Pyridazine derivatives. Part 40: Reactivity of 5-alkynylpyridazin-3(2H)- ones toward hydrochloric acid

Article abstract of DOI:10.1016/j.tet.2005.03.021

5-Alkynylpyridazin-3(2H)-ones or 5-(2-chloroalkenyl)pyridazin-3(2H)-ones were isolated during the cleavage of the methoxymethyl group in a series of 5-alkynyl-2-methoxymethylpyridazin-3(2H)-ones by treatment with hydrochloric acid. The efficient and selective cleavage of the methoxymethyl group in these compounds can be performed under mild conditions by employing aluminium chloride.

Full text of DOI:10.1016/j.tet.2005.03.021

Tetrahedron 61 (2005) 4785–4791
Pyridazine derivatives. Part 40: Reactivity of
5-alkynylpyridazin-3(2H)-ones toward hydrochloric acid*
a
Alberto Coelho, Hector Novoa, Oswald M. Peeters, Norbert Blaton, Mario Alvarado
b
b
b
a
´
and Eddy Soteloa,
*
a
´ ´ ´ ´
Departamento de Quımica Organica, Laboratorio de Quımica Farmaceutica, Facultad de Farmacia,
Universidad de Santiago de Compostela, Santiago de Compostela 15782, Spain
bKatholieke Universiteit Leuven, Laboratorium voor Analytische Chemie en Medicinale Fysicochemie,
Faculteit Farmaceutische Wetenschappen, E. Van Evenstraat 4, B-3000 Leuven, Belgium
Received 25 January 2005; revised 2 March 2005; accepted 4 March 2005
Available online 24 March 2005
Abstract—5-Alkynylpyridazin-3(2H)-ones or 5-(2-chloroalkenyl)pyridazin-3(2H)-ones were isolated during the cleavage of the
methoxymethyl group in a series of 5-alkynyl-2-methoxymethylpyridazin-3(2H)-ones by treatment with hydrochloric acid. The efficient
and selective cleavage of the methoxymethyl group in these compounds can be performed under mild conditions by employing aluminium
chloride.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
enolizable carbonyl group. Elegant and selective trans-
formations using the benzyloxymethyl (BOM) group have
´
The recent advances in combinatorial chemistry and high-
throughput screening have confirmed the tremendous
importance of heterocycles as templates in the search for
novel pharmacologically useful low molecular weight
compounds.2 Accordingly, the development of new, robust
and efficient syntheses of functionalized heterocyclic
compounds, both in solution or solid phase, is an expanding
field. The numerous syntheses of pyridazin-3(2H)-ones
published in recent years3 represent significant progress in
terms of the efficient protection and deprotection of position
2 of the heterocyclic ring. Although all structural studies on
this nucleus have shown that pyridazin-3(2H)-ones exist in
the keto form,3 reactions involving ambident rings that
possess a tautomeric or mesomeric structure are often
inefficient and lack regiocontrol. For this reason, most of the
studies reported for this scaffold use as starting materials
pyridazinones in which position 2 is blocked. Numerous
literature examples concern analogues in which position 2 is
substituted by groups such as Me, or Ph, which are not
strictly protecting groups in the true sense as they cannot be
removed—their role being limited to blocking the
been described by Matyus as part of a comprehensive
program aimed at the synthesis of 4,5-disubstituted- and
4,5-heterofused pyridazinones.4 Although the introduction
of the benzyl group can be easily achieved, cleavage by
classical methods (H2/Pd) is sometimes problematic in
polyfunctional derivatives.5 In this respect, several authors
have employed Lewis acids as an alternative and efficient
deprotection procedure.5a,b,6
A survey of the literature on protecting groups7 reveals that,
although there are excellent methods available for the
deprotection of O-alkyl and O-alkyloxyalkyl groups,
methods for the deprotection of the amide or lactam
functionality are limited and usually require acidic con-
ditions.7 As a consequence, new protecting groups and/or
reagents that are able to perform deprotection under mild
and selective conditions are lacking and new developments
in this area are, therefore, of great interest.
In the course of our ongoing project aimed at the
development of novel pyridazinone-based antiplatelet
agents,8 we recently described the synthesis of 5-aryl-,
5-alkenyl- and 5-alkynylpyridazin-3(2H)-ones through
palladium-catalysed reactions.1,9 The low reactivity of the
starting 5-halopyridazin-3(2H)-ones in these transform-
ations led us to block position 2 of the heterocycle by
introducing a methoxymethyl group in the heterocyclic
* For the previous paper in this series, see Ref. 1.
Keywords: Pyridazinones; Electrophilic addition; Protecting groups; X-ray
diffraction.
*
Corresponding author. Tel.: C34 981 594628; fax: C34 981 594912;
e-mail: qosotelo@usc.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.021

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A. Coelho et al. / Tetrahedron 61 (2005) 4785–4791
Scheme 1. Reaction of 5-alkynylpyridazin-3(2H)-ones 1 with hydrochloric acid.
lactam function. After the cross-coupling reaction had
finished, the cleavage of the methoxymethyl group in most
of these compounds was performed using the simplest
method, that is, employing hydrochloric acid. Despite the
fact that these conditions successfully afforded the expected
pyridazin-3(2H)-ones bearing aryl or alkenyl groups in
the 5-position,9 we have recently documented10 that this
reagent failed in the deprotection of several pyridazin-
3(2H)-ones that contained reactive alkynyl substituents.
The compounds obtained during the cleavage of the
methoxymethyl group employing 6 N hydrochloric acid in
a series of 5-alkynyl-6-phenyl-2-methoxymethylpyridazin-
3(2H)-ones 1 are shown in Scheme 1. It can be seen that the
behaviour of compounds 1 upon treatment with hydro-
chloric acid is highly dependent on the nature of the alkynyl
group at position 5 (Table 1).
Table 1. Reaction of 5-alkynylpyridazin-3(2H)-ones 1 with hydrochloric
acid
Figure 1. Plot showing the crystal structure and atomic numbering scheme
for 3a. Displacement ellipsoids are drawn at 50% probability level for
non-H atoms.
Compound
R
Yield (%)
Mp (8C)
2a
2b
2c
2d
3a
3b
3c
3d
Ph
TMS
(CH2)2OH
(CH2)4OH
H
CH2OH
CH(OH)CH3
CH2Cl
80
85
78
70
84
78
70
83
150–151
157–158
201–202
189–190
175–176
146–147
87–89
phenylpyridazin-3(2H)-one (3a) was confirmed by X-ray
crystallography (Fig. 1).
In the crystal structure of 3a the rings are essentially planar.
The dihedral angle between the least-squares planes of the
pyridazine moiety and the phenyl ring at C6 is 42.7(1)8.
Average bond distances are as follows: in the phenyl ring,
197–199
˚
˚
1.383(2) A; in the pyridazine ring, 1.372(1) A. The crystal
structure is stabilised by means of hydrogen bonds that
Pyridazinones bearing a sterically hindered or less reactive
acetylenic group (1a–d) afforded the desired 5-alkynyl-6-
phenylpyridazin-3(2H)-ones 2. In contrast, in compounds
containing a reactive ethynyl or propargyl residue at
position 5 (1e–h) hydrochloric acid promotes—in addition
to cleavage of the protecting group (MOM)—electrophilic
addition to the multiple bond to give 5-(chloroalkenyl)-6-
phenylpyridazin-3(2H)-ones 3. The screening of milder
conditions to perform deprotection revealed that such
addition even occurs when the experiments are performed
at room temperature or using more dilute hydrochloric acid.
˚
lead to the formation of dimers [N2/O31Z2.837(3) A,
(2Kx,Ky,1Kz), N2–H2/O31Z1598]. A packing diagram
for this system is shown in Figure 2.
The data obtained during the structural studies performed on
compounds 3a–d fully support the proposed structure,
confirming in all cases the presence of the chlorine atom at
C-2 of the alkenyl residue in the 5-position. Regiospecific
formation of compounds 3 can be rationalised in terms of
the conjugate electrophilic addition of the hydrochloric acid
to the triple bond of the acetylenic-pyridazinone or,
alternatively, as a consequence of the different stabilities
of the possible carbocation intermediates (strongly affected
by the p-deficient nature of the neighbouring azinone
system).
The identity of compounds 2, and especially of the addition
products 3, was unambiguously established on the basis of
their analytical and spectroscopic data (see Section 2).
Additionally, the structure of 5-[(Z)-2-chloro-1-vinyl]-6-

A. Coelho et al. / Tetrahedron 61 (2005) 4785–4791
4787
proved to be highly reactive and afforded the addition
products 5b–d in satisfactory yields (Table 2).
Interestingly, the reaction of 4c with hydrochloric acid
yielded a 3:1 mixture of the isomeric (E)- or (Z)-5-(2-
chloro-1-vinyl)pyridazin-3(2H)-ones 5c and 5d (see Section
2). Comparison of these results with similar experiments on
the 5-ethynyl-2-methoxymethyl-6-phenylpyridazin-3(2H)-
one 1e (Scheme 1) reveal the importance of steric effects,
which are produced by the phenyl group at position 6, on the
regiochemistry of these transformations.
While this work was in progress, a paper was published11
describing the reactivity of a series of 5-alkynyl-4-chloro-2-
methyl-and 4-alkynyl-5-chloro-2-methylpyridazin-3(2H)-
ones with oxygen and sulfur nucleophiles. Additionally
this work studied the synthesis of different series of bicyclic
pyridazinones but also mechanistic aspects of these
transformations. These previous results, along with the
findings presented here, confirm the high reactivity of
alkynylpyridazin-3(2H)-ones and their usefulness as attrac-
tive starting materials for future functionalization of the
heterocyclic scaffold.
Figure 2. Packing of the molecules of 3a in the unit cell, showing their
dimeric association through H-bonds of the type N–H/O.
Encouraged by the observed reactivity of compounds 1e–h,
we became interested in studying similar transformations
starting from derivatives without the phenyl group at
position 61 (Scheme 2). More specifically, we selected
several 5-alkynylpyridazin-3(2H)-ones that have a non-
removable methyl group at position 2 of the heterocycle (4).
The results of this study are represented in Scheme 2. The
5-alkynyl-2-methylpyridazin-3(2H)-ones 4 also proved to
be highly reactive toward electrophilic addition of hydro-
chloric acid under the aforementioned experimental con-
ditions. As shown in Scheme 2, the compounds isolated
from transformations are similar to those previously
described (i.e., having the 2-chloroalkenyl fragment at
position 5 of the heterocyclic ring). Thus, 2-methyl-5-
trimethylsilylethynylpyridazin-3(2H)-one (4a) is com-
pletely unreactive (even after more than 48 h of heating in
6 N hydrochloric acid). In contrast, pyridazinones 4b–c
In an effort to find selective conditions to cleave the MOM
group in pyridazinones bearing acid-sensitive function-
alities in the 5-position (such as 1e–g), other reagents
capable of removing this group under mild conditions were
studied. The best results were obtained on using Lewis acids
such as aluminium chloride or boron tribromide (Scheme 3).
These two compounds have come to be regarded as reagents
of choice for the efficient cleavage of ethers7 and have
already been employed by several authors to remove the
BOM4 or benzyl groups6 in pyridazinones. In order to test
the scope of these reagents to perform the cleavage of the
MOM group in these functionally sensitive pyridazinones,
we also included in this study the 5-alkynylpyridazin-3(2H)-
ones that were successfully deprotected using hydrochloric
acid (Scheme 3).
Scheme 2. Reaction of 5-alkynylpyridazin-3(2H)-ones 4 with hydrochloric acid.
Table 2. Reaction of 5-alkynylpyridazin-3(2H)-ones 4 with hydrochloric acid
Compound
R5
Yield (%)
Mp (8C)
5b
5c
5d
(Z) CH]C(Cl)CH2OH
(Z) CH]CH–Cl
(E) CH]CH–Cl
60
68
23
148–149
240–241
181–182

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A. Coelho et al. / Tetrahedron 61 (2005) 4785–4791
an Autospec Micromass spectrometer. 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. A series of NOE experiments provided
unequivocal confirmation of proposed structures for com-
pounds 3b–d and 5b.
Scheme 3. Selective cleavage of the MOM group in 1 employing Lewis
acids. Method A: AlCl3/toluene or dichloromethane. Method B: (i) BBr3/
CH2Cl2, K78 8C; (ii) CH3COONH4.
A quick preliminary screening showed that both reagents
cleaved the MOM group from the heterocyclic ring in
satisfactory yields without affecting the acetylenic group in
the 5-position. The best results were obtained working at
K78 8C for boron tribromide (see Section 2) and in
refluxing toluene or dichloromethane (Section 2) for
aluminium chloride (Scheme 3).
The X-ray crystallographic determination of 3a was
performed using a Siemens P4 four-circle diffractometer
with graphite monochromated Cu Ka radiation. The inten-
sity data were collected using 2q–u scans, with u scan
width equal to the difference of the background and the high
u background plus the separation between the Ka1 and Ka2
positions; 2526 reflections measured (3.71!q!68.948,
K1!h!6, K9!k!9, K14!l!14), 1935 unique
(merging RZ0.055) and 1463 observed [F2R2s(F)2]
reflections. Empirical absorption correction, via j scans
was applied.13 Three standard reflections were monitored
every 100 reflections (intensity decay: 6%).
Disappointingly, although not completely unexpectedly, the
deprotection of compounds 1c, 1d, 1f, 1g (which contain an
alcohol residue) with BBr3 led to the formation of variable
amounts of the corresponding bromo derivatives as a
consequence of the brominating properties of this reagent.12
These results, together with the easy manipulation and
cheapness of AlCl3, confirmed the superiority of this reagent
in the deprotection of the MOM group at position 2 of the
heterocycle (Table 3).
The crystal structure of 3a was solved by direct methods and
Fourier synthesis. Non-H atoms were refined anisotropically
by full-matrix least-squares techniques. H atoms were
calculated geometrically and included in the refinement,
but were restrained to ride on their parent atoms. The
isotropic displacement parameters of the H atoms were fixed
to 1.3 times Ueq of their parent atoms. Data collection:
XSCANS.14 Cell refinement: XSCANS.14 Data reduction:
XSCANS.14 Program used to solve structure: SIR92.15
Program used to refine structure: SHELXL97.16 Molecular
graphics: DIAMOND.17 Software used to prepare material
for publication: PLATON.18
Table 3. Selective cleavage of the MOM group in 5-alkynyl-2-
methoxymethyl-6-phenylpyridazin-3(2H)-ones employing AlCl3
Compound
R
Yield (%)
Mp (8C)
2a
2b
2c
2d
2e
2f
Ph
TMS
(CH2)2OH
(CH2)4OH
H
98
97
80
88
90
76
80
150–151
156–157
201–202
189–190
202–203
169–170
160–162
CH2OH
CH(OH)CH3
2g
2.1. Reaction of 5-substituted pyridazin-3(2H)-ones with
6 N hydrochloric acid. Representative procedure for the
synthesis of compounds 2a–d, 3a–b, and 5b–e
In summary, the electrophilic addition of hydrochloric acid
to several 5-alkynylpyridazin-3(2H)-ones has been studied.
The products obtained during these reactions have been
identified, confirming the presence of a chlorine atom at
position 2 of the double bond formed during the addition.
The cleavage of the MOM group at position 2 of
pyridazinones bearing acid-sensitive alkynyl substituents
at position 5 can be successfully achieved using aluminium
chloride.
A mixture of the corresponding 5-alkynylpyridazin-3(2H)-
one 1 or 4 (1.11 mmol), MeOH (5 mL) and 6 N 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 from
the appropriate solvent.
2. Experimental
2.1.1. 6-Phenyl-5-(phenylethynyl)pyridazin-3(2H)-one
(2a). Purification by column chromatography on silica gel
(AcOEt/hexane 1:5) and then recrystallization gave a white
solid; yield 80%. Mp: 158–160 8C (Isopropanol). IR (KBr):
nmax/cmK1 2130 (C^C), 1651 (CO), 1577 (Aromatics). 1H
NMR (CDCl3 300 MHz), d (ppm): 11.25 (br s, 1H, 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,
Melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. IR spectra were
measured using a Perkin–Elmer 1640 FTIR spectrophoto-
meter with samples as potassium bromide pellets. The NMR
spectra were recorded on Bruker AM300 and XM500
spectrometers. Chemical shifts are given as d values 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

A. Coelho et al. / Tetrahedron 61 (2005) 4785–4791
4789
128.9, 128.4, 121.7, 101.2, 84.8. MS (70 eV) m/z (%): 272
(MC, 100), 271 (40), 215 (32). Anal. Calcd for C18H12N2O:
C, 79.39; H, 4.44; N, 10.29. Found: C, 79.44; H, 4.49; N,
10.30.
(70 eV) m/z (%): 232 (MC, 12), 197 (100). Anal. Calcd for
C12H9ClN2O: C, 61.95; H, 3.90; N, 12.04. Found: C, 61.99;
H, 3.91; N, 11.89.
X-ray structure analysis. Crystals of 3a were grown by slow
evaporation from 1:1 isopropanol/ethanol solution. Crystal
2.1.2. 6-Phenyl-5-(trimethylsilylethynyl)pyridazin-
3(2H)-one (2b). Purification by column chromatography
on silica gel (AcOEt/hexane 1:3) and then recrystallization
gave a white solid; yield 85%. Mp: 156–157 8C (Isopropa-
nol). IR (KBr): nmax/cmK1 2855 (NH), 2136 (C^C), 1654
˚
data. C12H9N2OCl, MZ232.66, Triclinic, aZ5.7408(2) A,
˚
˚
bZ7.8800(6) A, cZ12.3240(8) A; aZ85.145(6)8, bZ
3
˚
77.999(4)8, gZ84.299(5)8, VZ541.45(6) A (by least-
squares refinement on diffractometer angles for 32 auto-
1
matically centered reflections with 10.77!q!27.988, lZ
(CO), 1555 (Aromatics). H NMR (CDCl3 300 MHz), d
˚
1.54178 A, TZ293(2) K), space group P1, ZZ2, DcZ
(ppm): 12.46 (br s, 1H, 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, 129.5, 129.2,
128.2, 108.9, 99.3, K0.4. MS (70 eV) m/z (%): 268 (MC,
100), 253 (94), 225 (24), 139 (26), 107 (28), 77 (60). Anal.
Calcd for C15H16N2OSi: C, 67.13; H, 6.01; N, 10.44. Found:
C, 67.15; H, 6.04; N, 10.45.
1.4271(2) g cmK3, mZ2.946 mmK1. A prism-like colour-
less crystal (0.40!0.18!0.04 mm3) was used for the
analysis. CCDC 230882 contains the supplementary crystal-
lographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or
by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: C44 1223 336033.
2.1.3. 5-(4-Hydroxybut-1-yn-1-yl)-6-phenylpyridazin-
3(2H)-one (2c). Purification by column chromatography
on silica gel (AcOEt/hexane 1:5) and then recrystallization
gave white crystals; yield 80%. Mp: 199–201 8C (Isopro-
panol). IR (KBr): nmax/cmK1 3566–2920 (OH, NH), 2226
2.1.6. 5-[(Z)-2-Chloro-3-hydroxyprop-1-en-1-yl]-6-
phenylpyridazin-3(2H)-one (3b). Purification by column
chromatography on silica gel (AcOEt/hexane 1:3) and then
recrystallization gave crystals of 3b; yield 90%. Mp: 146–
147 8C (Isopropanol). IR (KBr): nmax/cmK1 3360–2900
(OH, NH), 1662 (CO), 1569 (Aromatics). 1H NMR (CDCl3
300 MHz), d (ppm): 13.25 (br s, 1H, NH), 7.44 (m, 5H,
Aromatics), 7.04 (s, 1H, H4), 6.57 (s, 1H, CH), 5.71 (t, JZ
5.9 Hz, 1H, OH), 4.06 (d, JZ5.9 Hz, 2H, CH2). 13C NMR
(CDCl3 75 MHz), d (ppm): 160.3, 146.0, 140.5, 139.2,
135.4, 129.1, 128.9, 128.7, 128.6, 118.5, 65.0. MS (70 eV)
m/z (%): 262 (MC, 10), 215 (54), 139 (26), 105 (100). Anal.
Calcd for C13H11ClN2O2: C, 59.44; H, 4.22; N, 10.66.
Found: C, 59.46; H, 4.21; N, 10.68.
1
(C^C), 1652 (CO), 1558 (Aromatics). H NMR (CDCl3
300 MHz), d (ppm): 10.91 (br s, 1H, NH deuterium oxide
exchangeable), 7.67 (m, 2H, Aromatics), 7.43 (m, 3H,
Aromatics), 7.08 (s, 1H, H4), 3.67 (t, JZ6.2 Hz, 2H, –CH2–
), 2.62 (t, JZ6.2 Hz, 2H, CH2), 1.48 (br s, 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 (MC, 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, 5.06; N, 11.71.
2.1.4. 5-(6-Hydroxyhex-1-yn-1-yl)-6-phenylpyridazin-
3(2H)-one (2d). Purification by column chromatography
on silica gel (AcOEt/hexane 1:5) and then recrystallization
gave white crystals; yield 80%. Mp: 189–190 8C (Isopro-
panol). IR (KBr): nmax/cmK1 3450–2900 (OH, NH), 2500
(NH), 2250 (C^C), 1625 (CO). 1H NMR (CDCl3
300 MHz), d (ppm): 12.12 (1H, br s, NH deuterium oxide
exchangeable), 7.67 (m, 2H, Aromatics), 7.39 (m, 3H,
Aromatics), 7.07 (s, 1H, H4), 3.57 (t, JZ6.4 Hz, 2H, –CH2–),
2.61 (br s, 1H, OH), 2.35 (t, JZ6.4 Hz, 2H, CH2), 1.53 (m,
4H, 2!CH2). 13C NMR (CDCl3 75 MHz), d (ppm): 161.1,
147.9, 135.1, 132.4, 130.7, 129.6, 129.1, 128.3, 103.7, 76.8,
62.2, 31.8, 24.5, 19.8. MS (70 eV) m/z (%): 267 (MC, 48),
209 (51), 223 (30), 197 (100). Anal. Calcd for C16H16N2O2:
C, 71.62; H, 6.01; N, 10.44. Found: C, 71.75; H, 6.11; N,
10.73.
2.1.7. 5-[(Z)-2-Chloro-3-hydroxybut-1-en-1-yl]-6-phenyl-
pyridazin-3(2H)-one (3c). Purification by column chroma-
tography on silica gel (AcOEt/hexane 1:3) and then
recrystallization gave white crystals of 3c; yield 68%. Mp:
87–89 8C (Isopropanol). IR (KBr): nmax/cmK1 3566–2980
(OH, NH), 1654 (CO), 1586 (Aromatics). 1H NMR (CDCl3
300 MHz), d (ppm): 13.26 (br s, 1H, NH), 7.42 (m, 5H,
Aromatics), 6.96 (s, 1H, H4), 6.59 (s, 1H, CH), 5.60 (dq, JZ
6.6 Hz, 2.1 Hz, 1H, OH), 4.25 (br s, 1H, OH), 1.18 (d, JZ
6.6 Hz, 3H, CH3). 13C NMR (CDCl3 75 MHz), d (ppm):
160.3, 144.5, 146.1, 139.5, 135.2, 129.1, 128.9, 128.8,
128.7, 118.8, 70.1, 21.7. MS (70 eV) m/z (%): 276 (MC,
30), 258 (20), 139 (100). Anal. Calcd for C14H13ClN2O2: C,
60.77; H, 4.74; N, 10.12. Found: C, 60.79; H, 4.73; N, 10.15.
2.1.8. 5-[(Z)-2-Chloro-3-chloroprop-1-en-1-yl]-6-phenyl-
pyridazin-3(2H)-one (3d). Purification by column chroma-
tography on silica gel (AcOEt/hexane 1:4) and then
recrystallization gave white crystals of 3d; yield 83%.
Mp: 197–199 8C (Isopropanol). IR (KBr): nmax/cmK1 2852–
2.1.5.
5-[(Z)-2-Chloro-1-vinyl]-6-phenylpyridazin-
3(2H)-one (3a). Purification by column chromatography
on silica gel (AcOEt/hexane 1:5) and then recrystallization
gave crystals of 3a; yield 90%. Mp: 175–176 8C (Iso-
propanol). IR (KBr): nmax/cmK1 2989 (NH), 1661 (CO),
1
3300 (NH), 1665 (CO). H NMR (DMSO-d6 300 MHz), d
1
1589 (Aromatics). H NMR (CDCl3 300 MHz), d (ppm):
(ppm): 13.33 (br s, 1H, NH), 7.42 (m, 5H, Aromatics), 6.97
(s, 1H, H4), 6.87 (s, 1H, CH), 4.55 (s, 2H, CH2). 13C NMR
(DMSO-d6 75 MHz), d (ppm): 160.3, 145.7, 139.0, 135.8,
135.6, 129.3, 128.8, 128.6, 127.3, 125.5, 49.0. MS (70 eV)
m/z (%): 280 (MC, 38), 245 (50), 209 (40). Anal. Calcd for
13.04 (br s, 1H, NH), 7.42 (m, 5H, Aromatics), 7.03 (s, 1H,
H4), 6.53 (d, JZ8.2 Hz, 1H, CH), 6.32 (d, JZ8.2 Hz, 1H,
CH). 13C NMR (CDCl3 75 MHz), d (ppm): 162.4, 147.6,
138.8, 135.0, 129.6, 129.5, 129.3, 128.8, 125.3, 125.2. MS

4790
A. Coelho et al. / Tetrahedron 61 (2005) 4785–4791
C13H10Cl2N2O: C, 55.54; H, 3.59; N, 9.96. Found: C, 55.60;
H, 3.78; N, 9.99.
added under argon to a cold (K78 8C) solution of the
2-MOM-pyridazinone 1 (2 mmol) in dry dichloromethane.
The mixture was stirred under these conditions until the
starting material had been consumed (1–3 h) and a saturated
solution of ammonium acetate was added. The mixture was
stirred for a further 1 h and the resulting suspension was
extracted with dichloromethane. The organic extracts were
dried (Na2SO4) and concentrated in vacuo to give a solid
residue, which was purified by column chromatography.
2.1.9. 5-[(Z)-2-Chloro-3-hydroxyprop-1-en-1-yl]-2-
methylpyridazin-3(2H)-one (5b). Purification by column
chromatography on silica gel (AcOEt/hexane 1:4) and then
recrystallization gave white crystals of 5b; yield 60%. Mp:
148–149 8C (Isopropanol). IR (KBr): nmax/cmK1 3347
(OH), 1650 (CO). 1H NMR (DMSO-d6 300 MHz), d
(ppm): 8.06 (d, JZ2.0 Hz, 1H, H6), 7.12 (d, JZ2.0 Hz,
1H, H4), 6.81 (s, 1H, CH), 5.86 (t, JZ5.8 Hz, 1H, OH), 4.15
(d, JZ5.8 Hz, 2H, CH2), 3.62 (s, 3H, CH3). 13C NMR
(DMSO-d6 75 MHz), d (ppm): 160.6, 142.1, 138.2, 136.9,
126.1, 117.2, 65.6, 39.7. MS (70 eV) m/z (%): 200 (MC,
100). Anal. Calcd for C8H9ClN2O2, C 47.89, H 4.52, N
13.96; found, C 47.94, H 4.53, N 13.98.
2.3.1. 5-Ethynyl-6-phenylpyridazin-3(2H)-one (2e).
Further purification by column chromatography (AcOEt/
hexane 1:1.5) and recrystallization from isopropanol
furnished a white solid; yield 90%. Mp: 202–203 8C. IR
(KBr): nmax/cmK1 2984 (NH), 2113 (C^C), 1684 (CO),
1560 (Aromatics). 1H NMR (DMSO-d6, 300 MHz), d
(ppm): 13.35 (br s, 1H, NH deuterium oxide exchangeable),
7.64 (m, 2H, Aromatics), 7.45 (m, 3H, Aromatics), 7.18
(s, 1H, H4), 4.79 (s, 1H, CH). 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 (MC,
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.
2.1.10. 5-[(Z)-2-Chloro-1-vinyl]-2-methylpyridazin-
3(2H)-one (5c). Purification by column chromatography
on silica gel (AcOEt/hexane 1:6) and then recrystallization
gave white crystals of 5d; yield 68%. Mp: 240–241 8C
(Isopropanol). IR (KBr): nmax/cmK1 1643. 1H NMR
(DMSO-d6 300 MHz), d (ppm): 7.95 (d, JZ1.93 Hz, 1H,
H6), 7.17 (d, JZ1.93 Hz, 1H, H4), 6.56 (d, JZ8.2 Hz, 1H,
CH), 6.41 (d, JZ8.2 Hz, 1H, CH), 3.75 (s, 3H, CH3). 13C
NMR (DMSO-d6 75 MHz), d (ppm): 160.4, 137.4, 136.2,
127.3, 125.7, 123.4, 39.9. MS (70 eV) m/z (%): 170 (MC,
15), 142 (26). Anal. Calcd for C7H7ClN2O: C, 49.28; H,
4.14; N, 16.42. Found: C, 49.28; H, 4.16; N, 16.40.
2.3.2. 5-(3-Hydroxyprop-1-yn-1-yl)-6-phenylpyridazin-
3(2H)-one (2f). Purification by column chromatography
on silica gel (AcOEt/hexane 1:5) gave white crystals; yield
76%. Mp: 169–171 8C (Isopropanol). IR (KBr): nmax/cmK1
3566–2930 (OH, NH), 2237 (C^C), 1654 (CO), 1558
2.1.11. 5-[(E)-2-Chloro-1-vinyl]-2-methylpyridazin-
3(2H)-one (5d). Purification by column chromatography
on silica gel (AcOEt/hexane 1:5) and then recrystallization
gave crystals of 5e; yield 23%. Mp: 181–183 8C (Isopropa-
nol). IR (KBr): nmax/cmK1 1645 (CO). 1H NMR (DMSO-d6
300 MHz), d (ppm): 7.76 (d, JZ2.00 Hz, 1H, H6), 6.91 (d,
JZ13.6 Hz, 1H, CH), 6.72 (d, JZ2.00 Hz, 1H, H4), 6.63 (d,
JZ13.6 Hz, 1H, CH), 3.77 (s, 3H, CH3). 13C NMR (DMSO-
d6 75 MHz), d (ppm): 162.1, 137.8, 133.7, 128.1, 127.0,
124.5, 40.3. MS (70 eV) m/z (%): 170 (MC, 100). Anal.
Calcd for C7H7ClN2O: C, 49.28; H, 4.14; N, 16.42. Found:
C, 49.31; H, 3.14; N, 16.41.
1
(Aromatics). H NMR (CDCl3 300 MHz), d (ppm): 11.33
(br s, 1H, NH deuterium oxide exchangeable), 7.73 (m, 2H,
Aromatics), 7.48 (m, 3H, Aromatics), 7.16 (s, 1H, H4), 4.35
(s, 2H, –CH2–), 3.34 (br s, 1H, OH). 13C NMR (CDCl3
75 MHz), d (ppm): 162.6, 148.9, 136.3, 133.7, 131.1, 130.8,
130.2, 129.5, 101.9, 80.6, 51.3. MS (70 eV) m/z (%): 226
(MC, 60), 208 (100). Anal. Calcd for C13H10N2O2: C,
69.02; H, 4.46; N, 12.38. Found: C, 69.83; H, 4.69; N, 12.44.
2.3.3. 5-(3-Hydroxybut-1-yn-1-yl)-6-phenylpyridazin-
3(2H)-one (2g). Purification by column chromatography
on silica gel (AcOEt/hexane 2:1) gave a white solid; yield
80%. Mp 160–162 8C (Isopropanol). IR (KBr), n (cmK1):
3350–2920 (OH, NH), 2230 (C^C), 1652 (CO), 1585
2.2. Cleavage of the MOM group employing AlCl3
(Method A)—typical procedure
1
(Aromatics). H NMR (CDCl3 300 MHz), d (ppm): 12.25
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 correspond-
ing 2-methoxymethylpyridazin-3(2H)-one 1 (1.00 mmol) in
dry toluene (6 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 stirred for 30 min. The mixture was extracted with
chloroform 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.
(br s, 1H, NH deuterium oxide exchangeable), 7.67 (m, 2H,
Aromatics), 7.41 (m, 3H, Aromatics), 7.12 (s, 1H, H4), 4.61
(q, JZ6.6 Hz, 1H, CH), 3.45 (br s, 1H, OH), 1.40 (d, JZ
6.6 Hz, 3H, CH3). 13C NMR (CDCl3 75 MHz), d (ppm):
160.0, 146.7, 134.6, 132.8, 129.8, 129.3, 129.1, 128.4,
103.8, 79.0, 58.7, 23.6. MS (70 eV) m/z (%): 240 (MC, 35),
197 (30), 165 (82), 139 (100), 115 (61), 77 (84), 51 (100).
Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66.
Found: C, 70.09; H, 5.12; N, 11.87.
Acknowledgements
2.3. Cleavage of the MOM group employing BBr3
(Method B)—typical procedure
The authors thank Prof. E. Ravin˜a for the use of research
facilities.
A 2 M solution of boron tribromide (2.1 mmol) was slowly

A. Coelho et al. / Tetrahedron 61 (2005) 4785–4791
4791
Cano, E.; Ravin˜a, E. Bioorg. Med. Chem. 2002, 10, 2873.
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