Pyridazine derivatives. Part 33: Sonogashira approaches in the synthesis of 5-substituted-6-phenyl-3(2H)-pyridazinones

Article abstract of DOI:10.1016/S0040-4020(03)00263-1

Several 6-phenyl-3(2H)-pyridazinones bearing different alkynyl groups at position 5 have been prepared by a palladium-catalysed Sonogashira cross-coupling reaction. An interesting base-promoted electronically permitted isomerization has been observed duri

Full text of DOI:10.1016/S0040-4020(03)00263-1

Tetrahedron 59 (2003) 2477–2484
Pyridazine derivatives. Part 33:q Sonogashira approaches in the
synthesis of 5-substituted-6-phenyl-3(2H)-pyridazinones
*
Alberto Coelho, Eddy Sotelo and Enrique Ravin˜a
´ ´ ´ ´
Departamento de Quımica Organica, Laboratorio de Quımica Farmaceutica, Facultad de Farmacia,
Universidad de Santiago de Compostela, Santiago de Compostela 15782, Spain
Received 26 November 2002; revised 17 February 2003; accepted 17 February 2003
Abstract—Several 6-phenyl-3(2H)-pyridazinones bearing different alkynyl groups at position 5 have been prepared by a palladium-
catalysed Sonogashira cross-coupling reaction. An interesting base-promoted electronically permitted isomerization has been observed
during the coupling of 1-phenyl-2-propyn-1-ol. This rearrangement afforded the E-chalcone 6 in excellent yield. q 2003 Elsevier Science
Ltd. All rights reserved.
1. Introduction
structural and electronic properties of heterocycles in
comparison to the corresponding carbocyclic aryl com-
pounds.6 An example of this phenomenon can be seen in the
significant modification in the coupling behaviour (due to
the differences in acidity) between halopyridazines and
halo-3(2H)-pyridazinones.7 These reactivity differences
have allowed the use of 2-blocked-3-pyridazinones as
starting materials in palladium-catalysed transformations
and have also stimulated the search for new and efficient
protecting groups in this area.7,8
The interesting pharmacological activity displayed by
pyridazine derivatives has been demonstrated in recent
years not only by the growing number of papers and patents
describing them but also by the development of several
pyridazine-based drugs and pharmacological tools (Fig. 1).
Pyridazinones initially received special attention in the
search for drugs acting on the cardiovascular system2 and as
agrochemicals,3 but more recent publications have dealt
with the wide range of biological actions associated with
these compounds.4
As part of our medicinal chemistry program aimed at the
search for novel pyridazinone-based antiplatelet agents,9 it
became of interest to prepare several 5-alkynyl derivatives
II (structurally related to the previously prepared 5-sub-
stituted-6-phenyl-3(2H)-pyridazinones I), which were
required for structure–activity relationship (SAR) studies
(Fig. 2).
Despite the usefulness of pyridazines, simple methods for
the introduction of a range of substituents into this six-
membered heterocycle have not yet been extensively
developed and, for this reason, new advances in this area
continue to be of interest. Among the synthetic methods
described in the recent literature, transition metal mediated
cross-couplings have proven to be a powerful route for mild,
highly efficient carbon–carbon bond formation. In particu-
lar, processes involving palladium(0) catalysis are
extremely useful for the synthesis of a diverse range of
molecules owing to the excellent levels of selectivity and
high functional group compatibility. In this respect,
palladium cross-coupling reactions have become an
important tool in the synthesis of pyridazine derivatives.5
The most obvious synthetic strategy to prepare compounds
II involves the palladium-mediated cross-coupling trans-
formation of terminal acetylenes with the appropriately
Palladium chemistry involving heterocycles has unique
characteristics stemming from the inherently different
q See Ref. 1.
Keywords: pyridazinones; Sonogashira coupling; chalcone.
*
Corresponding author. Fax: þ34-981-594912; e-mail: qofara@usc.es
Figure 1. Several pharmacologically useful pyridazine derivatives.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00263-1

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A. Coelho et al. / Tetrahedron 59 (2003) 2477–2484
zinone 114 was used as the starting material (Scheme 1). In a
similar way to our previous studies on Suzuki arylation of
this system,7 all attempts to perform the cross-coupling
reactions between 1 and terminal acetylenes under
Sonogashira conditions afforded only around 5–10% of
the expected coupling products and more than 85% of 1 was
recovered.
The low reactivity of this system can be attributed to the
acidity of the NH group, or rather to the lactam function in
the pyridazinone ring (which is about as acidic as phenol
PKa<10). In a subsequent reaction the NH group of 1 was
protected with the methoxymethyl (MOM) group
(Scheme 2), which can be easily removed by treatment of
the corresponding 2-methoxymethyl-3-pyridazinone either
with 6N hydrochloric acid or a Lewis acid (see Section 2).
Figure 2.
Several experiments were performed using the cross-
coupling reaction of 2 with TMS-acetylene as model. A
brief screen of Pd(0) sources showed that Pd(PPh3)2Cl2 was
the best choice (Table 1). As can be seen from the results in
Table 1, which summarise some of the conditions tested, the
efficiency of the coupling reaction was highly dependent
upon the type of solvent used. DMF and dioxane proved to
be much better than THF, DCM or MeCN.
Scheme 1. (i) Pd(PPh3)2Cl2/CuI/Et3N/DMF/608C.
substituted 5-halo-3(2H)-pyridazinone using the well-
documented Sonogashira reaction.10 There are several
references describing the Sonogashira reaction on halo-
pyridazines11 but, to the best of our knowledge, there are
only two reports describing such a transformation on 3(2H)-
pyridazinones. The first report on the palladium-catalysed
Sonogashira synthesis of pyridazinones bearing alkynyl
groups was published by our group.12 More recently,
After some optimisation of the experimental conditions it
was found that alkynyl coupling of 2 can be readily
achieved, in moderate to excellent yields (Table 2), using
bis(triphenylphosphine)palladium chloride as the palladium
source, copper(I) iodide as a co-catalyst, triethylamine as a
base and DMF as a solvent (Scheme 2). Under these
conditions, reactions occurred cleanly and rapidly at
temperatures up to 558C and very little starting halide
remained after five hours in all cases. The coupling process
is free of side reactions, such as alkyne homocoupling,
which indicates that under these conditions carbon–carbon
bond formation is significantly faster than homocoupling.
The products were obtained with 80–90% purity after a
simple work-up and these materials were further purified by
column chromatography.
`
Lemiere and co-workers described the preparation of
symmetrically and unsymmetrically 4,5-substituted alkynyl
pyridazinones.13 As a continuation of our search for new,
simple and efficient palladium-catalysed procedures to
allow the pharmacomodulation of the 5 position of
6-phenyl-3(2H)-pyridazinone system, here we describe
results obtained by applying the Sonogashira reaction.
In the initial experiment 5-bromo-6-phenyl-3(2H)-pyrida-
Table 1. Sonogashira couplings with various catalytic systems
Catalyst system
Solvent
Yields (%)
Once the coupling reactions had been successfully carried
out, the methoxymethyl (MOM) group was removed from
compounds 3a–g. Our previous studies in this area have
shown that the use of hydrochloric acid is not tolerated by
the sensitive functionalities present on 38a and so the MOM
deprotection of acid sensitive compounds was achieved
using the milder Lewis acid aluminium chloride.
Pd(PPh3)4/CuI/Et3N
Pd(PPh3)4/CuI/Et3N
Pd(PPh3)2Cl2/CuI/Et3N
Pd(PPh3)2Cl2/CuI/Et3N
Pd(PPh3)2Cl2/CuIEt3N
Pd(PPh3)2Cl2/CuI/Et3N
CH3CN
DMF
Dioxane
DCM
CH3CN
DMF
39
45
70
51
63
90
All coupling reactions were conducted at 558C with 1.2 equiv. of alkyne,
10% Pd(PPh3)2Cl2, 10% CuI, 2 equiv. of amine, solvent.
Curiously, despite the fact that this method appears to be
Scheme 2. Palladium-mediated alkynylation of 2.

A. Coelho et al. / Tetrahedron 59 (2003) 2477–2484
2479
Table 2. Sonogashira cross-coupling reaction on 2
7.23 ppm with a coupling constant of 15.5 Hz, which
confirms a trans stereochemistry for the double bond. The
observation of signals corresponding to a ketonic carbonyl
function in the 13C NMR and IR spectra at 189.0 ppm and
1700 cm21, respectively, confirmed the existence of the
ketone.
The unusual formation of chalcone 6 is not dissimilar to
results described in previous papers concerning the
Sonogashira coupling of several halides with 1-phenyl-2-
propyn-1-ol15–20 or some transition metal-catalysed redox
isomerizations of propargyl alcohols to a,b-unsaturated
carbonyl compounds.21–23 This situation prompted a more
detailed study of this transformation.
Entry
R
Yield (%)
Time (h)
3a
3b
3c
3d
3e
3f
CH2OH
CH2CH2OH
Ph
85
90
80
6
4
6
3
–
5
–
TMS
H
90
60a
78
An exhaustive review of different reaction conditions
enabled the isolation of the expected phenyl-substituted
propargyl alcohol 5 by carrying out the reaction at room
temperature (258C) (Scheme 4). Identification of inter-
mediate 5 is supported by both analytical and spectroscopic
data (see Section 2); a small sharp absorption at 2226 cm21
in the IR spectrum and signals corresponding to the alkyne
unit (81.9, 101.0 ppm) in the 13C NMR spectrum. The fact
that compound 5 is the main intermediate during chalcone
formation has also been demonstrated by quantitative
formation of 6 after stirring 5 in presence of triethylamine
in a range of solvents (DCM, MeOH, THF, DMF)—even at
room temperature.
CHOHCH3
CH2OCOCH3
3g
72b
a
Overall yield (Sonogashira-couplingþdesilylation) from bromopyridazi-
none 2.
Overall yield (Sonogashira-couplingþacetylation) from bromopyridazi-
b
none 2.
quite general, it failed in the cross-coupling reaction of 2
with 1-phenyl-2-propyn-1-ol (Scheme 3). Thus, heating a
mixture of 2 and 1-phenyl-2-propyn-1-ol under the afore-
mentioned conditions did not give the expected 5-(3-
hydroxy-3-phenylprop-1-ynyl)-2-methoxymethyl-6-
phenyl-3-pyridazinone 5 but that the isomeric E-chalcone 6
was obtained in good yield (80%).
It is worth noting that this reaction produces the chalcone 6
with an E-selectivity greater than 95% after isolation and
purification by column chromatography. The exclusive
formation of the trans olefin can be understood in terms of
the severe steric interaction between the phenyl group at
position 5 of the heterocyclic ring and the carbonyl moiety
in the Z isomer.
The identity of E-5-(3-oxo-3-phenylpropenyl)-2-methoxy-
methyl-6-phenyl-3-pyridazinone (6) was unambiguously
established on the basis of the analytical and spectroscopic
data (see Section 2). The H NMR spectra of product 6
contained two doublets centred, respectively, at 8.03 and
1
Scheme 3. Sonogashira cross-coupling of 1-phenyl-2-propyn-1-ol with 2.
Scheme 4. Base-promoted isomerization of 5.

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A. Coelho et al. / Tetrahedron 59 (2003) 2477–2484
Scheme 5. Mechanistic proposal for the formation of chalcone 6.
On the evidence of this data the explanation given for a
similar transformation on pyrimidines15–17 (which is based
on a co-ordination of an intermediate during a hydro-
palladation–dehydropalladation catalytic cycle to the
heterocyclic nitrogen) is not applicable in this case due to
the absence of heteroatom co-ordination in pyridazinones.
Our results are, however, consistent with more recent
works19,20 indicating that the reaction is not only limited to
compounds containing iodine as the halogen18 and they
confirm that the formation of 6 occurs exclusively in a base-
catalysed manner—the isomerization process being
facilitated by the electron-deficient nature of the pyridazi-
none system.
against tetramethylsilane as internal standard and J values
are given in Hz. Mass spectra were obtained on a Varian
MAT-711 instrument. High resolution mass spectra were
obtained on an Autospec Micromass. Elemental analyses
were performed on a Perkin–Elmer 240B apparatus at the
Microanalysis Service of the University of Santiago de
Compostela. The reactions were monitored by TLC with
2.5 mm Merck silica gel GF 254 strips, and the purified
compounds each showed a single spot; unless stated
otherwise, iodine vapour and/or UV light were used for
detection of compounds. Commercially available starting
materials and reagents were purchased and used without
further purification.
The mechanistic pathway proposed for this transformation
is outlined in Scheme 5. Sonogashira coupling of 2 with
1-phenyl-2-propyn-1-ol affords the substituted propargyl
alcohol 5 which, upon deprotonation at the propargyl centre
with triethylamine, leads to a propargyl-allenyl anion 7.
Protonation of this species afforded the allene 8. Finally, the
allenol-enone tautomerism furnishes the trans-configured
enone 6.
2.1. Synthesis of 5-alkynyl-6-phenyl-2-methoxymethyl-3-
pyridazinones 3a–g. General procedure
To a degassed (argon) suspension of bromopyridazinone 2
(1.02 mmol), PdCl2(PPh3)2 (0.01 mmol) and CuI
(0.01 mmol) in DMF (15 mL) was added the corresponding
alkyne (1.52 mmol) and triethylamine (2.032 mmol). The
mixture was heated at 558C under argon until the starting
material had been consumed (during this time the solution
turned dark brown). The mixture was cooled to room
temperature, diluted with dichloromethane and filtered
through Celite. The filtrate was concentrated in vacuo and
purified by column chromatography on silica gel. Further
purification was carried out by recrystallization.
In summary, we have prepared several 5-alkenyl-6-phenyl-
3(2H)-pyridazinones by using the Sonogashira cross-
coupling reaction of 2 with different acetylenes. The
palladium-mediated alkynylation of 2 using 1-phenyl-2-
propyn-1-ol afforded the isomeric E-chalcone 6 in
excellent yield. Our detailed study of this transformation
leads to the conclusion that the key factor in the
isomerization step is the electron-deficient nature of the
starting halide.
2.1.1. 5-(3-Hydroxyprop-1-ynyl)-2-methoxymethyl-6-
phenyl-3-pyridazinone (3a). Purification by column chro-
matography on silica gel using AcOEt/hexane (3:1) as
eluent afford a pale yellow oil; yield 85%. IR (KBr):
n
max/cm21 3054 (OH), 2305 (CuC), 1663 (CO), 1559
(Aromatics), 1097 (C–O–C). 1H NMR (CDCl3 300 MHz),
d (ppm): 7.69 (m, 2H, Aromatics), 7.43 (m, 3H, Aromatics),
7.15 (s, 1H, H4), 5.43 (s, 2H, O–CH2), 5.37 (s, 2H, –CH2–),
3.45 (s, 3H, CH3–O), 3.37 (brs, 1H, OH). 13C NMR (CDCl3
75 MHz), d (ppm): 160.0, 146.6, 134.5, 133.4, 130.0, 129.1,
129.1, 128.5, 100.9, 82.1, 80.0, 58.2, 51.4. MS (70 eV)
m/z (%): 270 (Mþ, 10), 240 (56), 227 (54), 139 (50), 115
(100).
2. Experimental
Melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. IR spectra were
measured using a Perkin–Elmer 1640 FTIR spectro-
photometer with samples as potassium bromide pellets.
The NMR spectra were recorded on Bruker AM300 and
XM500 spectrometers. Chemical shifts are given as d values

A. Coelho et al. / Tetrahedron 59 (2003) 2477–2484
2481
2.1.2. 5-(4-Hydroxybut-1-ynyl)-2-methoxymethyl-6-phe-
nyl-3-pyridazinone (3b). Purification by column chroma-
tography on silica gel using AcOEt/hexane (3:1) as eluent
afford a pale yellow oil; yield 90%. IR (KBr): nmax/cm21
3438 (OH), 2229 (CuC), 1649 (CO), 1567 (Aromatics),
1098 (C–O–C). 1H NMR (CDCl3 300 MHz), d (ppm): 7.69
(m, 2H, Aromatics), 7.44 (m, 3H, Aromatics), 7.07 (s, 1H,
H4), 5.46 (s, 2H, O–CH2), 3.67 (t, J¼6.2 Hz, –CH2–), 3.49
(s, 3H, CH3–O), 2.60 (t, J¼6.2 Hz, –CH2–), 3.39 (brs, 1H,
OH). 13C NMR (CDCl3 75 MHz), d (ppm): 160.0, 146.4,
133.0, 135.0, 129.9, 129.1, 128.4, 100.4, 81.9, 77.0, 60.7,
58.2, 30.0, 24.4. MS (70 eV) m/z (%): 284 (Mþ, 19), 254
(100), 253 (68), 241 (79), 183 (46), 152 (61).
(CuC), 1654 (CO), 1584 (Aromatics), 1094 (C–O–C). 1H
NMR (CDCl3 300 MHz), d (ppm): 7.67 (m, 2H, Aromatics),
7.41 (m, 3H, Aromatics), 7.12 (s, 1H, H4), 5.41 (s, 2H, CH2),
4.60 (d, J¼6.6 Hz, 1H, CH), 3.78 (brs, 1H, OH), 3.43 (s, 3H,
CH3), 1.39 (d, J¼6.6 Hz, 3H, CH3). 13C NMR (CDCl3
75 MHz), d (ppm): 160.0, 146.7, 134.5, 133.1, 129.9, 129.2,
129.1, 128.4, 104.3, 82.0, 78.6, 58.6, 58.2, 23.6. MS (70 eV)
m/z (%): 284 (Mþ, 16), 254 (100), 241 (100), 139 (86), 115
(44), 76 (65), 57 (77).
2.1.7. 5-(3-Acetoxyprop-1-ynyl)-2-methoxymethyl-6-
phenyl-3-pyridazinone (3g). This compound was prepared
by acetylation of 3a. To a solution of compound 3a
(200 mg, 0.74 mmol) in pyridine (4.5 mL) was added acetic
anhydride (2 mL, 2.22 mmol). The reaction mixture was
stirred at room temperature overnight. The mixture was
evaporated in vacuo and the oily residue was precipitated
with 30 mL of ice containing 20 mL of 10% HCl. The
product was extracted with ethyl acetate, the organic phase
was dried with anhydrous Na2SO4 and the solvent
evaporated in vacuo. The resulting oily residue was purified
by column chromatography on silica gel using AcOEt/
hexane (1:1) as eluent to afford a yellow oil, which
crystallised on standing to give white needles; yield 85%.
Mp 68–698C. IR (KBr): nmax/cm21 2338 (CuC), 1748
2.1.3. 2-Methoxymethyl-6-phenyl-5-(2-phenylethynyl)-3-
pyridazinone (3c). Purification by column chromatography
on silica gel using AcOEt/hexane (1:4) as eluent gave a
colourless oil; yield 80%. IR (KBr): nmax/cm21 2212
(CuC), 1671 (CO), 1585 (Aromatics), 1080 (C–O–C).
1H NMR (CDCl3 300 MHz), d (ppm): 7.80 (m, 2H,
Aromatics), 7.54 (m, 1H, Aromatics), 7.44 (m, 3H,
Aromatics), 7.35 (m, 4H, Aromatics), 7.17 (s, 1H, H4),
5.50 (s, 2H, –CH2O), 3.52 (s, 3H, –OCH3). 13C NMR
(CDCl3 75 MHz), d (ppm): 159.9, 146.4, 134.9, 132.5,
132.3, 130.4, 130.0, 129.9, 129.2, 128.9, 128.4, 121.6,
101.1, 84.6, 81.9, 58.3. MS (70 eV) m/z (%): 316 (Mþ, 15),
286 (59), 273 (46), 215 (100), 126 (32).
1
(CO), 1669 (CO), 1587 (Aromatics), 1096 (C–O–C). H
NMR (CDCl3 300 MHz), d (ppm): 7.68 (m, 2H, Aromatics),
7.42 (m, 3H, Aromatics), 7.10 (s, 1H, H4), 5.45 (s, 2H, O–
CH2), 4.77 (s, 2H, –CH2–), 3.48 (s, 3H, CH3–O), 2.05 (s,
3H, –COCH3). 13C NMR (CDCl3 75 MHz), d (ppm): 170.2,
159.5, 146.0, 134.5, 133.9, 129.8, 129.1, 128.4, 128.3, 95.2,
82.0, 81.1, 58.2, 52.4, 20.9. MS (70 eV) m/z (%): 312 (Mþ,
20), 282 (100), 269 (73), 151 (57), 115 (17), 77 (13).
2.1.4. 2-Methoxymethyl-6-phenyl-5-(3-trimethylsilanyl-
ethynyl)-3-pyridazinone (3d). Purification by column
chromatography on silica gel using AcOEt/hexane (1:3) as
eluent afford a yellow oil; yield 75%. IR (KBr): nmax/cm21
2162 (CuC), 1670 (CO), 1586 (Aromatics), 1090 (C–O–
1
C). H NMR (CDCl3 300 MHz), d (ppm): 7.69 (m, 2H,
Aromatics), 7.42 (m, 3H, Aromatics), 7.05 (s, 1H, H4), 5.46
(s, 1H, CH2O), 3.51 (s, 3H, –OCH3), 0.12 (s, 9H, 3£CH3).
13C NMR (CDCl3 75 MHz), d (ppm): 159.7, 146.2, 134.6,
133.6, 129.7, 129.2, 129.0, 128.2, 108.7, 99.1, 81.8, 58.1,
20.4. MS (70 eV) m/z (%): 312 (Mþ, 23), 282 (94), 269
(100), 211 (51), 107 (57).
2.1.8. 5-(3-Hydroxy-3-phenyl-prop-1-ynyl)-2-methoxy-
methyl-6-phenyl-3-pyridazinone (5). This intermediate
can be isolated by performing the cross-coupling reaction
at room temperature (258C) (2 h) and following the course
of the reaction by TLC. The solvent was removed in vacuo
at room temperature and the resulting oily residue contained
a mixture of the starting material 2, the alkyne 5 and the
chalcone 6. This mixture was separated by column
chromatography on silica gel using AcOEt/hexane (1:4) as
eluent to afford 15% of 2, 50% of chalcone 6 and 30% of the
intermediate 5 as a yellow oil. IR (KBr): nmax/cm21 3352
(OH), 2226 (CuC), 1656 (CO), 1584 (Aromatics), 1094
2.1.5. 5-Ethynyl-2-methoxymethyl-6-phenyl-3-pyridazi-
none (3e). This compound was prepared by desilylation of
3d. A solution of compound 3d (100 mg, 0.320 mmol) in
1 M methanolic KOH (4 mL) was stirred at room tempera-
ture during 15 min. The mixture was acidified to pH 7 with
3N HCl and the organic material was extracted with
dichloromethane and dried with anhydrous Na2SO4. Puri-
fication by column chromatography using AcOEt/hexane
(1:2) furnished a colourless oil; yield 53 mg (70%). IR
1
(C–O–C). H NMR (CDCl3 75 MHz), d (ppm): 7.65 (m,
2H, Aromatics), 7.34 (m, 8H, Aromatics), 7.16 (s, 1H, H4),
5.58 (s, 1H, CH), 5.46 (s, 2H, CH2), 3.49 (s, 1H, OH), 3.48
(s, 1H, CH3). 13C NMR (CDCl3 300 MHz), d (ppm): 159.8,
145.4, 139.5, 133.7, 130.3, 129.8, 129.3, 129.1, 129.1,
128.7, 128.5, 126.9, 101.0, 82.0, 81.9, 65.2, 58.2. MS
(70 eV) m/z (%): 346 (Mþ, 38), 316 (100), 303 (71), 215
(30), 202 (17), 77 (11). HRMS, m/z: calcd for C21H18N2O3
(Mþ) 346.3793, found 346.3897.
(KBr):
n
max/cm21 2105 (CuC), 1669 (CO), 1585
1
(Aromatics), 1084 (C–O–C). H NMR (CDCl3 75 MHz),
d (ppm): 7.73 (m, 2H, Aromatics), 7.42 (m, 3H, Aromatics),
7.19 (s, 1H, H4), 5.48 (s, 2H, CH2), 3.50 (s, 3H, CH3), 3.48
(s, 1H, CH). 13C NMR (CDCl3 300 MHz), d (ppm): 159.5,
146.3, 135.1, 134.5, 129.9, 129.1, 128.5, 128.3, 89.3, 82.0,
78.2, 58.3. MS (70 eV) m/z (%): 240 (Mþ, 7), 210 (33), 197
(25), 139 (51), 118 (14), 77 (12), 58 (100).
2.1.9. 2-Methoxymethyl-5-(3-oxo-3-phenylpropenyl)-6-
phenyl-3-pyridazinone (6). Column chromatography on
silica gel using AcOEt/hexane (1:2) as eluent to give a white
solid; yield 80%. Mp 177–1788C (Isopropanol). IR (KBr):
2.1.6. 5-(3-Hydroxybut-1-ynyl)-2-methoxymethyl-6-phe-
nyl-3-pyridazinone (3f). Purification by column chroma-
tography on silica gel using AcOEt/hexane (3:1) as eluent
afforded a yellow oil; yield 78%. IR (KBr): nmax/cm21 2224
n
max/cm21 1700 (CO), 1662 (CO), 1588 (Aromatics), 1091
1
(C–O–C). H NMR (DMSO-d6 300 MHz), d (ppm): 8.11
(m, 2H, Aromatics), 8.03 (d, J¼15.5 Hz, 1H, CH), 7.63 (m,

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A. Coelho et al. / Tetrahedron 59 (2003) 2477–2484
8H, Aromatics), 7.51 (s, 1H, H4), 7.23 (d, J¼15.5 Hz, 1H,
CH), 5.38 (s, 2H, CH2), 3.37 (s, 3H, CH3). 13C NMR
(DMSO-d6 75 MHz), d (ppm): 189.0, 159.9, 146.7, 139.5,
137.2, 137.0, 134.7, 134.1, 129.6, 129.5, 129.4, 129.2,
129.1, 128.9, 127.2, 81.0, 57.4. MS (70 eV) m/z (%): 346
(Mþ, 45), 315 (67), 287 (29), 245 (15), 105 (13). Anal. calcd
for C21H18N2O3 C 72.82, H 5.24, N 8.09; found, C 72.86, H
5.26, N 8.12.
stirred for 30 min. The mixture was extracted with chloro-
form and the organic layer dried with anhydrous Na2SO4.
The solvent was removed in vacuo and the resulting solid
was washed with ether, purified by column chromatography
on silica gel and then recrystallized (Table 3).
2.4.1. 5-(3-Hydroxyprop-1-ynyl)-6-phenyl-3(2H)-pyrida-
zinone (4a). Method B. Purification by column chromato-
graphy on silica gel (AcOEt/hexane 1:5) gave white
crystals; yield 80%. Mp 167–1698C (Isopropanol). IR
(KBr): nmax/cm21 3566 (OH), 2237 (CuC), 1654 (CO),
1558 (Aromatics), 1098 (C–O–C). 1H NMR (MeOD
300 MHz), d (ppm): 11.33 (1H, brs, NH), 7.73 (m, 2H,
Aromatics), 7.48 (m, 3H, Aromatics), 7.16 (s, 1H, H4), 4.35
(s, 2H, –CH2), 3.34 (bs, 1H, OH). 13C NMR (MeOD
75 MHz), d (ppm): 162.6, 148.9, 136.3, 133.7, 131.1, 130.8,
130.2, 129.5, 101.9, 80.6, 51.4. MS (70 eV) m/z (%): 226
(Mþ, 60), 208 (100), 152 (62), 115 (61). Anal. calcd for
C13H10N2O2, C 69.02, H 4.46, N 12.38; found, C 69.12, H
4.42, N 12.43.
2.2. Base-promoted isomerization of intermediate 5
under basic conditions
A mixture of 5-(3-Hydroxy-3-phenyl-prop-1-ynyl)-2-meth-
oxymethyl-6-phenyl-3-pyridazinone 5 (60 mg), MeOH
(7 mL) and a catalytic amount of triethylamine was heated
under reflux until the starting material had been completely
transformed in the chalcone 6. The solvent was evaporated
in vacuo, the resulting residue was purified by column
chromatography on silica gel under the experimental
conditions above described.
2.3. Representative procedure for the deprotection of 2-
methoxymethyl-3-pyridazinones. Method A (6N HCl)
2.4.2. 5-(4-Hydroxybut-1-ynyl)-6-phenyl-3(2H)-pyrida-
zinone (4b). Method A. Purification by column chromato-
graphy on silica gel (AcOEt/hexane 1:5) gave white
crystals; yield 80%. Mp 199–2018C (Isopropanol). IR
(KBr): nmax/cm21 3566 (OH), 2226 (CuC), 1652 (CO),
A mixture of the corresponding 2-methoxymethyl-3-
pyridazinone 3 (1.11 mmol), MeOH (5 mL) and 6N HCl
(15 mL) was heated under reflux until the starting material
had been completely consumed (24–48 h). The mixture was
extracted with dichloromethane, the organic layer dried
with anhydrous Na2SO4 and the solvent evaporated in
vacuo. The resulting residue was purified by column
chromatography on silica gel and then crystallised.
1
1558 (Aromatics). H NMR (CDCl3 300 MHz), d (ppm):
10.91 (1H, brs, NH deuterium oxide exchangeable), 7.67
(m, 2H, Aromatics), 7.43 (m, 3H, Aromatics), 7.08 (s, 1H,
H4), 3.67 (t, J¼6.2 Hz, 2H, –CH2–), 2.62 (t, J¼6.2 Hz, 2H,
CH2), 1.48 (brs, 1H, OH). 13C NMR (CDCl3 75 MHz), d
(ppm): 159.6, 145.6, 135.0, 132.3, 129.3, 128.9, 128.8,
128.2, 100.9, 77.0, 59.3, 23.8. MS (70 eV) m/z (%): 240
(Mþ, 60), 209 (51), 181 (64), 152 (100), 77 (43). Anal. calcd
for C14H12N2O2, C 69.99, H 5.03, N 11.66; found, C 70.05,
H 5.03, N 11.71.
2.4. Representative procedure for the deprotection of 2-
methoxymethyl-3-pyridazinones. Method B (AlCl3)
In a carefully purged flask, AlCl3 (670 mg, 5.03 mmol) was
suspended in dry toluene (8 mL) and the mixture was stirred
at room temperature during 10 min. The corresponding
2-methoxymethyl-3-pyridazinone 3 (1.00 mmol) in toluene
(3 mL) was added dropwise and the mixture was heated
under reflux for 1 h. Once the starting material had been
consumed, 50 mL of ice was added and the mixture was
2.4.3. 6-Phenyl-5-(2-phenylethynyl)-3(2H)-pyridazinone
(4c). Method A. Purification by column chromatography on
silica gel (AcOEt/hexane 1:5) gave a white solid; yield 80%.
Mp 158–1508C (Isopropanol). IR (KBr): nmax/cm21 1651
1
(CO), 1577 (Aromatics). H NMR (CDCl3 300 MHz), d
(ppm): 11.25 (1H, brs, NH deuterium oxide exchangeable),
7.78 (m, 2H, Aromatics), 7.49 (m, 3H, Aromatics), 7.36 (m,
5H, Aromatics), 7.19 (s, 1H, H4). 13C NMR (CDCl3
75 MHz), d (ppm): 160.7, 147.4, 134.9, 132.3, 132.2,
130.4, 130.1, 129.8, 129.2, 128.9, 128.4, 121.7, 101.2, 84.8.
MS (70 eV) m/z (%): 272 (Mþ, 100), 271 (40), 215 (40).
Anal. calcd for C18H12N2O, C 79.39, H 4.44, N 10.29;
found, C 79.44, H 4.49, N 10.30.
Table 3. Deprotection of 2-Methoxymethyl-3-pyridazinones 3a–g
2.4.4. 6-Phenyl-5-(3-trimethylsilanylethynyl)-3(2H)-pyr-
idazinone (4d). Method A. Purification by column chroma-
tography on silica gel (AcOEt/hexane 1:3) gave a white
solid; yield 85%. Mp 156–1578C (Isopropanol). IR 2855
(NH), 2136 (CuC), 1654 (CO), 1525 (Aromatics), 1133
Entry
R
Yield(%)
Deprotecting agent
1
(C–O–C). H NMR (CDCl3 300 MHz), d (ppm): 12.46
4a
4b
4c
4d
4e
4f
CH2OH
CH2CH2OH
Ph
70
78
80
85
51
80
85
AlCl3
HCl
HCl
(1H, brs, NH deuterium oxide exchangeable), 7.73 (m, 2H,
Aromatics), 7.42 (m, 3H, Aromatics), 7.13 (s, 1H, H4), 0.16
(s, 9H, 3£CH3). 13C NMR (CDCl3 75 MHz), d (ppm):
161.2, 147.4, 134.7, 133.1, 129.7, 129.2, 128.2, 108.9, 99.3,
20.4. MS (70 eV) m/z (%): 268 (Mþ, 100), 253 (94), 225
(24), 139 (26), 107 (28), 77 (60). Anal. calcd for
TMS
H
HCl
AlCl3
AlCl3
AlCl3
CHOHCH3
CH2OCOCH3
4g

A. Coelho et al. / Tetrahedron 59 (2003) 2477–2484
2483
C15H16N2OSi, C 67.13, H 6.01, N 10.44; found, C 67.15, H
6.04, N 10.45.
135.2, 134.0, 129.3, 129.2, 129.2, 129.1, 129.0, 128.9,
127.6. MS (70 eV) m/z (%): 302 (Mþ, 0.5), 215 (6), 139
(26), 105 (100), 77 (84). Anal. calcd for C19H14N2O2, C
75.48, H 4.67, N 9.27; found, C 75.52, H 4.71, N 9.33.
2.4.5. 5-Ethynyl-6-phenyl-3(2H)-pyridazinone (4e). A
solution of compound 4d (100 mg, 301 mmol) in 1 M
methanolic KOH (4 mL) was stirred at room temperature
during 10 min. The mixture was acidified to pH 7 with 3N
HCL and then extracted with dichloromethane to give a
yellow solid. Further purification by column chromato-
graphy (AcOEt/hexane 1:1.5) and recrystallization from
isopropanol furnished a white solid; yield 51%. Mp 202–
2038C. IR (KBr): nmax/cm21 2984 (NH), 2113 (CuC), 1684
(CO), 1560 (Aromatics). 1H NMR (DMSO-d6, 300 MHz), d
(ppm): 13.35 (1H, brs, NH deuterium oxide exchangeable),
7.64 (m, 2H, Aromatics), 7.45 (m, 3H, Aromatics), 7.18 (s,
1H, H4), 4.79 (s, 1H, CH), 3.37 (s, 9H, 3£CH3). 13C NMR
(DMSO-d6, 75 MHz), d (ppm): 159.4, 145.5, 134.9, 134.1,
129.4, 128.8, 128.3, 127.7, 91.8, 78.7. MS (70 eV) m/z (%):
196 (Mþ, 66), 139 (38), 69 (41), 63 (51), 57 (100), 58 (93).
Anal. calcd for C12H8N2O, C 73.46, H 4.11, N 14.28; found,
C 73.52, H 4.14, N 14.31.
Acknowledgements
A. Coelho is indebted to Fondos FEDER for a doctoral
fellowship. E. Sotelo thanks the University of Santiago de
Compostela for his appointment as Post doctoral fellow.
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