A new method for the synthesis of 3-aryl-6-(2-pyrrolyl)pyridazines

Article abstract of DOI:10.1016/j.tet.2010.05.055

A new method for the synthesis of 3-halo-6-(N-tosyl-2-pyrrolyl)pyridazine 7 was developed.Suzuki cross-coupling reactions of 7 with arylboronic acids and in situ de-tosylation gave a variety of novel 3-aryl-6-(2-pyrrolyl)pyridazines. It found that protection of the pyrrolyl moiety was necessary for efficient coupling reaction.

Full text of DOI:10.1016/j.tet.2010.05.055

Tetrahedron 66 (2010) 5378e5383
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A new method for the synthesis of 3-aryl-6-(2-pyrrolyl)pyridazines
*
*
Chuanjun Song , Peng Zhao, Yan Liu, Hui Liu, Wenjia Li, Shuai Shi, Junbiao Chang
Department of Chemistry, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the synthesis of 3-halo-6-(N-tosyl-2-pyrrolyl)pyridazine 7 was developed. Suzuki
cross-coupling reactions of 7 with arylboronic acids and in situ de-tosylation gave a variety of novel
3-aryl-6-(2-pyrrolyl)pyridazines. It found that protection of the pyrrolyl moiety was necessary for effi-
cient coupling reaction.
Received 22 December 2009
Received in revised form 7 May 2010
Accepted 14 May 2010
Available online 20 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrole acylation
3-Halo-6-(N-tosyl-2-pyrrolyl)pyridazine
Suzuki cross-coupling
Nucleophilic aromatic substitution
3-Aryl-6-(2-pyrrolyl)pyridazine
1. Introduction
obtained. In an attempt to react pyrrolylmagnesium bromide with
3,6-dichloropyridazine 1, Jones and Whitmore isolated 3-chloro-6-
3-Aryl-6-(2-pyrrolyl)pyridazines are pharmaceutically important
molecules.1-6 However, there are very few literature reports de-
scribing their synthesis. Probably the most straightforward approach
involves the sequential palladium catalyzed Suzuki cross-coupling
reaction of 3,6-dichloropyridazine 1 with arylboronic acid followed
by coupling with N-protected 2-pyrrolylboronic acid, although the
overallyield isgenerally verylow (Scheme 1).1,5,7 Thisismainly due to
the competitive cross-coupling reaction of 3-aryl-6-chloropyridazine
2 with a second molecule of arylboronic acid to generate symmetrical
3,6-diarylpyridazine. Also, accesstothepyrrolylboronicacidmoietyis
not easy.8e10 Other reported methods for the synthesis of 3/6-(2-
pyrrolyl)pyridazine-containing molecules include Sauer’s synthesis
of 3-(2-pyrrolyl)-5-tributylstannylpyridazines by a regioselective
[4þ2] cycloaddition reaction between 3-(2-pyrrolyl)-1,2,4,5-tetra-
zine and ethynyltributyltin.11 However, the reaction is slow (3e10
days) and the yield for the synthesis of the tetrazine starting material
is low. A small amount of 3,4-disubstituted pyridazine was also
(2-pyrrolyl)-pyridazine, which was reluctant to react further to give
the desired 3,6-dipyrrolylpyridazine.12
Condensation of g-keto esters with hydrazine followed by aro-
matization and treatment of the resulting pyridazin-3-ones with
phosphorus oxychloride gave 3-chloropyridazines, which could
react further to give 3,6-disubstituted pyridazines.13 To our
surprise, although several groups have reported the synthesis of
6-(2-pyrrolyl)pyridazin-3-one,14e16 further elaboration to the
corresponding pyrrolylpyridazine derivatives has not been
explored. Previously, we developed a new pyrrole acylation method
using carboxylic acids and TFAA,17 we now report the application of
this methodology to the synthesis of 3-halo-6-(N-tosyl-2-pyrrolyl)
pyridazine 7 (Scheme 2) and the subsequent transformation into
3-substituted-6-(2-pyrrolyl)pyridazines.
Scheme 1.
* Corresponding authors. Tel.: þ86 0371 67781788 (C.S.); tel.: þ86 0371 67783017
(J.C.); e-mail addresses: chjsong@zzu.edu.cn (C. Song), changjunbiao@zzu.edu.cn
(J. Chang).
Scheme 2. Reagents and conditions: (i) monoethyl succinate, TFAA, DCE; (ii)
NH2NH2$H2O, AcOH, reflux; (iii) SeO2, dioxane, reflux; (iv) POCl3 or POBr3etoluene,
reflux; (v) ArB(OH)2, Pd(PPh3)4, K2CO3, tolueneeMeOH, 80 ꢀC, 12 h.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.055

C. Song et al. / Tetrahedron 66 (2010) 5378e5383
5379
Table 1
2. Results and discussion
Results of Suzuki cross-coupling reactions of chloride 7a with boronic acids
Initial optimization was carried out with N-tosylpyrrole 3a.
As shown in Scheme 2, the pyrrole acylation product 4a was
condensed with hydrazine hydrate to give 5a in 69% isolated
yield. DDQ oxidation of 5a, either under reflux or at ambient
temperature, led to the formation of pyridazin-3-one 6a in only
moderate yield. However, good yield was obtained when sele-
nium dioxide was employed as the oxidant. Treatment of 6a
with phosphorus oxychloride gave the desired 3-chloro-6-(N-
tosyl-2-pyrrolyl)pyridazine 7a in excellent yield. Applying the
same sequence of transformations to 2-phenyl-N-tosylpyrrole 3b,
3-bromo-6-(5-phenyl-N-tosyl-2-pyrrolyl)pyridazine 7b was syn-
thesized in good overall yield. 3-Chloro-6-(5-phenyl-N-tosyl-2-
pyrrolyl)pyridazine (7, R¼Ph, X¼Cl) could also be obtained by
treating the pyridazin-3-one 6b with phosphorus oxychloride,
but only in a disappointing 10% yield. However, an excellent
yield of the equivalent 3-bromopyridazine 7b was obtained
when phosphorus oxybromide was applied. It proved problem-
atic, although still possible, to convert 2-ethyl-N-tosylpyrrole 3c
to the corresponding 3-bromopyridazine 7c using our sequence
of transformations. Condensation of the acylation product 4c,
which was obtained in good yield, with hydrazine hydrate gave
poor conversion and prolonged reaction times only led to de-
creased yields. At best, the dihydropyridazin-3-one 5c was iso-
lated in 35% yield, together with 20% recovered starting
material. The isolated yields for the following two steps were
also quite low (35% and 20%, respectively).
Entry
1
Boronic acid
Product
Yield (%)
87
86
86
2
3
4
75
66
5
6
38
44
Next, using 3-chloro-6-(N-tosyl-2-pyrrolyl)pyridazine 7a as an
example, the Suzuki cross-coupling reaction18 with various
arylboronic acids was investigated. A mixture of the chloride 7a,
phenylboronic acid, potassium carbonate and a catalytic amount
(5 mol %) of tetrakis(triphenylphosphine) palladium was refluxed for
12 h until TLC indicated the reactionwas completed. The de-tosylated
cross-coupling product 3-phenyl-6-(2-pyrrolyl) pyridazine (i.e., 8,
Ar¼Ph) was obtained in 87% isolated yield. Employing the cyclo-
palladated ferrocenylimine catalyst developed by Wu et al.,19 or
change of base (K3PO4, NaOH) gave similar results, thus we employed
the first described conditions for the rest of our study. The results
of cross-couplings with other boronic acids are listed in Table 1.
As expected, an electron-donating substituent on the phenyl
ring (entries 2 and 3) led to higher yields than electron-with-
drawing groups (entry 4). Steric effects also played a significant
role, as could be seen from the decreased yield of 2-methyl-
phenylboronic acid (entry 5) compared to phenylboronic acid
(entry 1). It is perhaps not surprising that thiophenyl-2-boronic
acid did not undergo cross-coupling reaction, but led to formation
of 3-chloro-6-(2-pyrrolyl)pyridazine 9 and 3-methoxy-6-(2-pyr-
rolyl)-pyridazine 10 in 44% and 21% isolated yield, respectively.
Following known literature procedure,12 other pyrrolylpyr-
idazine derivatives could be obtained by nucleophilic aromatic
substitution of the chloride in 9, but rather slowly. For example,
compound 10 was obtained in good yield only after prolonged
reflux (72 h) in methanol when sodium methoxide was used as the
nucleophile. We reasoned that an electron-withdrawing group
should greatly facilitate this process. Indeed, reaction of the tosyl-
protected compound 7a with methanol in the presence of
potassium carbonate was completed in 5 h and resulted in the
formation of 10 in 79% isolated yield (Scheme 3). Removal of the
tosyl protecting group is usually carried out under strongly basic or
acidic conditions.20 We assumed that the facile in situ de-tosylation
observed during the Suzuki cross-coupling reactions of 7a (Table 1)
and during the nucleophilic substitution reaction shown in Scheme
3 was due to the strong electron-withdrawing nature of the
pyridazine moiety.21
7
21
Scheme 3.
Next, thecross-couplingreactionbetween3-chloro-6-(2-pyrrolyl)
pyridazine 9 and 4-methoxyphenylboronic acid was attempted.
However, no coupling product was observed. Instead, compound 10
resulting from nucleophilic aromatic substitution of the chloridewith
methoxy group was obtained in quantitive yield (Scheme 4).
Scheme 4. Reagents and conditions: p-methoxyphenylboronic acid, Pd(PPh3)4, K2CO3,
tolueneeMeOH, 80 ꢀC, 12 h, quant.
We then prepared the N-benzyl derivative 11, Suzuki cross-
coupling of which with phenylboronic acid proceeded smoothly to
give compound 12 in 82% isolated yield (Scheme 5). This, together
with the previous results, indicated that protection of the pyrrolyl
moiety was necessary for efficient cross-coupling reaction.

5380
C. Song et al. / Tetrahedron 66 (2010) 5378e5383
(both CH), 60.5, 35.6, 28.5, 22.0 (all CH2), 21.6, 14.1 and 12.9 (all
CH3); m/z (ESI) 400 (MþþNa, 100%) and 378 (MþþH, 5) [found:
MþþNa, 400.1195. C19H23NNaO5S requires 400.1195].
4.4. 6-(N-Tosyl-20-pyrrolyl)-4,5-dihydropyridazin-3-one 5a
Scheme 5. Reagents and conditions: (i) NaH, BnBr, THF, rt, 72 h, 41%; (ii) phenyl-
boronic acid, Pd(PPh3)4, K2CO3, tolueneeMeOH, 80 ꢀC, 14.5 h, 82%.
A mixture of acylpyrrole 4a (4.14 g, 11.9 mmol), hydrazine
hydrate (10 mL, 165 mmol) and acetic acid (30 mL) was heated to
reflux for 23 h, then evaporated in vacuo. The residue was washed
with water (3ꢁ5 mL) and filtrated. The filter cake was washed with
EtOAc (3ꢁ5 mL) to give dihydropyridazin-3-one 5a (2.61 g, 69%) as
a colourless solid; mp 222e225 ꢀC; nmax/cmꢂ1 3200 (NH), 1673
(CO), 1353, 1172, 1146 and 1066; 1H NMR (300 MHz, DMSO) 10.90
(1H, s), 7.78 (2H, d, J¼8.3 Hz), 7.56 (1H, dd, J¼3.4, 1.7 Hz), 7.39 (2H,
d, J¼8.3 Hz), 6.55(1H, dd, J¼3.4, 1.7 Hz), 6.38 (1H, t, J¼3.4 Hz),
2.77e2.72 (2H, m) and 2.43e2.38 (5H, m); 13C NMR (75 MHz,
DMSO) 166.9 (CO), 144.9, 143.6, 135.3, 131.6 (all C), 129.7 (2ꢁCH),
127.6 (2ꢁCH), 126.0, 117.3, 112.4 (all CH), 26.3, 25.6 (both CH2) and
21.1 (CH3); m/z (ESI) 340 (MþþNa, 10%) and 318 (MþþH, 100)
[found: MþþH, 318.0831. C15H16N3O3S requires 318.0912].
3. Conclusion
In summary, a new method for the synthesis of 3-halo-6-(N-
tosyl-2-pyrrolyl)pyridazine 7 based on pyrrole acylation has been
developed. Suzuki cross-coupling reactions of 3-chloro-6-(N-tosyl-
2-pyrrolyl)pyridazine 7a with arylboronic acids were studied and
gave, with in situ de-tosylation, a variety of novel 3-aryl-6-(2-pyr-
rolyl)pyridazines in good yields.
4. Experimental
4.1. Ethyl 4-oxo-4-(N-tosyl-20-pyrrolyl)butanoate 4a22
4.5. 6-(50-Phenyl-N-tosyl-20-pyrrolyl)-4,5-dihydropyridazin-3-
one 5b
A solution of N-tosylpyrrole 3a (7.86 g, 35 mmol), trifluoroacetic
anhydride (26.4 mL, 190 mmol) and monoethyl succinate (13.82 g,
95 mmol) in DCE (200 mL) was heated to reflux for 14 h. After being
allowed to cool to rt, water (30 mL) was added dropwise to quench
the reaction. The separated aqueous phase was extracted with DCM
(3ꢁ20 mL). The combined organic extracts were dried (Na2SO4),
filtrated and evaporated in vacuo. The residue was purified by
column chromatography on silica gel with petroleum ethereEtOAc
(10:1) as eluent to give acylpyrrole 4a (10.55 g, 85%) as a colourless
solid; mp 83e85 ꢀC; 1H NMR (300 MHz, CDCl3) 7.88 (2H, d,
J¼8.4 Hz), 7.79 (1H, dd, J¼3.2,1.7 Hz), 7.30 (2H, d, J¼8.4 Hz), 7.12 (1H,
dd, J¼3.2, 1.7 Hz), 6.34 (1H, t, J¼3.2 Hz), 4.08 (2H, q, J¼7.1 Hz), 3.04
(2H, t, J¼7.0 Hz), 2.62 (2H, t, J¼7.0 Hz), 2.41 (3H, s) and 1.20 (3H, t,
J¼7.1 Hz); 13C NMR (75 MHz, CDCl3) 186.3 (CO), 172.6 (CO), 144.8,
135.8, 132.7 (all C), 130.2 (CH), 129.3 (2ꢁCH), 128.3 (2ꢁCH), 123.6,
110.3 (both CH), 60.6, 33.9, 28.3 (all CH2), 21.7 and 14.1 (both CH3).
Compound 5b was synthesized according the procedure
described for the synthesis of 5a by refluxing a mixture of 4b,
hydrazine hydrate and acetic acid for 36 h. The crude product was
purified by column chromatography to give 5b (49%) as a pale solid;
mp 197e201 ꢀC; nmax/cmꢂ1 3323 (NH), 1670 (CO), 1348, 1287, 1154,
1132 and 1028; 1H NMR (300 MHz, DMSO-d6) 12.32 (1H, m), 10.84
(1H, s), 7.49e7.41 (7H, m), 7.26 (2H, d, J¼8.4 Hz), 7.01 (1H, d,
J¼2.7 Hz), 2.88 (2H, t, J¼8.1 Hz), 2.42 (2H, t, J¼8.1 Hz) and 2.31 (3H,
s); 13C NMR (75 MHz, DMSO-d6) 167.1 (CO), 143.1, 142.9, 140.4, 137.0
(all C), 129.9 (2ꢁCH), 129.5 (2ꢁCH), 128.9 (CH), 128.8 (C), 127.6
(2ꢁCH), 126.2 (2ꢁCH), 121.7 (C), 112.1 (CH), 26.0, 21.8 (both CH2)
and 20.9 (CH3); m/z (ESI) 416 (MþþNa, 100) and 394 (MþþH, 93)
[found: MþþH, 394.1223. C21H20N3O3S requires 394.1225].
4.2. Ethyl 4-oxo-4-(50-phenyl-N-tosyl-20-pyrrolyl)butanoate 4b
4.6. 6-(50-Ethyl-N-tosyl-20-pyrrolyl)-4,5-dihydropyridazin-3-
one 5c
Compound 4b was synthesized according to the procedure
described for the synthesis of 4a by refluxing a mixture of 3b, TFAA
and monoethyl succinate in DCE for 22 h, in 68% isolated yield as
a brown oil; nmax/cmꢂ1 1733 (CO), 1690 (CO), 1370 and 1174; 1H
NMR (300 MHz, CDCl3) 7.32e7.11 (7H, m), 7.04 (2H, d, J¼8.1 Hz),
6.84 (1H, d, J¼3.3 Hz), 6.05 (1H, d, J¼3.3 Hz), 4.08 (2H, q, J¼7.2 Hz),
3.18 (2H, t, J¼6.9 Hz), 2.72 (2H, t, J¼6.9 Hz), 2.29 (3H, s) and 1.19
(3H, t, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3) 191.6 (CO), 173.1 (CO),
145.1, 144.8, 139.1, 135.2 (all C), 130.0 (2ꢁCH), 129.1 (2ꢁCH), 128.2
(CH), 127.7 (4ꢁCH), 122.0, 114.9 (both CH), 60.8, 36.6, 28.9 (all CH2),
21.6 and 14.1 (both CH3); m/z (ESI) 448 (MþþNa, 13%), 426 (MþþH,
100), 398 (12) and 372 (10) [found: MþþH, 426.1377. C23H24NO5S
requires 426.1375].
Compound 5c was synthesized according the procedure
described for the synthesis of 5a by refluxing a mixture of 4c,
hydrazine hydrate and acetic acid for 23 h. The crude product was
purified by column chromatography to give 5c (35%) as a colour-
less solid; mp 170e171 ꢀC; nmax/cmꢂ1 3224 (NH), 1678 (CO), 1365,
1341, 1173 and 1133; 1H NMR (300 MHz, DMSO-d6) 10.89 (1H, s),
7.60 (2H, d, J¼8.2 Hz), 7.40 (2H, d, J¼8.2 Hz), 6.37 (1H, d,
J¼3.2 Hz), 6.08 (1H, d, J¼3.2 Hz), 2.75 (2H, t, J¼7.9 Hz), 2.65 (2H,
q, J¼7.4 Hz), 2.43 (2H, t, J¼7.9 Hz), 2.37 (3H, s) and 1.11 (3H, t,
J¼7.4 Hz); 13C NMR (75 MHz, DMSO-d6) 167.3 (CO), 147.2, 145.3,
140.9, 134.8, 134.1 (all C), 130.1 (2ꢁCH), 126.1 (2ꢁCH), 116.5, 112.5
(both CH), 27.7, 26.5, 21.4 (all CH2), 21.0 and 13.1 (both CH3); m/z
(ESI) 368 (MþþNa, 80%), 346 (MþþH, 100), 330 (10), 318 (18) and
302 (10) [found: MþþH, 346.1225. C17H20N3O3S requires
346.1225].
4.3. Ethyl 4-oxo-4-(50-ethyl-N-tosyl-20-pyrrolyl)butanoate 4c
Compound 4c was synthesized according to the procedure de-
scribed for the synthesis of 4a by reacting a mixture of 3c, TFAA and
monoethyl succinate in DCE at rt for 12 h, in 75% isolated yield as
a colourless solid; mp 54e56 ꢀC; nmax/cmꢂ1 1731 (CO), 1690 (CO),
1490, 1366, 1322, 1175 and 1109; 1H NMR (300 MHz, CDCl3) 7.87
(2H, d, J¼8.1 Hz), 7.24 (2H, d, J¼8.1 Hz), 6.81 (1H, d, J¼3.6 Hz), 5.97
(1H, d, J¼3.6 Hz), 4.04 (2H, q, J¼6.9 Hz), 3.03 (2H, t, J¼6.9 Hz), 2.84
(2H, q, J¼7.2 Hz), 2.62 (2H, t, J¼6.9 Hz), 2.34 (3H, s) and 1.21e1.13
(6H, m); 13C NMR (75 MHz, CDCl3) 189.5 (CO), 172.8 (CO), 146.7,
144.7, 136.6, 135.8 (all C), 129.5 (2ꢁCH), 127.6 (2ꢁCH), 121.1, 110.3
4.7. 6-(N-Tosyl-20-pyrrolyl)-pyridazin-3-one 6a
A mixture of dihydropyridazin-3-one 5a (5.86 g, 18.5 mmol) and
selenium dioxide (2.67 g, 24 mmol) in dioxane (200 mL) was
heated to reflux for 22 h. After being allowed to cool to rt, the bulk
of the solvent was evaporated in vacuo. The residue was partitioned
between water (30 mL) and DCM (30 mL). The separated aqueous
phase was extracted with DCM (4ꢁ10 mL). The combined organic
extracts were dried (Na2SO4), filtrated and evaporated in vacuo. The

C. Song et al. / Tetrahedron 66 (2010) 5378e5383
5381
residue was purified by column chromatography on silica gel with
DCMeEtOAc (5:1) as eluent to give pyridazin-3-one 6a (3.93 g, 67%)
as a yellow solid; mp 212e233 ꢀC; nmax/cmꢂ1 3146 (NH), 1685 (CO),
1596, 1368, 1170, 1149 and 1065; 1H NMR (300 MHz, DMSO-d6)
13.16 (1H, s), 7.69 (2H, d, J¼8.1 Hz), 7.57 (1H, dd, J¼3.3, 1.8 Hz), 7.53
(1H, d, J¼9.6 Hz), 7.40 (2H, d, J¼8.1 Hz), 6.89 (1H, d, J¼9.6 Hz), 6.57
(1H, dd, J¼3.3, 1.8 Hz), 6.43 (1H, t, J¼3.3 Hz) and 2.38 (3H, s); 13C
NMR (75 MHz, CDCl3), 160.6 (CO), 145.4, 139.9 (both C), 136.2 (CH),
135.6 (C), 129.9 (2ꢁCH), 128.4 (CH), 127.0 (2ꢁCH), 125.7, 118.0, 112.9
(all CH) and 21.7 (CH3); m/z (ESI) 338 (MþþNa, 15%), 316 (MþþH,
100), 261 (15) and 217 (18) [found: MþþH, 316.0753. C15H14N3O3S
requires 316.0756].
(Mþ
(
35Cl)þH, 100) [found: MþþH, 334.0412. C15H1335ClN3O2S
requires 334.0417].
4.11. 3-Bromo-6-(50-phenyl-N-tosyl-20-pyrrolyl)pyridazine 7b
Compound 7b was synthesized according to the procedure
described for the synthesis of 7a by refluxing a mixture of 6b and
phosphorus oxybromide in toluene for 6.5 h, in 80% isolated yield
as a yellow solid; mp 258e264 ꢀC; nmax/cmꢂ1 1587, 1470, 1402,
1302, 1169, 1161, 1146 and 1136; 1H NMR (300 MHz, DMSO-d6)
12.98 (1H, m), 8.21 (1H, d, J¼9.0 Hz), 8.06 (1H, d, J¼9.0 Hz),
7.58e7.43 (8H, m), 7.28 (2H, d, J¼7.8 Hz) and 2.32 (3H, s); 13C NMR
(75 MHz, DMSO-d6) 151.6, 145.7, 143.2, 140.1, 137.9 (all C), 132.2
(CH), 129.9 (2ꢁCH), 129.5 (2ꢁCH), 129.4 (C), 129.0 (CH),127.7
(2ꢁCH), 126.3 (2ꢁCH), 125.9 (CH), 122.9 (C), 113.1 (CH) and 20.9
4.8. 6-(50-Phenyl-N-tosyl-20-pyrrolyl)-pyridazin-3-one 6b
(CH3); m/z (ESI) 478 (Mþ
(
81Br)þNa, 95%), 476 (Mþ
(
79Br)þNa, 93),
Compound 6b was synthesized according to the procedure
described for the synthesis of 6a by refluxing a mixture of 5b and
selenium dioxide in dioxane for 22 h, in 66% isolated yield as an
amorphous solid; nmax/cmꢂ1 3264 (NH), 1680 (CO), 1604, 1570,
1404, 1162 and 1134; 1H NMR (300 MHz, DMSO-d6) 13.08 (1H, s),
12.44 (1H, m), 7.99 (1H, d, J¼9.9 Hz), 7.51e7.41 (7H, m), 7.26 (2H, d,
J¼8.1 Hz), 7.20 (1H, d, J¼2.7 Hz), 6.95 (1H, d, J¼9.9 Hz) and 2.32
(3H, s); 13C NMR (75 MHz, DMSO-d6) 160.1 (CO), 143.1, 140.5, 138.0,
136.8 (all C), 131.1, 130.0 (both CH), 129.9 (2ꢁCH), 129.5 (2ꢁCH),
128.7 (CH), 128.0 (C), 127.7 (2ꢁCH), 126.3 (2ꢁCH), 121.9 (C), 110.5
(CH) and 20.9 (CH3); m/z (ESI) 414 (MþþNa, 100%) and 392
(MþþH, 100) [found: MþþH, 392.1068. C21H18N3O3S requires
392.1069].
456 (Mþ
(
81Br)þH, 100) and 454 (Mþ
(
79Br)þH, 96) [found: MþþH,
454.0225. C21H17BrN3O2S requires 454.0225].
4.12. 3-Bromo-6-(50-ethyl-N-tosyl-20-pyrrolyl)pyridazine 7c
Compound 7c was synthesized according to the procedure
described for the synthesis of 7a by refluxing a mixture of 6c and
phosphorus oxybromide in toluene for 2 h, in 20% isolated yield as
a brown oil; nmax/cmꢂ1 1596, 1533, 1370 and 1173; 1H NMR
(300 MHz, CDCl3) 7.56 (2H, s) 7.53 (2H, d, J¼8.4 Hz), 7.17 (2H, d,
J¼8.4 Hz), 6.52 (1H, d, J¼3.6 Hz), 6.03 (1H, dt, J¼3.6, 0.9 Hz), 2.75
(2H, qd, J¼7.5, 0.9 Hz), 2.30 (3H, s) and 1.16 (3H, t, J¼7.5 Hz); 13C
NMR (75 MHz, CDCl3) 154.8, 146.8, 145.2, 143.2, 134.9 (all C), 131.7,
130.0 (both CH), 129.9 (2ꢁCH), 126.7 (2ꢁCH), 119.7, 112.7 (both CH),
4.9. 6-(50-Ethyl-N-tosyl-20-pyrrolyl)-pyridazin-3-one 6c
22.1 (CH2), 21.6 and 13.0 (both CH3); m/z (ESI) 430 (Mþ
(
81Br)þNa,
55%), 428 (Mþ
(
79Br)þNa, 49), 408 (Mþ
(
81Br)þH, 100) and 406 (Mþ
Compound 6c was synthesized according to the procedure
described for the synthesis of 6a by refluxing a mixture of 5c,
selenium dioxide in dioxane for 22 h, in 35% isolated yield as
a brown solid; mp 164e166 ꢀC; nmax/cmꢂ1 1676 (CO), 1653, 1604,
1366 and 1175; 1H NMR (300 MHz, DMSO-d6) 13.13 (1H, s),
7.57e7.53 (3H, m), 7.40 (2H, d, J¼8.1 Hz), 6.85 (1H, d, J¼9.6 Hz),
6.47 (1H, d, J¼3.6 Hz), 6.16 (1H, d, J¼3.6 Hz), 2.71 (2H, q,
J¼7.2 Hz), 2.37 (3H, s) and 1.44 (3H, t, J¼7.2 Hz); 13C NMR
(75 MHz, DMSO-d6) 160.1 (CO), 145.3, 140.7, 140.1 (all C), 136.3
(CH), 135.0, 132.0 (both C), 130.2 (2ꢁCH), 127.5 (CH), 126.1
(2ꢁCH), 117.2, 112.3 (both CH), 21.4 (CH2), 21.0 and 13.1 (both
CH3); m/z (ESI) 366 (MþþNa, 100%), 344 (MþþH, 56), 330 (11),
318 (15) and 302 (11) [found: MþþNa, 366.0890. C17H17N3NaO3S
requires 366.0888].
(
79Br)þH, 100) [found: MþþH, 406.0224. C17H1779BrN3O2S requires
406.0225].
General procedure for Suzuki cross-coupling reaction: A solu-
tion of chloropyridazine 7a/11 (0.24 mmol), arylboronic acid
(0.32 mmol), tetrakis(triphenylphosphine) palladium (0.01 mmol)
and potassium carbonate (0.64 mmol) in toluene (20 mL)/methanol
(5 mL) was heated to reflux under nitrogen for 12 h (14.5 h in the
case of compound 11), then cooled, filtered and evaporated. The
crude product was purified by column chromatography.
4.13. 3-Phenyl-6-(20-pyrrolyl)pyridazine (8, Ar[Ph)
Yellow solid; mp 220e223 ꢀC; nmax/cmꢂ1 1595, 1474, 1399, 1365,
1175, 1147 and 1085; 1H NMR (300 MHz, CDCl3) 9.97 (1H, br s),
8.11e8.07 (2H, m), 7.82 (1H, d, J¼9.0 Hz), 7.73 (1H, d, J¼9.0 Hz),
7.57e7.48 (3H, m), 7.05 (1H, m), 6.81 (1H, m) and 6.36 (1H, m); 13C
NMR (75 MHz, CDCl3) 156.4, 150.9, 136.3 (all C), 129.8 (CH), 129.0
(2ꢁCH), 128.3 (C), 126.6 (2ꢁCH), 124.3, 122.4, 121.7, 110.6 and 109.4
(all CH); m/z (ESI) 244 (MþþNa, 100%), 222 (MþþH, 95) and 195
(75) [found: MþþH, 222.1034. C14H12N3 requires 222.1031].
4.10. 3-Chloro-6-(N-tosyl-20-pyrrolyl)pyridazine 7a
A
mixture of pyridazin-3-one 6a (1.49 g, 4.7 mmol) and
phosphorus oxychloride (25 mL) was heated to reflux for 2.5 h.
The excess of POCl3 was evaporated in vacuo. The residue was
partitioned between water (50 mL) and ethyl acetate (20 mL).
The separated aqueous phase was extracted with ethyl acetate
(3ꢁ10 mL). The combined organic extracts were dried (Na2SO4),
filtered and evaporated in vacuo. The residue was purified by
column chromatography on silica gel (20% ethyl acetate in DCM)
to give chloropyridazine 7a (1.23 g, 78%) as a yellow solid; mp
138e140 ꢀC; nmax/cmꢂ1 1595, 1474, 1399, 1365, 1175, 1147 and
1085; 1H NMR (300 MHz, CDCl3) 7.75 (1H, d, J¼8.9 Hz), 7.58 (2H,
d, J¼8.7 Hz), 7.52 (1H, d, J¼8.9 Hz), 7.49 (1H, dd, J¼3.4, 1.8 Hz),
7.24 (2H, d, J¼8.7 Hz), 6.63 (1H, dd, J¼3.4, 1.8 Hz), 6.39 (1H, t,
J¼3.4 Hz) and 2.38 (3H, s); 13C NMR (75 MHz, CDCl3) 155.7,
153.1, 145.4, 135.4 (all C), 130.8 (CH), 129.8 (2ꢁCH), 127.3
(2ꢁCH), 127.1, 126.6, 119.4, 113.3 (all CH) and 21.6 (CH3); m/z
4.14. 3-(40-tert-Butylphenyl)-6-(200-pyrrolyl)pyridazine (8, Ar
[4-tBuPh)
Yellow solid; mp 243e245 ꢀC; nmax/cmꢂ1 3270 (NH), 1594, 1564,
1457 and 1123; 1H NMR (300 MHz, CDCl3) 9.97 (1H, br s), 8.04 (2H,
d, J¼8.6 Hz), 7.81 (1H, d, J¼9.0 Hz), 7.71 (1H, d, J¼9.0 Hz), 7.55 (2H,
d, J¼8.6 Hz), 7.04 (1H, m), 6.79 (1H, m), 6.36 (1H, m) and 1.38 (9H,
s); 13C NMR (75 MHz, CDCl3) 156.3, 153.2, 150.6, 133.3, 128.0 (all C),
126.3 (2ꢁCH), 126.0 (2ꢁCH), 124.3, 122.6, 122.2, 110.5, 109.6 (all CH)
and 31.2 (3ꢁCH3); m/z (ESI) 300 (MþþNa, 26%) and 278 (MþþH,
100) [found: MþþH, 278.1657. C18H20N3 requires 278.1657].
(ESI) 356 (Mþ
(
35Cl)þNa, 5%), 336 (Mþ
(
37Cl)þH, 30) and 334

5382
C. Song et al. / Tetrahedron 66 (2010) 5378e5383
4.15. 3-(40-Methoxyphenyl)-6-(200-pyrrolyl)pyridazine (8, Ar
4.21. 3-(N-Benzyl-20-pyrrolyl)-6-chloropyridazine 11
[4-MeOPh)
To a suspension of NaH (29 mg, 1.2 mmol) in dry THF (10 mL),
were added chloropyridazine 9 (178 mg, 1 mmol) and benzyl
bromide (256 mg, 1.5 mmol). The resulting mixture was stirred at
rt for 72 h. Water (2 mL) was added dropwise to quench the
reaction. The bulk of THF was removed in vacuo. The residue was
partitioned between water (15 mL) and DCM (10 mL). The sepa-
rated aqueous layer was extracted with DCM (3ꢁ10 mL). The
combined organic extracts were dried (Na2SO4), filtrated and
evaporated in vacuo. The residue was purified by column chro-
matography on silica gel with EtOAcepetroleum ether (1:5) as
eluent to give chloropyridazine 11 (109 mg, 41%) as a yellow solid;
mp 96e97 ꢀC; nmax/cmꢂ1 1574, 1540, 1472, 1438, 1427, 1394, 1332,
1157 and 1086; 1H NMR (300 MHz, CDCl3) 7.60 (1H, d, J¼9.0 Hz),
7.35 (1H, d, J¼9.0 Hz), 7.24e6.93 (5H, m), 6.94 (1H, dd, J¼2.7,
1.8 Hz), 6.72 (1H, dd, J¼3.9, 1.8 Hz), 6.28 (1H, dd, J¼3.9, 2.7 Hz)
and 5.81 (2H, s); 13C NMR (75 MHz, CDCl3) 153.6, 153.3, 138.6 (all
C), 128.5 (CH), 128.4 (2ꢁCH), 128.1 (CH), 127.4 (C), 127.2 (CH),
127.9 (2ꢁCH), 126.8, 113.9, 109.2 (all CH) and 52.9 (CH2); m/z
Yellow solid; mp 225e227 ꢀC; nmax/cmꢂ1 3242 (NH), 1607, 1568,
1510, 1458, 1437, 1397, 1297, 1255, 1182, 1122 and 1034; 1H NMR
(300 MHz, CDCl3) 9.91 (1H, br s), 8.05 (2H, d, J¼9.0 Hz), 7.77 (1H, d,
J¼9.0 Hz), 7.69 (1H, d, J¼9.0 Hz), 7.06e7.03 (3H, m), 6.79 (1H, m),
6.36 (1H, m) and 3.89 (3H, s); 13C NMR (75 MHz, CDCl3) 161.2, 156.0,
150.0, 128.5 (all C), 128.0 (2ꢁCH), 127.7 (C), 124.1, 122.9, 122.3 (all
CH), 114.5 (2ꢁCH), 110.7, 109.9 (both CH) and 55.4 (CH3); m/z (ESI)
274 (MþþNa, 14%) and 252 (MþþH, 100) [found: MþþH, 252.1137.
C15H14N3O requires 252.1137].
4.16. 3-(30-Nitrophenyl)-6-(200-pyrrolyl)pyridazine (8, Ar[3-
O2NPh)
Yellow solid; mp 214e217 ꢀC; nmax/cmꢂ1 3267 (NH), 1525,
1454, 1443, 1417, 1348 and 1119; 1H NMR (300 MHz, DMSO-d6)
12.00 (1H, s), 8.99 (1H, s), 8.62 (1H, d, J¼7.9 Hz), 8.37e8.34 (2H,
m), 8.11 (1H, d, J¼9.1 Hz), 7.86 (1H, t, J¼7.9 Hz), 7.05 (2H, m) and
6.26 (1H, m); 13C NMR (75 MHz, DMSO-d6) 153.3, 152.1, 148.5,
137.8 (all C), 132.5, 130.6 (both CH), 127.7 (C), 124.9, 124.0, 122.8,
122.5, 120.6, 110.8 and 110.0 (all CH); m/z (ESI) 267 (MþþH,
40%), 239 (25) and 217 (100) [found: MþþH, 267.0884.
C14H11N4O2 requires 267.0882].
(ESI) 294 (Mþ
(
37Cl)þNa, 15%), 292 (Mþ
(
35Cl)þNa, 55), 272 (Mþ
(
37Cl)þH, 25) and 270 (Mþ
(
35Cl)þH, 100) [found: MþþH,
270.0797. C15H13ClN3 requires 270.0798].
4.22. 3-(N-Benzyl-20-pyrrolyl)-6-phenylpyridazine 12
Yellow solid; mp 138e140 ꢀC; nmax/cmꢂ1 1587, 1551, 1472, 1453,
1402, 1082 and 1070; 1H NMR (300 MHz, CDCl3) 8.08e8.04 (2H, m),
7.77 (1H, d, J¼9.0 Hz), 7.70 (1H, d, J¼9.0 Hz), 7.52e7.49 (3H, m),
7.26e7.09 (5H, m), 6.91 (1H, dd, J¼2.7, 1.8 Hz), 6.74 (1H, dd, J¼3.9,
1.8 Hz), 6.31 (1H, dd, J¼3.9, 2.7 Hz) and 5.95 (2H, s); 13C NMR
(75 MHz, CDCl3) 155.9, 153.2, 138.8, 136.2 (all C), 129.7 (CH), 128.9
(2ꢁCH), 128.6 (C), 128.4 (2ꢁCH), 127.7, 127.1 (both CH), 127.0
(2ꢁCH), 126.7 (2ꢁCH), 125.1, 124.1, 113.2, 109.0 (all CH) and 52.7
(CH2); m/z (ESI) 334 (MþþNa, 15%) and 312 (MþþH, 100) [found:
MþþH, 312.1502. C21H18N3 requires 312.1501].
4.17. 3-(20-Methylphenyl)-6-(200-pyrrolyl)pyridazine (8, Ar[2-
MePh)
Yellow solid, mp 143e145 ꢀC; nmax/cmꢂ1 3259 (NH), 1592, 1563,
1462,1422 and 1122;1H NMR(300 MHz, CDCl3) 10.79(1H, s), 7.74 (1H,
d,J¼8.9 Hz), 7.53e7.32(5H, m), 7.05(1H, m), 6.82 (1H, m), 6.33 (1H, m)
and 2.44 (3H, s); 13C NMR(75 MHz,CDCl3) 159.0,150.6,137.2,136.2(all
C), 131.0, 129.6, 129.0 (all CH), 127.9(C), 127.8,126.1, 122.7, 122.0, 110.3,
109.7 (all CH) and 20.4 (CH3); m/z (ESI) 258 (MþþNa, 12%) and 236
(MþþH, 100) [found: MþþH, 236.1187. C15H14N3 requires 236.1188].
Acknowledgements
4.18. 3-(40-Fluorophenyl)-6-(200-pyrrolyl)pyridazine (8, Ar[4-
FPh)
We are grateful to NSFC (Young Scholarship to C. Song,
#20902085) for financial support, Dr. Peter Seden (Oxford Univer-
sity, Oxford, UK) for proof-reading the manuscript of the paper.
Yellow solid; mp 207e209 ꢀC; nmax/cmꢂ1 3276 (NH), 1602, 1458,
1234 and 1119; 1H NMR (300 MHz, DMSO-d6) 11.93 (1H, s), 8.25e8.21
(2H, m), 8.17 (1H, d, J¼9.1 Hz), 8.03 (1H, d, J¼9.1 Hz), 7.39 (2H, t,
J¼8.8 Hz), 7.00 (2H, d, J¼8.8 Hz) and 6.23 (1H, m); 13C NMR (75 MHz,
DMSO-d6) 163.1 (C, d, JFC 245.3),154.4,151.5,132.6 (all C),128.5 (2ꢁCH,
d, J 8.5),127.9(C),124.2(CH),122.4 (2ꢁCH),116.0,115.7,110.1 and 109.8
(all CH); m/z (ESI) 262 (MþþNa, 10%) and 240 (MþþH, 100) [found:
MþþH, 240.0937. C14H11FN3 requires 240.0937].
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.05.055. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
4.19. 3-Chloro-6-(20-pyrrolyl)pyridazine 912
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Colourless solid; mp 174e175 ꢀC (lit.12 mp 182.4e182.7 ꢀC); 1H
NMR (300 MHz, CDCl3) 9.89 (1H. br s), 7.63 (1H, d, J¼9.0 Hz), 7.41
(1H, d, J¼9.0 Hz), 7.05 (1H, m), 6.77 (1H, m) and 6.34 (1H, m); m/z
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(ESI) 204 (Mþ
(
37Cl)þNa, 86%), 202 (Mþ
(
35Cl)þNa, 100), 182 (Mþ
(
37Cl)þH, 12) and 180 (Mþ
(
35Cl)þH, 33).
4.20. 3-Methoxy-6-(20-pyrrolyl)pyridazine 1012
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Colourless solid; mp 135e137 ꢀC; 1H NMR (300 MHz, CDCl3)
9.76 (1H. br s), 7.62 (1H, d, J¼9.3 Hz), 6.99e6.95 (2H, m), 6.66 (1H,
m), 6.31 (1H, m) and 4.13 (3H, s).

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