Pyridazines. Part 30:1 Palladium-catalysed synthesis of 5-substituted 6-phenyl-3(2H)-pyridazinones asissted by a retro-ene transformation

Article abstract of DOI:10.1055/s-2002-35567

The efficient one-pot functionalization, through palladium-catalysed reactions, of position 5 of the 6-phenyl-3(2H)-pyridazinone system has been performed using a retro-ene-assisted fragmentation. This route allows access through a short synthetic sequenc

Full text of DOI:10.1055/s-2002-35567

2062
LETTER
Pyridazines. Part 30:1 Palladium-Catalysed Synthesis of 5-Substituted
6-Phenyl-3(2H)-pyridazinones Asissted by a Retro-Ene Transformation
P
alladium-Catalys
l
ed Synt
b
hesis of 5-Su
e
bstituted 6
r
-Phenyl-
t
3(2
H
)-
o
pyridazinones Coelho, Enrique Raviña, Eddy Sotelo*
Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela,
15782 Santiago de Compostela, España
Fax +34(98)1594912; E-mail: qosotelo@usc.es
Received 25 September 2002
This paper is dedicated to Professor Raúl Mocelo of the University of Havana, Cuba, on the occasion of his birthday.
Most of the literature examples on this topic refer to 2-
Abstract: The efficient one-pot functionalization, through pal-
blocked-pyridazinones, and their role is limited to block-
ing the enolisable carbonyl group, probably because the
mesomeric or tautomeric structure of the lactam function
ladium-catalysed reactions, of position 5 of the 6-phenyl-3(2H)-
pyridazinone system has been performed using a retro-ene-assisted
fragmentation. This route allows access through a short synthetic
sequence to several pharmacologically useful 3(2H)-pyridazinones. present in 3(2H)-pyridazinones completely inhibits palla-
dium-catalysed transformations.10,11 Several works have
Key words: pyridazinone, ene-adducts, palladium, catalysis
described the use of benzyl and benzyloxymethyl
groups13 but procedures for the protection of the amide or
lactam functionality are limited.14 Thus, in the absence of
The pyridazine nucleus and its 3-oxo derivatives [3(2H)-
protecting groups and/or reagents that are able to perform
pyridazinones] are recognised as versatile pharmacoph-
deprotection under mild conditions, new methods are
ores in medicinal chemistry. Within this class of com-
needed.
pound, 6-aryl-3(2H)-pyridazinones and their 4,5-dihydro
We recently described the use of the methoxymethyl
(MOM) group as a convenient protecting group for these
transformations.10,11 However, the strong acidic condi-
tions required to remove the MOM group from these com-
pounds (refluxing 6 N HCl) are not tolerated by
pyridazinones with acid-sensitive functionalities. In this
regard, the successful use of Lewis acids (aluminium
chloride and boron tribromide) as an alternative procedure
to perform the efficient and mild deprotection of 2-substi-
tuted pyridazinones has been described.15
derivatives have received a great deal of attention in re-
cent years because they show a wide range of biological
actions.2 Several papers on this topic have described the
pharmacological utility of these compounds3–5 and we re-
cently described the platelet inhibitory activity of a series
of 5-substituted 6-phenyl-3(2H)-pyridazinones I.6–8 The
structural manipulation at position 5 of this system has al-
lowed us to develop new and potent antiplatelet agents II
and III (Figure 1).1,9
The results mentioned above have directed our project,
which is concerned with the search for new pyridazinone-
based antiplatelet agents, to the development of efficient
synthetic procedures that allow the rapid pharmacomodu-
lation of position 5 of this system. More specifically, we
have recently focused our synthetic efforts on the palladi-
um-catalysed cross-coupling reactions of 5-halo-3(2H)-
pyridazinones.10,11 and dihalopyridazines.12
As part of these studies we were interested in developing
a shorter synthetic strategy that avoided the use of our pre-
viously described 2-blocked pyridazinones such as 2-
methoxymethyl-3-pyridazinones10,11 [obtained from the
corresponding 3(2H)-pyridazinone and the highly toxic
methoxymethyl chloride], which have to be deprotected
after the coupling reaction. Our goal was to find a new,
simple, more convenient and less toxic route to 2-blocked
pyridazinones with a labile group at position 2 that could
be easily removed under coupling conditions. It was en-
visaged that such a material could be used as a reactive
starting material in palladium-catalysed reactions. We re-
port herein a rapid, efficient and convenient one-pot syn-
thesis of 5-substituted 6-phenyl-3-(2H)-pyridazinones 3
starting from 5-bromo-2-hydroxymethyl-6-phenyl-3-py-
ridazinone (2) (Scheme 1).
O
O
O
H
H
H
N
N
X
N
N
N
N
Y
S
X
III
II
I
Compound 2 can be obtained (89%) by refluxing 5-bro-
mo-6-phenyl-3(2H)-pyridazinone (1) in 35% formalde-
hyde solution.16 The easy preparation of this compound
represents a valuable advantage, although the most note-
worthy aspect concerning the synthetic applicability of
this compound as a 2-blocked pyridazinone in cross-coup-
ling reactions is derived from its chemical and thermal
Figure 1
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2062,2064,ftx,en;D16502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Palladium-Catalysed Synthesis of 5-Substituted 6-Phenyl-3(2H)-pyridazinones
2063
O
OH
O
O
Table 1 Palladium-catalysed Reactions on 2 and Physical data of
Compounds 319,20
H
N
H
N
N
N
N
a)
b), c) or d)
Compound
R
Yield (%)
Mp (°C)
178–180
198–200
222–223
172–173
157–158
200–201
133–135
169–170
N
Br
Br
R
3a
3b
3c
3d
3e
3f
Ph
72
74
82
72
81
82
88
81
4-CH3Ph
4-ClPh
1
2
3
Scheme 1 a) CH2O/reflux, b) ArB(OH)2, Pd(PPh3)4, K2CO3, DME–
H2O, reflux, c) alkyne, CuI, Pd(PPh3)2Cl2, DMF, 55 °C, d) organotin,
PdCl2(PPh3)2, toluene, reflux.
4-CHOPh
C C–TMS
C C–CH2OH
C C–CH(OEt)2
CH=CH2
stability. This compound is a 1-O, 3-N, 5-O ene-adduct,17
which easily loses formaldehyde through a retro-ene reac-
tion promoted by base and/or by heat.
3g
3h
Once position 2 had been blocked we proceeded to study
several palladium-catalysed reactions on 2 (Scheme 1).
We first examined the Suzuki arylation of 2, which is al-
ready known to require the presence of a base in the reac-
tion medium. The transformation was carried out by
heating under reflux an equimolar mixture of 2 and the ap-
propriate boronic acid under Suzuki conditions18 [sodium
or potassium carbonate as base, tetrakis(triphenylphos-
phine)palladium(0) as catalyst and a mixture of DME–
water as solvent, Scheme 1]. Suzuki arylation of 2 pro-
ceeds with exclusive formation of 3(2H)-pyridazinones 3
in high yields after 8–24 hours (Table 1). In a similar way,
Sonogashira19 or Stille coupling of 2 using the appropriate
reagents and conditions, led to the expected 5-substituted
6-phenyl-3(2H)-pyridazinones in high yields (Table 1)20
regardless of whether the reaction conditions involved the
use of base or not. These results confirm that the operating
retro-ene reaction for these examples can be promoted by
heat.
References
(1) For the previous paper in this series, see: Sotelo, E.; Fraiz,
N.; Yañez, M.; Terrades, V.; Laguna, R.; Cano, E.; Raviña,
E. Bioorg. Med. Chem. 2002, 10, 2873.
(2) Frank, H.; Heinisch, G. Pharmacologically Active
Pyridazines, In Progress in Medicinal Chemistry, 27; Ellis,
G. P.; West, G. B., Eds.; Elsevier: Amsterdam, 1990, 1–49.
(3) Raviña, E.; García-Mera, G.; Santana, L.; Orallo, F.; Calleja,
J. M. Eur. J. Med. Chem. 1985, 20, 475.
(4) Raviña, E.; Terán, C.; Dominguez, N.; Masaguer, C. F. Arch.
Pharm. (Weinheim) 1991, 324, 455.
(5) Gil Longo, J.; Laguna, R.; Verde, I.; Castro, M.; Orallo, F.;
Fontenla, J.; Calleja, J. M.; Raviña, E.; Terán, C. J. Pharm.
Sci. 1993, 82, 286.
(6) Laguna, R.; Montero, A.; Cano, E.; Raviña, E.; Sotelo, E.;
Estévez, I. Acta Pharmaceutica Hungarica 1996, 66, S43;
Chem. Abstr. 1997, 126, 165993.
(7) Laguna, R.; Rodriguez-Liñares, B.; Cano, E.; Estévez, I.;
Raviña, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45, 1151.
(8) Montero-Lastres, A.; Fraiz, N.; Cano, E.; Laguna, R.;
Estévez, I.; Raviña, E. Biol. Pharm. Bull. 1999, 22, 1376.
(9) Sotelo, E.; Fraiz, N.; Yañez, M.; Laguna, R.; Cano, E.; Brea,
J.; Raviña, E. Bioorg. Med. Chem. Lett. 2002, 10, 1575.
(10) Estévez, I.; Coelho, A.; Raviña, E. Synthesis 1999, 1666.
(11) Coelho, A.; Sotelo, E.; Estévez, I.; Raviña, E. Synthesis
2001, 871.
Although all of the reactions gave excellent yields
(Table 1), Sonogashira couplings on 2 proved to be partic-
ularly efficient and occurred readily under mild condi-
tions. This high reactivity is especially significant since
several of the acetylene derivatives previously prepared
by us were unstable under the range of conditions used to
perform the cleavage of the protecting group.15
(12) Sotelo, E.; Raviña, E. Synlett 2002, 223.
(13) (a) Zára-Kaczián, E.; Mátyus, P. Heterocycles 1993, 36,
519. (b) Haider, N.; Heinisch, G. J. Chem. Soc., Perkin
Trans. 1 1988, 401. (c) Haider, N.; Geinisch, G.
Heterocycles 1989, 29, 1309.
(14) Greene, T.; Wuts, G. P. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999, 632.
(15) Sotelo, E.; Coelho, A.; Raviña, E. Tetrahedron Lett. 2001,
42, 8633.
Since 5-bromo-6-phenyl-3(2H)-pyridazinone 1 is not re-
active toward palladium-catalysed reactions,10,11 the first
step of these transformations most probably involves the
cross-coupling reaction on 2 to afford a 5-substituted ene
adduct, which was not isolated. In the second step this in-
termediate loses formaldehyde to give 3 in a transforma-
tion that may be regarded as a retro-ene fragmentation.
(16) Representative Procedure for Preparation of Compound
2. A mixture of 1 (2.64 g, 0.105 mmol) and 35%
formaldehyde (0.828 mL, 0.105 mmol) was flushed with
argon for 5 min. The suspension was stirred and heated
under reflux (oil bath 110 °C) under argon until the starting
material had disappeared (24 h). The mixture was cooled and
the suspension was concentrated to dryness under reduced
pressure. The obtained solid was purified by column
chromatography on silica gel (EtOAc–hexanes, 1:2).
Physical and spectral data for compound 2: Yield: 89%, mp
In summary, we have developed a versatile, practical and
efficient one-pot palladium-catalysed procedure to pre-
pare several 5-substituted 6-phenyl-3(2H)-pyridazinones
3 using the ene adduct 2 as a reactive intermediate. The
use of other 2-hydroxymethylpyridazinones as precursors
in several different palladium-catalysed transformations
and the biological evaluation of the resulting compounds
is currently under investigation.
Synlett 2002, No. 12, 2062–2064 ISSN 0936-5214 © Thieme Stuttgart · New York

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A. Coelho et al.
LETTER
237–238 °C. IR (KBr): 3100–3000, 1642 cm–1. 1H NMR
(CDCl3, 300 MHz): = 7.55–7.40 (m, 5 H, Ph), 5.58 (d,
J = 8.1 Hz, 2 H, CH2), 4.74 (t, J = 8.1 Hz, 1 H, OH).
13C NMR (CDCl3, 300 MHz): = 159.6, 147.0, 134.9, 133.4,
131.7, 130.0, 129.6, 128.6, 77.1. HRMS (Autospec
Micromass): m/z calcd for C11H9 BrN2O2 (M+): 279.9847.
Found: 279.9859.
(20) Selected Physical and Spectral Data for Representative
Compounds 3. 3a: Yield: 90%. IR (KBr): 3100–2923, 1668,
1589 cm–1. 1H NMR (CDCl3, 300 MHz): = 11.58 (br s, 1
H, NH), 7.38–7.20 (m, 10 H, phenyl), 7.01 (s, 1 H, H4). 3b:
Yield: 78%., IR (KBr): 3500–2924, 1642 cm–1. 1H NMR
(CDCl3, 300 MHz): = 11.40 (br s, 1 H, NH), 7.41–7.29 (m,
5 H, phenyl), 7.18 (d, J = 8.0 Hz, 2 H, phenyl), 7.06 (d, J
= 8.0 Hz, 2 H, phenyl), 7.01 (s, 1 H, H4), 2.33 (s, 3 H, CH3).
3c: Yield: 78%. IR (KBr): 3500–2924, 1642 cm–1. 1H NMR
(CDCl3, 300 MHz): = 11.65 (br s, 1 H, NH), 7.40–7.30 (m,
5 H, Arom), 7.16 (d, J = 8.4 Hz, 2 H, Arom), 7.05 (d, J
= 8.4 Hz, Arom), 6.97 (s, 1 H, H4). 3e: Yield: 70%. IR
(KBr): = 3000–3100, 2136, 1654 cm–1. 1H NMR (CDCl3,
300 MHz): = 12.46 (br s, 1 H), 7.73 (m, 2 H, Arom), 7.42
(m, 3 H, Arom), 7.13 (s, 1 H), 0.16 (s, 9 H, 3 CH3). 3f:
Yield: 86%. IR (KBr): 3100, 1680 cm–1. 1H NMR (MeOD,
300 MHz): = 13.18 (br s, 1 H, NH), 7.75 (m, 2 H, Arom),
7.47 (m, 3 H, Arom), 7.16 (s, 1 H, H4), 4.35 (s, 2 H, CH2),
3.34 (t, 1 H, J = 1.6 Hz, OH). 3g: Yield: 81%. IR (KBr):
3246–2885, 2236, 1667, 1053 cm–1. 1H NMR (MeOD, 300
MHz): = 12.40 (br s, 1 H, NH), 7.70–7.64 (m, 2 H, Arom),
7.42–7.37 (m, 3 H, Arom), 7.17 (s, 1 H, H4), 5.35 (s, 1 H,
CH), 3.52 (m, 4 H, 2 OCH2), 1.15 (m, 6 H, 2 CH3). 3h:
Yield: 86%. IR (KBr): 1669, 1092 cm–1. 1H NMR (CDCl3,
300 MHz): = 12.68 (br s, 1 H, NH), 7.43 (m, 5 H, Arom),
7.11 (s, 1 H, H4), 6.45 (dd, 1 H, J = 10.9, 17.2 Hz,
(17) Ripoll, J.; Vallé, Y. Synthesis 1993, 3, 659.
(18) Representative Procedure for Suzuki Arylations on
Compound 2. A mixture of 2 (0.45 g, 1.6 mmol),
arylboronic acid (1.6 mmol), Pd(PPh3)4 (0.036 g, 0.032
mmol) and Na2CO3 (0.67 g, 6.4 mmol) in 18 mL of 3:1
DME–H2O was flushed with argon for 5 min. The mixture
was stirred and heated under reflux (oil bath 120 °C) under
argon until the starting material had disappeared. The
mixture was cooled and the solution was concentrated to
dryness under reduced pressure. The residue was purified by
column chromatography on silica gel.
(19) Representative Procedure for Sonogashira Couplings on
Compound 2. A mixture of 2 (0.28 g, 1.0 mmol), acetylene
derivative (1.5 mmol), Pd(PPh3)2Cl2 (0.03 g, 0.01 mmol),
CuI (0.01 g, 0.01 mmol) and anhyd triethylamine (0.282 mL,
2.0 mmol) in 10 mL of DMF was flushed with argon for
5 min. The reaction mixture was stirred and heated (oil bath
55 °C) under argon until the starting material had dis-
appeared. The reaction mixture was cooled and the solution
was concentrated to dryness under reduced pressure. The
residue was purified by column chromatography on silica
gel.
CH=CH2), 5.87 (d, 1 H, J = 17.2 Hz, CH=CH2), 5.50 (d, 1
H, J = 10.9 Hz, CH=CH2).
Synlett 2002, No. 12, 2062–2064 ISSN 0936-5214 © Thieme Stuttgart · New York