choi, W. Y.; Yoon, Y. J. J. Heterocycl. Chem. 1996,
33, 1579.