New enediyne derivatives: Synthesis of symmetrically and unsymmetrically disubstituted 4,5-dialkynyl-3(2H)-pyridazinones

Article abstract of DOI:10.1016/S0040-4020(01)01030-4

4,5-Dialkynyl-2-(methyl or phenyl)-3(2H)-pyridazinones (2a-c) were efficiently prepared via Sonogashira cross-coupling reaction on 4,5-dichloro-2-(methyl or phenyl)-3(2H)-pyridazinones (1a,b). Selective Sonogashira reactions were successfully achieved on

Full text of DOI:10.1016/S0040-4020(01)01030-4

TETRAHEDRON
Pergamon
Tetrahedron 57 12001) 10009±10016
New enediyne derivatives: synthesis of symmetrically and
unsymmetrically disubstituted 4,5-dialkynyl-3ꢀ2H)-pyridazinones
p
Omar R'kyek, Bert U. W. Maes, Tim H. M. Jonckers, Guy L. F. Lemiere and Roger A. Dommisse
Á
Department of Chemistry, University of Antwerp ꢀRUCA), Groenenborgerlaan 171, B-2020 Antwerp, Belgium
Received 2 July 2001; revised 6 September 2001; accepted 27 September 2001
AbstractÐ4,5-Dialkynyl-2-1methyl or phenyl)-312H)-pyridazinones 12a±c) were ef®ciently prepared via Sonogashira cross-coupling
reaction on 4,5-dichloro-2-1methyl or phenyl)-312H)-pyridazinones 11a,b). Selective Sonogashira reactions were successfully achieved
on 4-chloro-2-methyl-5-tri¯uoromethanesulfonyloxy- 16) and 5-chloro-2-methyl-4-tri¯uoromethanesulfonyloxy-312H)-pyridazinone 111),
yielding 5-alkynyl-4-chloro- 17a±c) and 4-alkynyl-5-chloro-2-methyl-312H)-pyridazinones 13a,c,e), respectively. Compounds 7a±c and
3a,c,e were subjected to a second Sonogashira reaction giving 4,5-dialkynyl-2-methyl-312H)-pyridazinones 18a±c) bearing two different
acetylene substituents. Suzuki cross-coupling reaction was also achieved on compounds 7a and 3a producing 4-aryl-5-phenylethynyl- and
5-aryl-4-phenylethynyl-2-methyl-312H)-pyridazinones, respectively, in excellent yield. q 2001 Elsevier Science Ltd. All rights reserved.
Enediynes have attracted considerable interest in the past
decades from chemists as well as from medicinal chemists.
From a chemical point of view, the enediyne moiety is
attractive since it can be transformed into a benzene ring
via a Bergman cyclization reaction.1 From a medicinal point
of view, compounds containing an enediyne moiety are
well known as antitumour antibiotics.2 The chemical and
medicinal interest for this structural entity prompted us to
investigate the preparation of hitherto unknown enediynes
based on the 312H)-pyridazinone core via a palladium
catalysed alkynylation approach 1Sonogashira reaction).
312H)-pyridazinones via palladium catalysed Sonogashira
reaction of terminal alkynes with 5-bromo-2-methoxy-
methyl-6-phenyl-312H)-pyridazinone.10
Recently, our laboratory described that chloro-312H)-pyri-
dazinones are valuable starting materials for palladium
catalysed cross-coupling reactions. Suzuki arylation as
well as Buchwald±Hartwig amination can be very
ef®ciently executed on these skeletons using triarylphos-
phine based palladium catalysts.11,12 Since 4,5-dichloro-
312H)-pyridazinones are cheap and easily accessible, we
decided to investigate Sonogashira reactions on these
compounds in order to prepare the hitherto unknown
4,5-dialkynyl-312H)-pyridazinones.
Several articles have been published dealing with the syn-
thesis of monoalkynylpyridazines via Sonogashira reac-
tion.3 Igeta,4 Yamanaka,5 Bailey,6 Stanforth7 and Haider8
reported palladium catalysed alkynylation of the pyridazine
core starting from halopyridazines 1chloro- and iodo-).
Generally, the most ef®cient reactions are performed start-
ing from iodopyridazines. Chloropyridazines often give bad
results since harsh reaction conditions are usually required.
Besides halopyridazines, tri¯uoromethanesulfonyloxypyri-
dazines have also been used in Sonogashira reactions.9
These tri¯uoromethanesulfonyloxypyridazines are very
attractive starting materials since they can be easily
prepared from the corresponding pyridazinones under
mild reaction conditions.9,16,17 In contrast to the pyridazine
core, there is only one report describing Sonogashira
reactions on the 312H)-pyridazinone system. RavinÄa and
co-workers prepared 5-alkynyl-2-methoxymethyl-6-phenyl-
First we focused our attention on the synthesis of 2-substi-
tuted 4,5-dialkynyl-312H)-pyridazinones with two identical
alkynyl substituents 12). These compounds were prepared
using modi®ed Sonogashira conditions13 starting from
2-substituted 12-methyl- or 2-phenyl-) 4,5-dichloro-312H)-
pyridazinones and an excess 13 equiv.) of terminal alkyne
1phenylacetylene or trimethylsilylacetylene). Efforts to use
these reaction conditions to prepare 2-methyl-4,5-di1pent-1-
ynyl)-312H)-pyridazinone 12e) gave only incomplete reac-
tions even after 3 days of heating as con®rmed by DCI±MS
analysis. Amass spectrum of the crude reaction mixture
revealed the presence of 2e and a monopentynylated
312H)-pyridazinone 13e). Gradual increase of the amount
of 1-pentyne as well as the amount of catalyst and co-
catalyst did not lead to better results. The exact structure
of 3e could only be proven after a selective alkynylation
reaction 1see later). The data of Table 1 prove that the nature
of the acetylene is very important for the success of the
Sonogashira reactions and consequently that the oxidative
Keywords: pyridazinones; Sonogashira reaction; alkynes; palladium and
compounds.
p
Corresponding author. Tel.: 132-3-21-80-226; fax: 132-3-21-80-233;
e-mail: lemiere@ruca.ua.ac.be
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020101)01030-4

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O. R'kyek et al. / Tetrahedron 57 ꢀ2001) 10009±10016
Table 1. Sonogashira cross-coupling reaction on 4,5-dichloro-312H)-pyridazinones
Entry
R1
R2
C6H5
Time 1h)
Yield of 2a 1%)
Yield of 3a 1%)
1
2
3
4
5
CH3
C6H5
CH3
C6H5
CH3
30
16
50
30
72
82 12a)
75 12b)
70 12c)
80 12d)
34 12e)
0
0
0
0
C6H5
1CH3)3Si
1CH3)3Si
C3H7
36 13e)
a
Reaction conditions: 2.5 mmol 1a or b, 3 equiv. 1-alkyne, 3 mol% PdCl21PPh3)2, 3 mol% CuI, Et3N, THF at 808C 1oil bath) under N2 atmosphere.
addition is not the rate determining step as often observed
for this type of reaction.14
achieved and hence disubstitution problems might be
avoided. Because of its ease of preparation, the tri¯ate
group was our substituent of choice. Starting from 4-chloro-
5-methoxy-2-methyl-312H)-pyridazinone 14) or from
Secondly, we investigated the synthesis of 2-substituted
4,5-dialkynyl-312H)-pyridazinones bearing two different
acetylenes. Attempts to use 1 equiv. of the terminal alkyne
at room temperature or at re¯ux to replace selectively one of
the chlorine atoms of 1a failed, and a mixture of mono and
dialkynylated products was obtained as indicated by DCI±
MS analysis. Since it is well known that the C±I, C±Br and
C±OTf bonds readily undergo oxidative addition with
different reactivity order, we envisaged the possibility of
replacing one of the chlorine atoms in compound 1a with
a different halogen or a pseudohalogen. In this way, selec-
tive palladium-catalysed cross-coupling reactions can be
5-chloro-4-methoxy-2-methyl-312H)-pyridazinone
19),11
which were hydrolysed in aqueous KOH solution,15 the
hydroxy products 5 and 10 were transformed with tri¯uoro-
methanesulfonic anhydride in CH2Cl2 and Et3N to hitherto
unknown 4-chloro-2-methyl-5-tri¯uoromethanesulfonyl-
oxy-312H)-pyridazinone 16) and 5-chloro-2-methyl-4-
tri¯uoromethanesulfonyloxy-312H)-pyridazinone
111),
respectively 1Schemes 1 and 2).16 As illustrated in Tables
2 and 4, selective Sonogashira reactions starting from 6
or 11 were achieved successfully. 5-Alkynyl-4-chloro-
17a±c) and 4-alkynyl-5-chloro-2-methyl-312H)-pyridazinones
Scheme 1. Preparation of 4-chloro-2-methyl-5-tri¯uoromethanesulfonyloxy-312H)-pyridazinone 16).
Scheme 2. Preparation of 5-chloro-2-methyl-4-tri¯uoromethanesulfonyloxy-312H)-pyridazinone 111).

O. R'kyek et al. / Tetrahedron 57 ꢀ2001) 10009±10016
10011
Table 2. Selective cross-coupling reaction on 6
Entry
R3
C6H5
1CH3)3Si
C3H7
Time 1h)
Yielda 1%)
1
2
3
2
2
24
83 17a)
72 17b)
60 17c)
a
Reaction conditions: 2 mmol 6, 1.01 equiv. 1-alkyne, 3 mol% PdCl21PPh3)2, 30 mol% CuI, 3 equiv. n-Bu4NI, 3 equiv. Et3N, THF at room temperature under
N2 atmosphere.
Table 3. Introduction of a second alkynyl group on 7a±c
Entry
R2
C6H5
C6H5
1CH3)3Si
R3
Time 1h)
Yield of 8a 1%)
1
2
3
1CH3)3Si
C3H7
C6H5
7
45
24
79 18a)
51 18b)
50 18c)
a
Reaction conditions: 1.12 mmol 7a±c, 1.3 equiv. 1-alkyne, 3 mol% PdCl21PPh3)2, 5 mol% CuI, Et3N, THF at 808C 1oil bath) under N2 atmosphere.
Table 4. Selective cross-coupling reaction on 11
Entry
R2
C6H5
1CH3)3Si
C3H7
Time 1h)
Yield of 3a 1%)
1
2
3
2
24
8
95 13a)
55 13c)
82 13e)
a
Reaction conditions: 1.4 mmol 11, 1.01 equiv. 1-alkyne, 3 mol% PdCl21PPh3)2, 30 mol% CuI, 3 equiv. n-Bu4NI, Et3N/THF 11:1) at room temperature under
N2 atmosphere.

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O. R'kyek et al. / Tetrahedron 57 ꢀ2001) 10009±10016
Table 5. Introduction of a second alkynyl group on 3a,c
Entry
R2
R3
Time 1h)
Yield of 8a 1%)
1
2
C6H5
1CH3)3Si
C3H7
C6H5
46
20
97 18b)
52 18c)
a
Reaction conditions: 1.12 mmol 3a,c, 1.3 equiv. 1-alkyne, 3 mol% PdCl21PPh3)2, 5 mol% CuI, Et3N, THF at 808C 1oil bath) under N2 atmosphere.
Table 6. Suzuki cross-coupling reaction on 7a
Entry
R
Time 1h)
Yield of 9a 1%)
1
2
C6H5
3-CF31C6H4)
15
16
86 19a)
78 19b)
a
Reaction conditions: 0.7 mmol 7a, 1.5 equiv. RB1OH)2, 3 mol% Pd1PPh3)4, aq. Na2CO3 12 M, 1.1 mL) at 1208C 1oil bath) under N2 atmosphere.
13a,c,e) were obtained in moderate to good yield. Under our
optimised conditions, no dialkynylated products were
observed. In contrast, increasing the amount of the terminal
alkyne, and using higher reaction temperatures or longer
reaction times were not suitable for the selectivity and
only favoured the formation of the disubstituted products.
All the spectral data of the previously obtained product 13e,
see Table 1, entry 5) were identical to those of the pentynyl
Table 7. Suzuki cross-coupling reaction on 3a
Entry
R
Time 1h)
Yield of 10a 1%)
1
2
C6H5
3-CF31C6H4)
6
6
99 110a)
94 110b)
a
Reaction conditions: 0.7 mmol 3a, 1.5 equiv. RB1OH)2, 3 mol% Pd1PPh3)4, aq. Na2CO3 12 M, 1.1 mL) at 1208C 1oil bath) under N2 atmosphere.

O. R'kyek et al. / Tetrahedron 57 ꢀ2001) 10009±10016
10013
derivative synthesised from 11, con®rming that 3e is the
5-chloro-2-methyl-4-1pent-1-ynyl)-312H)-pyridazinone. The
exact structure of the monoalkynylated pyridazinones was
proved using 2D-NMR spectroscopy. Especially the use of
the long-range HETCOR experiment turned out to be
valuable since we were able to detect a three-bond corre-
lation 13J) between the proton H-6 of the pyridazinones and
the carbon atom C-10 of the alkynyl group in the case of the
5-alkynylated compounds. Such a coupling was absent
when performing the same experiment on the 4-alkynylated
isomers.
tri¯uoromethanesulfonic anhydride 1Acros, Aldrich), and
PdCl21PPh3)2 1Fluka) were obtained from commercial
sources. THF 1Acros) was dried over sodium/benzophenone
and freshly distilled before use. Flash column chroma-
tography was performed on Kiesel gel 601Merck), 0.040±
0.063 mm.
1.1. General procedure for the preparation of 2-substi-
tuted 4,5-dialkynyl-3ꢀ2H)-pyridazinones ꢀ2a±e)
To a solution of 2-substituted 4,5-dichloro-312H)-pyridazi-
none 1450 mg, 2.5 mmol) in THF 112 mL), Pd2Cl21PPh3)2
152 mg, 0.075 mmol), CuI 114 mg, 0.075 mmol), Et3N
10.95 mL, 7.0 mmol) and the 1-alkyne 17.5 mmol) were
added. The mixture was heated at 808C under a N2 atmos-
phere until the starting material had been consumed 1TLC
analysis and/or DCI±MS). The reaction mixture was then
cooled to room temperature, diluted with EtOAc and ®ltered
through a pad of Celitew. The ®ltrate was concentrated in
vacuo and then puri®ed on silica gel. The following
products were prepared by this procedure.
Finally, a second Sonogashira reaction on the remaining
chlorine atom of 7a±c and 3a,c was investigated. In fact,
each monoalkynyl precursor was smoothly coupled with a
different terminal alkyne yielding the desired dialkynylated
312H)-pyridazinones in moderate to good yield 1Tables 3
and 5). To the best of our knowledge, there are no reports
dealing with the preparation of 2-substituted 312H)-pyrida-
zinone compounds bearing identical or different acetylenic
groups at C-4 and C-5 positions, neither with an alkynyl
substituent at C-4 and a chlorine atom at C-5 nor vice versa.
1.1.1. 2-Methyl-4,5-bisꢀphenylethynyl)-3ꢀ2H)-pyridazi-
none ꢀ2a). Chromatography eluent: heptane/EtOAc
185:15); yield 1640 mg, 82%); mp 1138C 1brown solid,
decomp.); nmax 1KBr): 3034, 2944, 2216, 2197, 1644,
Encouraged by these results, and since we know from
previous results that the Suzuki cross-coupling reaction
works well on the chloro-312H)-pyridazinone skeleton,11
we investigated the introduction of an aryl group in C-4
and C-5 positions. Thus, the compounds 7a and 3a were
reacted with phenylboronic acid and 3-tri¯uoromethyl-
benzeneboronic acid to produce a new class of 312H)-pyri-
dazinone based compounds 1Tables 6 and 7).
1569, 1490, 1383, 1356, 1056, 943, 758, 690, 530 cm21
;
dH 1CDCl3): 7.80 1s, 1H, H-6), 7.66±7.62 1m, 2H,
HPh4-2,6 or HPh5-2,6), 7.61±7.58 1m, 2H, HPh4-2,6 or
HPh5-2,6), 7.47±7.34 1m, 6H, HPh4-3,4,5 and HPh5-3,4,5),
3.82 1s, 3H, NCH3); dC 1CDCl3): 158.70 1C-3), 136.64
1C-6), 132.33, 132.15 1CPh4-2,6 or CPh5-2,6), 130.03,
129.67 1CPh4-4 or CPh5-4), 128.69, 128.50 1CPh4-3,5 or
CPh5-3,5), 128.56, 125.62 1C-4 or C-5), 122.36, 121.65
1CPh4-1 or CPh5-1), 105.34, 102.21 1C-20 or C-200), 83.91,
83.76 1C-10 or C-100), 40.62 1NCH3); MS 1ESI) m/z: 311
1100%), 268, 254, 239; HRMS 1ESI) for C21H15N2O
[M1H]1: calcd 311.1184, found 311.1186.
In conclusion, by using the Sonogashira cross-coupling
reaction and starting from easily accessible starting
materials, 2-substituted 4,5-dialkynyl-312H)-pyridazinones
with identical or different acetylenic groups can be
prepared. We have also demonstrated that a selective
Sonogashira reaction can be achieved by using 2-substituted
4-chloro-5-tri¯uoromethanesulfonyloxy-312H)-pyridazinone
or its 5-chloro-4-tri¯ate isomer.
1.1.2. 2-Phenyl-4,5-bisꢀphenylethynyl)-3ꢀ2H)-pyridazi-
none ꢀ2b). Chromatography eluent: heptane/EtOAc
185:15); yield 1750 mg, 75%); mp 1218C 1brown solid,
decomp.); nmax 1KBr): 3059, 2924, 2201, 1658, 1572,
1492, 1130, 899, 755, 689, 529 cm21; dH 1CDCl3): 7.95
1s, 1H, H-6), 7.67±7.61 1m, 6H, HPh4-2,6 and HPh5-2,6 and
HNPh-2,6), 7.51±7.34 1m, 9H, HPh4-3,4,5 and HPh5-3,4,5 and
HNPh-3,4,5); dC 1CDCl3): 158.04 1C-3), 141.44 1CNPh-1),
137.41 1C-6), 132.37, 132.23 1CPh4-2,6 or CPh5-2,6),
130.16, 129.76 1CPh4-4 or CPh5-4), 128.76, 128.73, 128.53
1CPh4-3,5 or CPh5-3,5 or CNPH-3,5), 128.39 1CNPh-4), 128.21,
127.05 1C-5 or C-4), 125.29 1CNPh-2,6), 122.30, 121.61
1CPh4-1 or CPh5-1), 105.73, 102.89 1C-20 or C-200), 84.05,
83.96 1C-10 or C-100); MS 1ESI) m/z: 373 1100%), 330,
268, 240; HRMS 1ESI) for C26H17N2O [M1H]1: calcd
373.1341, found 373.1347.
1. Experimental
1H and 13C NMR spectra were recorded on a Varian Unity
400 spectrometer in CDCl3 with TMS as the internal
standard. Chemical shifts are given in ppm and J values
in Hz. HRMS and product ion spectra were recorded on
quadrupole-time of ¯ight mass spectrometer 1QTof 2,
Micromass, Manchester, UK) equipped with a standard
electrospray ionisation 1ESI) interface. Samples were
infused in a 0.1% formic acid/MeOH 110:90) mixture at
5 mL/min. Product ion spectra were recorded selecting the
protonated molecule [M1H]1 in the quadrupole. This
precursor ion is fragmented in the collision cell using Ar
as collision gas and a collision energy of 30 eV. IR spectra
were obtained as potassium bromide pellets or as liquid
®lms between two potassium bromide pellets with a Brucker
Vector 22 spectrometer. Melting points were recorded using
a BuÈchi B-545 apparatus and are uncorrected. 4,5-Dichloro-
2-1methyl and phenyl)-312H)-pyridazinones 1Lancaster,
Acros, Avocado), 4-chloro-5-methoxy-2-methyl-312H)-
pyridazinone 1Avocado), 1-alkynes 1Aldrich, Acros),
1.1.3. 2-Methyl-4,5-bisꢀtrimethylsilylethynyl)-3ꢀ2H)-pyri-
dazinone ꢀ2c). Chromatography eluent: heptane/EtOAc
185:15); yield 1530 mg, 70%); brownish oil; nmax 1liquid
®lm): 2961, 1668, 1251, 1077, 949, 846, 761 cm21; dH
1CDCl3): 7.66 1s, 1H, H-6), 3.76 1s, 3H, NCH3), 0.29 1s,
18H, 2£11CH3)3Si); dC 1CDCl3): 158.60 1C-3), 136.60
1C-6), 129.02, 125.75 1C-4 or C-5), 112.55 1C-20), 109.34

10014
O. R'kyek et al. / Tetrahedron 57 ꢀ2001) 10009±10016
1C-200), 98.03, 97.31 1C-100 or C-10), 40.51 1NCH3), 20.28
11CH3)3Si), 20.43 11CH3)3Si); MS 1ESI) m/z: 303, 231, 73
1100%); HRMS 1ESI) for C15H23N2OSi2 [M1H]1: calcd
303.1349, found 303.1335.
1666, 1431, 1209, 1133, 958, 813, 624, 512 cm21; dH
1CDCl3): 7.84 1s, 1H, H-6), 3.85 1s, 3H, NCH3); dC
1CDCl3): 155.14 1C-3), 142.47 1C-4), 135.57 1C-6),
130.40 1C-5), 118.45 1q, JCFˆ321.2 Hz, CF3), 40.63
1NCH3); MS 1ESI) m/z: 160 135Cl), 162 137Cl), 104
1100%); HRMS 1ESI) for C6H635ClF3N2O4S [M1H]1:
calcd 292.9611, found 292.9606.
1.1.4. 2-Phenyl-4,5-bisꢀtrimethylsilylethynyl)-3ꢀ2H)-pyri-
dazinone ꢀ2d). Chromatography eluent: heptane/EtOAc
185:15); yield 1790 mg, 80%); dark brown oil; nmax 1liquid
®lm): 3068, 2936, 2901, 1672, 1573, 1490, 1251, 1137,
1036, 846, 763, 693, 629, 588 cm21; dH 1CDCl3): 7.81 1s,
1H, H-6), 7.58 1br d, 2H, HPh-2,6), 7.44 1br t, 2H, HPh-3,5),
7.37 1br t, 1H, HPh-4), 0.31 1s, 9H, 1CH3)3Si), 0.29 1s, 9H,
1CH3)3Si); dC 1CDCl3): 157.94 1C-3), 141.28 1CPh-1),
137.34 1C-6), 128.75, 127.30 1C-4 or C-5), 128.64
1CPh-2,6), 128.33 1CPh-4), 125.16 1CPh-3,5), 113.02 1C-20),
110.22 1C-200), 98.10, 97.42 1C-10 or C-100), -0.31
11CH3)3Si), 20.42 11CH3)3Si); MS 1ESI) m/z: 365, 293, 73
1100%); HRMS 1ESI) for C20H25N2OSi2 [M1H]1: calcd
365.1505, found 365.1495.
1.3. General procedure for the preparation of 5-alkynyl-
4-chloro-2-methyl-3ꢀ2H)-pyridazinones ꢀ7a±c)
To a solution of 6 1600 mg, 2 mmol) in THF 111 mL),
Pd2Cl21PPh3)2 142 mg, 0.06 mmol), CuI 1106 mg,
0.6 mmol) and n-Bu4NI 12.21 g, 6 mmol) were added.
After a few seconds of stirring, Et3N 10.76 mL, 6 mmol)
and the 1-alkyne 12.02 mmol) were added successively.
The reaction mixture was stirred under a N2 atmosphere at
room temperature until the starting material had been
consumed 1TLC analysis and/or DCI±MS). The mixture
was diluted with EtOAc and ®ltered through a pad of
Celitew. The ®ltrate was concentrated in vacuo and the
residue obtained was puri®ed on silica gel.
1.1.5. 2-Methyl-4,5-diꢀpent-1-ynyl)-3ꢀ2H)-pyridazinone
ꢀ2e). Chromatography eluent: heptane/EtOAc 185:15);
yield 1320 mg, 34%); dark yellow oil; nmax 1liquid ®lm):
2964, 2935, 2873, 2221, 1658, 1574, 1462, 1378, 1231,
990, 882, 772, 660 cm21; dH 1CDCl3): 7.61 1s, 1H, H-6),
3.75 1s, 3H, NCH3), 2.54 1t, Jˆ7.0 Hz, 2H, H-30 or H-300),
2.47 1t, Jˆ7.0 Hz, 2H, H-30 or H-300), 1.67 1br hex,
J<7.0 Hz, 2H, H-40 or H-400), 1.66 1br hex, J<7.0 Hz, 2H,
H-40 or H-400), 1.08 1t, Jˆ7.3 Hz, 3H, H-50 or H-500), 1.07 1t,
Jˆ7.3 Hz, 3H, H-50 or H-500); dC 1CDCl3): 159.41 1C-3),
137.25 1C-6), 129.21, 126.24 1C-4 or C-5), 107.10, 103.75
1C-20 or C-200), 75.88, 75.15 1C-10 or C-100), 40.47 1NCH3),
22.34, 21.89 1C-30 or C-300), 21.84, 21.74 1C-40 or C-400),
13.45 1C-50 and C-500); MS 1ESI) m/z: 243, 213, 199, 185,
129 1100%), 115; HRMS 1ESI) for C15H19N2O [M1H]1:
calcd 243.1497, found 243.1505
1.3.1. 4-Chloro-2-methyl-5-phenylethynyl-3ꢀ2H)-pyrida-
zinone ꢀ7a). Chromatography eluent: heptane/EtOAc
185:15); yield 1380 mg, 83%); mp 1518C 1dark yellow
solid); nmax 1KBr): 3057, 2218, 1650, 1582, 1444, 1332,
1215, 872, 764, 689, 537 cm21; dH 1CDCl3): 7.76 1s, 1H,
H-6), 7.57±7.62 1m, 2H, HPh5-2,6), 7.38±7.48 1m, 3H,
HPh5-3,4,5), 3.83 1s, 3H, NCH3); dC 1CDCl3): 157.07
1C-3), 136.79 1C-4), 136.15 1C-6), 132.25 1CPh5-2,6),
130.27 1CPh5-4), 128.68 1CPh5-3,5), 126.17 1C-5), 121.11
1CPh5-1), 103.27 1C-200), 81.36 1C-100), 41.04 1NCH3); MS
1ESI) m/z: 245 135Cl), 247 137Cl), 154 1100%), 139, 113;
HRMS 1ESI) for C13H1035ClN2O: calcd 245.0482, found
245.0475.
1.2. General procedure for the preparation of 4-chloro-
2-methyl-5-tri¯uoromethanesulfonyloxy-3ꢀ2H)-pyri-
dazinone ꢀ6) and its isomer 5-chloro-4-tri¯uoromethane-
sulfonyloxy-3ꢀ2H)-pyridazinone ꢀ11)
1.3.2. 4-Chloro-2-methyl-5-trimethylsilylethynyl-3ꢀ2H)-
pyridazinone ꢀ7b). Chromatography eluent: heptane/
EtOAc 185:15); yield 1380 mg, 72%); mp 688C 1pale
brown solid); nmax 1KBr): 3073, 2952, 1655, 1579, 1273,
1252, 1149, 1056, 845, 759, 660, 548 cm21; dH 1CDCl3):
7.66 1s, 1H, H-6), 3.81 1s, 3H, NCH3), 0.29 1s, 9H,
1CH3)3Si); dC 1CDCl3): 156.97 1C-3), 137.61 1C-4),
136.21 1C-6), 125.72 1C-5), 111.02 1C-200), 95.64 1C-100),
40.95 1NCH3), 20.57 11CH3)3Si); MS 1ESI) m/z: 241
135Cl), 243 137Cl), 183, 148, 73 1100%); HRMS 1ESI) for
C10H1435ClN2OSi [M1H]1: calcd 241.0564, found
241.0567.
Asolution of compound 5 or 10 1340 mg, 2.125 mmol),
Et3N 10.4 mL, 2.76 mmol) in dichloromethane 110.5 mL),
was chilled in an ice-acetone bath 1temperature of the
bath was 258C). Under stirring, tri¯uoromethanesulfonic
anhydride 10.4 mL, 2.34 mmol) was added dropwise to the
solution. The resulting yellow solution was stirred for
30 min at 258C. The reaction mixture was then poured
into dilute HCl 130 mL, 0.5 M) and extracted with CH2Cl2
13£50 mL). The combined organic layers were washed with
a 1% NaHCO3 solution 170 mL), brine 170 mL), and then
dried 1MgSO4). The ®ltrate was concentrated under reduced
pressure.
1.3.3. 4-Chloro-2-methyl-5-ꢀpent-1-ynyl)-3ꢀ2H)-pyrida-
zinone ꢀ7c). Chromatography eluent: heptane/EtOAc
185:15); yield 1300 mg, 60%); yellow oil; nmax 1liquid
®lm): 2972, 2939, 2878, 2232, 1652, 1592, 1284, 1166,
871, 753, 657 cm21; dH 1CDCl3): 7.61 1s, 1H, H-6), 3.78
1s, 3H, NCH3), 2.47 1t, Jˆ7.0 Hz, 2H, H-300), 1.66 1br hex,
J<7.0 Hz, 2H, H-400), 1.05 1t, Jˆ7.4 Hz, 3H, H-500); dC
1CDCl3): 157.19 1C-3), 136.68 1C-61C-4), 126.77 1C-5),
106.18 1C-200), 73.66 1C-100), 40.91 1NCH3), 21.87, 21.63
1C-300 or C-400), 13.45 1C-500); MS 1ESI) m/z: 211 135Cl),
213 137Cl), 182 1100%), 169, 91; HRMS 1ESI) for
C10H1235ClN2O [M1H]1: calcd 211.0638, found 211.0635.
1.2.1.
4-Chloro-2-methyl-5-tri¯uoromethanesulfonyl-
oxy-3ꢀ2H)-pyridazinone ꢀ6). Brown oil. Because of its
instability, this isomer was used immediately after its
preparation, therefore, no spectral data were recorded.
1.2.2.
5-Chloro-2-methyl-4-tri¯uoromethanesulfonyl-
oxy-3ꢀ2H)-pyridazinone ꢀ11). Yield 1910 mg, 90%, crude
product); mp 628C 1pale brown solid); nmax 1KBr): 3083,

O. R'kyek et al. / Tetrahedron 57 ꢀ2001) 10009±10016
10015
1.4. General procedure for the preparation of 4-alkynyl-
5-chloro-2-methyl-3ꢀ2H)-pyridazinones ꢀ3a,c,e)
had been consumed 1TLC analysis and/or DCI±MS). The
reaction mixture was then cooled to room temperature,
diluted with EtOAc and ®ltered through a pad of Celitew.
The solvent was removed under reduced pressure and the
residue obtained was puri®ed on silica gel.
To a solution of 5-chloro-2-methyl-4-tri¯uoromethane-
sulfonyloxy-312H)-pyridazinone 11 1400 mg, 1.4 mmol) in
THF 16 mL), Pd2Cl21PPh3)2 129 mg, 0.042 mmol), CuI
173 mg, 0.42 mmol) and n-Bu4NI 11.5 g, 4.2 mmol) were
added. After a few seconds of stirring, Et3N 16 mL,
43.4 mmol) and the 1-alkyne 11.41 mmol) were added
successively. The reaction mixture was stirred under an
N2 atmosphere at room temperature until the starting
material had been consumed 1TLC analysis and/or DCI±
MS). The mixture was diluted with EtOAc and ®ltered
through a pad of Celitew. The ®ltrate was concentrated in
vacuo and the residue obtained was puri®ed on silica gel.
1.5.1. 2-Methyl-4-phenylethynyl-5-trimethylsilylethynyl-
3ꢀ2H)-pyridazinone ꢀ8a). Chromatography eluent: hep-
tane/EtOAc 18:2); yield 1270 mg, 79%); brown oil; nmax
1liquid ®lm): 3062, 2960, 2901, 2206, 2160, 1658, 1569,
1250, 1159, 1070, 942, 847, 758, 690, 529 cm21; dH
1CDCl3): 7.70 1s, 1H, H-6), 7.61 1br dd, 2H, HPh-2,6), 7.37
1m, 3H, HPh-3,4,5), 3.79 1s, 3H, NCH3), 0.30 1s, 9H,
1CH3)3Si); dC 1CDCl3): 158.57 1C-3), 136.72 1C-6),
132.37 1CPh-2,6), 129.61 1CPh-4), 128.37 1CPh-3,5), 128.07,
126.37 1C-4 or C-5), 122.29 1CPh-1), 109.26 1C-200), 105.31
1C-20), 98.26 1C-100), 83.58 1C-10), 40.55 1NCH3), 20.42
11CH3)3Si); MS 1ESI) m/z: 307, 221, 73 1100%); HRMS
1ESI) for C18H19N2OSi [M1H]1: calcd 307.1267, found
307.1250.
1.4.1. 5-Chloro-2-methyl-4-phenylethynyl-3ꢀ2H)-pyrida-
zinone ꢀ3a). Chromatography eluent: heptane/EtOAc
185:15); yield 1324 mg, 95%); mp 1138C 1yellow solid);
nmax 1KBr): 3075, 2925, 2206, 1647, 1568, 1224, 1033,
934, 756, 689, 530 cm21; dH 1CDCl3): 7.78 1s, 1H, H-6),
7.65±7.61 1m, 2H, HPh4-2,6), 7.35±7.44 1m, 3H, HPh4-3,4,5),
3.80 1s, 3H, NCH3); dC 1CDCl3): 158.53 1C-3), 139.36
1C-5), 135.88 1C-6), 132.40 1CPh4-2,6), 129.87 1CPh4-4),
128.48 1CPh4-3,5), 123.44 1C-4), 121.86 1CPh4-1), 106.04
1C-20), 81.16 1C-10), 40.57 1NCH3); MS 1ESI) m/z: 245
135Cl, 100%), 247 137Cl), 105, 77; HRMS 1ESI) for
C13H1035ClN2O [M1H]1: calcd 245.0482, found 245.0476.
1.5.2. 2-Methyl-5-ꢀpent-1-ynyl)-4-phenylethynyl-3ꢀ2H)-
pyridazinone ꢀ8b). Chromatography eluent: heptane/
EtOAc 17:3); yields 1135 mg, 51% from 7c; 210 mg, 97%
from 3a); brown oil; nmax 1liquid ®lm): 3063, 2964, 2933,
2873, 2204, 1657, 1572, 1379, 1245, 1026, 758, 690,
529 cm21; dH 1CDCl3): 7.66 1s, 1H, H-6), 7.61±7.58 1m,
2H, HPh4-2,6), 7.39±7.32 1m, 3H, HPh4-3,4,5), 3.78 1s, 3H,
NCH3), 2.52 1t, Jˆ7.0 Hz, 2H, H-300), 1.68 1br hex, J<
7.0 Hz, 2H, H-400), 1.07 1t, Jˆ7.3 Hz, 3H, H-500); dC
1CDCl3): 158.75 1C-3), 137.10 1C-6), 132.22 1CPh4-2,6),
129.36 1CPh4-4), 129.19, 125.41 1C-4 or C-5), 128.29
1CPh4-3,5), 122.36 1CPh4-1), 104.75, 104.10 1C-20 or C-200),
83.53 1C-10), 75.80 1C-100), 40.41 1NCH3), 21.86 1C-300),
21.70 1C-400), 13.42 1C-500); MS 1ESI) m/z: 277, 248, 220,
178 1100%), 165; HRMS 1ESI) for C19H15N2O [M1H]1:
calcd 277.1341, found 277.1329.
1.4.2. 5-Chloro-2-methyl-4-trimethylsilylethynyl-3ꢀ2H)-
pyridazinone ꢀ3c). Chromatography eluent: heptane/
EtOAc 185:15); yield 1180 mg, 55%); mp 988C 1brown
solid); nmax 1KBr): 3084, 3055, 2963, 1645, 1563, 1248,
1029, 935, 845, 763 cm21; dH 1CDCl3): 7.74 1s, 1H, H-6),
3.76 1s, 3H, NCH3), 0.29 1s, 9H, 1CH3)3Si); dC 1CDCl3):
158.49 1C-3), 140.36 1C-5), 135.72 1C-6), 122.93 1C-4),
113.89 1C-20), 94.99 1C-10), 40.48 1NCH3), 20.44
11CH3)3Si); MS 1ESI) m/z: 241 135Cl), 243 137Cl), 91, 73
1100%); HRMS 1ESI) for C10H1435ClN2OSi [M1H]1:
calcd 241.0564, found 241.0565.
1.5.3. 2-Methyl-5-phenylethynyl-4-trimethylsilylethynyl-
3ꢀ2H)-pyridazinone ꢀ8c). Chromatography eluent: hep-
tane/EtOAc 18:2); yields 1194 mg, 50% from 7a; 100 mg,
52% from 3c); mp 968C 1yellow solid); nmax 1KBr): 2957,
2899, 2212, 1650, 1568, 1250, 1056, 948, 846, 762,
688 cm21; dH 1CDCl3): 7.75 1s,1H, H-6), 7.55±7.60 1m,
2H, HPh-2,6), 7.38±7.46 1m, 3H, HPh-3,4,5), 3.78 1s, 1H,
NCH3), 0.30 1s, 9H, 1CH3)3Si); dC 1CDCl3): 158.66 1C-3),
136.41 1C-6), 132.18 1CPh-2,6), 129.97 1CPh-4), 129.49,
125.01 1C-4 or C-5), 128.57 1CPh-3,5), 121.55 1CPh-1),
112.44 1C-200), 102.15 1C-20), 97.59 1C-100), 83.72 1C-10),
40.51 1NCH3), 20.28 11CH3)3Si); MS 1ESI) m/z: 307, 305,
291, 165, 73 1100%); HRMS 1ESI) for C18H19N2OSi
[M1H]1: calcd 307.1267, found 307.1269.
1.4.3. 5-Chloro-2-methyl-4-ꢀpent-1-ynyl)-3ꢀ2H)-pyrida-
zinone ꢀ3e). Chromatography eluent: heptane/EtOAc
185:15); yield 1235 mg, 82%); mp 388C 1yellow solid);
nmax 1KBr): 3090, 2963, 2875, 2225, 1651, 1567, 1207,
955, 712, 628 cm21; dH 1CDCl3): 7.73 1s, 1H, H-6), 3.76
1s, 3H, NCH3), 2.55 1t, Jˆ7.0 Hz, 2H, H-30), 1.68 1br hex,
J<7.3 Hz, 2H, H-40), 1.08 1t, Jˆ7.3 Hz, 3H, H-50); dC
1CDCl3): 159.08 1C-3), 139.25 1C-5), 135.88 1C-6),
123.98 1C-4), 109.19 1C-20), 72.98 1C-10), 40.51 1NCH3),
22.29 1C-30), 21.72 1C-40), 13.45 1C-50); MS 1ESI) m/z: 211
135Cl), 213 137Cl), 182, 157, 128, 100 1100%); HRMS 1ESI)
for C10H1235ClN2O [M1H]1: calcd 211.0638, found
211.0643.
1.6. General procedure for the Suzuki reaction on
compounds 7a and 3a ꢀ9a,b and 10a,b)
1.5. General procedure for the introduction of a second
alkynyl group ꢀ8a±c)
Amixture of 7a or 3a 1170 mg, 0.7 mmol), Pd1PPh3)4
1250 mg, 0.021 mmol), boronic acid 10.13 g, 1.05 mmol)
and aqueous 2 M Na2CO3 11.1 mL) in toluene 14 mL) was
¯ushed with N2 for 5 min under stirring. Then the reaction
mixture was heated at 1208C until the starting material
had been consumed 1TLC analysis and/or DCI±MS).
After cooling to room temperature, the reaction mixture
To a solution of 7a±c or 3a,c 1270 mg, 1.12 mmol) in THF
16 mL), Pd2Cl21PPh3)2 125 mg, 0.034 mmol), CuI 1111 mg,
0.06 mmol), Et3N 11.44 mL, 10.1 mmol) and the 1-alkyne
11.46 mmol) were added. The reaction mixture was heated
at 808C under an N2 atmosphere until the starting material

10016
O. R'kyek et al. / Tetrahedron 57 ꢀ2001) 10009±10016
was evaporated to dryness under reduced pressure. EtOAc
was added and the suspension was placed in an ultrasonic
bath for a few minutes. The mixture was ®ltered through
a pad of Celitew and then concentrated under reduced
pressure. The residue obtained was puri®ed on silica gel.
142.28 1C-5), 135.96 1C-6), 135.26 1C-100), 132.18
1CPh4-2,6), 131.90 1C-600), 131.35 1q, JCFˆ32.8 Hz, C-300),
129.66, 129.31, 121.96, 121.56 1C-4 or CPh4-1 or C-500 or
CPh4-4), 128.44 1CPh4-3,5), 126.54 1q, JCFˆ3.8 Hz, C-200),
125.72 1q, JCFˆ3.8 Hz, C-400), 123.84 1q, JCFˆ272.4 Hz,
CF3), 103.84 1C-20), 82.84 1C-10), 40.76 1NCH3); MS
1ESI) m/z: 355 1100%), 298, 278, 258, 202; HRMS 1ESI)
for C20H14F3N2O [M1H]1: calcd 355.1058, found
355.1044.
1.6.1. 2-Methyl-4-phenyl-5-phenylethynyl-3ꢀ2H)-pyrida-
zinone ꢀ9a). Chromatography eluent: heptane/EtOAc 18:2);
yield 1171 mg, 86%); mp 1478C 1light yellow solid); nmax
1KBr): 3057, 2925, 2214, 1646, 1443, 1347, 1038, 754, 687,
579 cm21; dH 1CDCl3): 7.86 1s, 1H, H-6), 7.74 1br d, 2H,
HPh4-2,6), 7.49±7.40 1m, 3H, HPh4-3,4,5), 7.39±7.29 1m,
5H, H-5Ph), 3.83 1s, 3H, NCH3); dC 1CDCl3): 159.55
1C-3), 140.41 1C-4), 137.78 1C-6), 132.64 1C-10), 131.95
1CPh5-2,6), 130.10 1C-20,60), 129.67, 129.43 1CPh5-4 or
C-40), 128.53 1CPh5-3,5), 127.75 1C-30,50), 124.07 1C-5),
121.71 1CPh5-1), 99.23 1C-200), 84.29 1C-100), 40.69
1NCH3); MS 1ESI) m/z: 287, 230, 202 1100%); HRMS
1ESI) for C19H15N2O [M1H]1: calcd 287.1184, found
287.1170.
Acknowledgements
We thank Ing. J. Aerts, J. Schrooten, V. Van Heurck and
Ing. J. Verreydt for technical assistance and Professor Dr E.
Esmans for the use of his MS facilities. We also wish to
Á
thank Dr F. Lemiere for his assistance and his contribution
for the completion of this work. Tim Jonckers would like to
thank the IWT for a scholarship. Dr B. Maes and T. Jonckers
are grateful to the foundation `Rosa Blanckaert' for a
research grant. Dr B. Maes thanks the Fund for Scienti®c
Research 1FWO-Vlaanderen) for an appointment as Post-
doctoral Fellow.
1.6.2. 2-Methyl-5-phenylethynyl-4-ꢀ3-tri¯uoromethyl-
phenyl)-3ꢀ2H)-pyridazinone
ꢀ9b).
Chromatography
eluent: heptane/EtOAc 18:2); yield 1193 mg, 78%); mp
1398C 1pale yellow solid); nmax 1KBr): 2922, 2213, 1644,
1349, 1171, 1130, 1071, 1035, 882, 809, 753, 689 cm21; dH
1CDCl3): 8.07 1br s, 1H, H-20), 7.96 1br d, Jˆ7.8 Hz, 1H,
H-60), 7.90 1s, 1H, H-6), 7.70 1br d, Jˆ7.8 Hz, 1H, H-40),
7.59 1br t, Jˆ7.8 Hz, 1H, H-50), 7.41±7.30 1m, 5H,
HPh5-2,6), 3.85 1s, 3H, NCH3); dC 1CDCl3): 159.19 1C-3),
138.42 1C-4), 137.74 1C-6), 133.59, 133.38 1C-10 or C-60),
132.01 1CPh5-2,6), 130.39 1q, JCFˆ32.8 Hz, C-30), 130.00
1CPh5-4), 128.60 1CPh5-3,5), 128.30 1C-50), 127.11 1q, JCFˆ
3.8 Hz, C-20), 126.08 1q, JCFˆ3.8 Hz, C-40), 124.68 1C-5),
124.12 1q, JCFˆ272.4 Hz, CF3), 121.23 1CPh5-1), 100.30
1C-200), 83.54 1C-100), 40.77 1NCH3); MS 1ESI) m/z: 355,
335, 292, 264 1100%), 258, 202; HRMS 1ESI) for
C20H14F3N2O [M1H]1: calcd 355.1058, found 355.1052.
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1.6.3. 2-Methyl-5-phenyl-4-phenylethynyl-3ꢀ2H)-pyrida-
zinone ꢀ10a). Chromatography eluent: heptane/EtOAc
18:2); yield 1200 mg, 99%); mp 1078C 1yellow solid); nmax
1KBr): 3054, 2924, 2207, 1648, 1600, 1443, 1353, 1248,
1023, 928, 757, 697, 526 cm21; dH 1CDCl3): 7.88 1s, 1H,
H-6), 7.73 1br d, 2H, H-200,600), 7.51 1m, 3H, H-300,400,500),
7.44 1br d, 2H, HPh4-2,6), 7.32 1m, 3H, HPh4-3,4,5), 3.87 1s,
3H, NCH3); dC 1CDCl3): 159.72 1C-3), 144.10 1C-5), 136.72
1C-6), 134.42 1C-100), 132.14 1CPh4-2,6), 129.90 1C-400),
128.73, 128.62, 128.37 1CPh4-3,5 or CPh5-2,6 or CPh5-3,5),
122.43, 120.86 1CPh4-1 or C-4), 102.75 1C-200), 83.53 1C-100),
40.63 1NCH3); MS 1ESI) m/z: 287, 230 1100%), 202; HRMS
1ESI) for C19H15N2O [M1H]1: calcd 287.1184, found
287.1176.
È
È
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Ï
Á
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Ï Á
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phenyl)-3ꢀ2H)-pyridazinone ꢀ10b). Chromatography
eluent: heptane/EtOAc 18:2); yield 1218 mg, 94%); mp
1278C 1light yellow solid); nmax 1KBr): 3062, 2926, 2204,
1645, 1322, 1171, 1113, 1078, 936, 804, 750, 686,
525 cm21; dH 1CDCl3): 8.06 1br s, 1H, H-200), 7.88 1br d,
1H, H-600), 7.87 1s, 1H, H-6), 7.77 1br d, 1H, H-400), 7.67 1br
t, 1H, H-500), 7.43 1br d, 2H, HPh4-2,6), 7.39±7.29 1m, 3H,
HPh4-3,4,5), 3.89 1s, 3H, NCH3); dC 1CDCl3): 159.40 1C-3),
Ï Â
15. Konecny, V. Chem. Zvesti 1976, 30, 663±673.
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