Pyridazine derivatives 32: Stille-based approaches in the synthesis of 5-substituted-6-phenyl-3(2H)-pyridazinones

Article abstract of DOI:10.1248/cpb.51.427

A series of 6-phenyl-3(2H)-pyridazinones bearing different substituents in the 5-position of the pyridazinone ring were prepared using Stille-based approaches in the search for new platelet-aggregation inhibitors.

Full text of DOI:10.1248/cpb.51.427

April 2003
Notes
Chem. Pharm. Bull. 51(4) 427—430 (2003)
427
Pyridazine Derivatives 321): Stille-Based Approaches in the Synthesis of
5-Substituted-6-phenyl-3(2H)-pyridazinones
Eddy SOTELO, Alberto COELHO, and Enrique RAVIÑA*
Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Farmacia, Universidad de
Santiago de Compostela; 15782 Santiago de Compostela, Spain.
Received October 29, 2002; accepted January 19, 2003
A series of 6-phenyl-3(2H)-pyridazinones bearing different substituents in the 5-position of the pyridazinone
ring were prepared using Stille-based approaches in the search for new platelet-aggregation inhibitors.
Key words pyridazinone; palladium
Thrombosis is the pathological extension of the normal method to introduce a wide range of residues at position 5 of
haemostatic process that is required to prevent blood loss fol- halopyridazinones, which in turn allows a rapid pharmaco-
lowing damage to the vascular wall. Uncontrolled platelet ag- modulation of this series.22,23)
gregation and platelet adhesion to the subendotelium of dam-
As part of a programme aimed at developing simple and
aged blood vessels causes life-threatening diseases such as efficient syntheses of pharmacologically useful pyridazinones
myocardial infarction, transient ischemic attack and unstable we report here the application of a practical Stille cross-cou-
angina.2)
pling reaction24,25) to synthesize a variety of novel and di-
In recent years, the 6-aryl-3(2H)-pyridazinones have versely functionalized 5-oxygenated-6-phenyl-3(2H)-pyri-
demonstrated a range of pharmacological activities,3) most of dazinones.
which are related to the cardiovascular system and especially
The general synthetic strategy followed for the preparation
to their properties as ionotropic or platelet aggregation in- of the 5-substituted pyridazinones is outlined in Charts 1—3.
hibitors.4—7) Among these compounds, Imazodan (Ia), CI- The starting material chosen for these transformations was
930 (Ib), Indolindan (II), Bemoradan (III), Pimobendan (IV) the inexpensive 5-bromo-6-phenyl-3(2H)-pyridazinone 1.21)
and Zardaverine (V) (Fig. 1) are a few examples of pyridazi- Compound 1, like other haloderivatives in the 3(2H)-pyri-
nones that are active as cardiotonic agents.
dazinone series, is almost unreactive under palladium cross-
For several years we have been involved in a medicinal coupling reactions and the NH group in 1 was therefore pro-
chemistry programme to study the pharmacological exploita- tected as the methoxymethyl derivative 2 (85%). Once the
tion of the 6-aryl-3(2H)-pyridazinone system. Many of the precursor had been suitably protected the functionalization of
pyridazines and 6-aryl-3(2H)-pyridazinones obtained in our 2 could be studied using the classical Stille reaction condi-
laboratory during this period show antihypertensive ac- tions.
tion8—10) or platelet inhibitory activity.11—13) Of particular in-
Optimisation of the experimental conditions revealed that
terest are our systematic studies on 5-substituted-3(2H)-pyri- reaction of 2 with tributyl(vinyl)tin proceeded almost in-
dazinones, which have led to the development of new potent stantly using dry toluene as the solvent and bis(triphenyl-
platelet antiaggregation agents.14,15) These results motivated phosphine)palladium(II) dichloride as a palladium source to
us to develop new and efficient synthetic strategies to allow afford the 5-vinylderivative 3 in almost quantitative yield
the preparation of pyridazinones bearing different functional (Chart 1). Ozonolysis of the vinyl group in 3 and subsequent
groups at position 5 of the heterocyclic ring.16) We have treatment with dimethylsulfide gave the methoxymethyl de-
therefore decided to focus on the direct preparation of these rivative 4, which is a useful intermediate for further elabora-
compounds by palladium-catalysed carbon–carbon bond for- tion, and hydrolysis with hydrochloric acid gave aldehyde 5.
mation17—20) from readily obtainable, inexpensive 5-bromo- Compound 5 has previously been obtained by our group
6-phenyl-3(2H)-pyridazinone 1.21) The palladium cross-cou- using a long-winded multistep route14) and so this new Stille-
pling procedures offer the potential of a simple and adaptable based synthetic strategy is a much-improved, highly efficient
Fig. 1. Examples of Pharmacologically Useful 3(2H)-Pyridazinones
* To whom correspondence should be addressed. e-mail: gofara@usc.es
© 2003 Pharmaceutical Society of Japan

428
Vol. 51, No. 4
a: ClCH2OCH3, N,N-diisopropylethylamine, 4-DMAP, CH2Cl2, 0 °C; b:
tributyl(vinyl)tin, PdCl2(PPh3)2, toluene, 90 °C; c: O3, SMe2, CH2Cl2, ꢁ78 °C; d: 6 N
HCl, reflux; e: MeLi, THF, ꢁ78 °C; f: MnO2/THF.
Chart 1
a: Tributyl(1-ethoxyvinyl)tin, PdCl2(PPh3)2, toluene, 90 °C, 2 h; b: 5% HCl, r.t.; c: 6 N
HCl reflux; d: NaBH4, MeOH
and mild procedure to obtain 5.
Chart 2
Unfortunately, all attempts to obtain compound 7 by direct
addition of methyllithium to the aldehyde 5 were unsuccess-
ful (Chart 1). It was therefore decided to replace aldehyde 5
with the methoxymethyl derivative 4, which does react with
methyllithium to afford alcohol 6 (65%). Removal of the pro-
tecting group was accomplished by treatment of 6 with hy-
drochloric acid to give the desired alcohol 7 in moderate
yield (65%). Manganese dioxide oxidation of 7 allow to pre-
pare the methyl ketone 10 in 86%.
In order to shorten the synthetic steps to prepare ketone 10
and to obtain novel 5-substituted-pyridazinones, we develop-
ed another efficient and highly versatile Stille-based synthetic
alternative to prepare pyridazinones containing oxygenated
functions at position 5 of the heterocyclic ring (Chart 2).
Starting from 5-bromo-2-methoxymethyl-6-phenyl-3-pyri-
dazinone 2, the palladium-catalysed reaction with tributyl(1-
ethoxyvinyl)tin afforded, in high yield and depending on the
final reaction conditions, the isolable 5-ethoxyvinyl-2-
methoxymethyl-6-phenyl-3-pyridazinone 8, the methylketone
10 or the protected methylketone 9. Reduction of the car-
bonyl group in ketones 9 and 10 by treatment with sodium
borohydride in methanol allow to obtain the alcohols 6, 7.
Curiously, during these proceses we have also isolated vari-
able ammounts of by products as consequence of the reduc-
tion of the double bond at positions 4- and 5- of the heterocy-
cle.
Condensation of ketone 10 with N,N-dimethylformamide
dimethyl acetal (DMFDMA) gave enamine 11. On using a
large excess of DMFDMA in this reaction we obtained the
methyl derivative 12 in excellent yield (90%) (Chart 3).
Analysis of the NMR data for compounds 11 and 12 reveals
a trans stereochemistry of the double bonds (Jꢀ15—16 Hz).
In summary, we have developed two practical and efficient
Stille-Based procedures which permit to access, in a shorten
synthetic sequence, to different 6-phenyl-5-substituted-
a: DMFDMA, benzene, reflux; b: DMFDMA, reflux
Chart 3
compounds is under study and will be published in due time.
Experimental
Melting points were measured on a Gallenkamp melting point apparatus
and are uncorrected. Infrared spectra (IR) were recorded on a Perkin-Elmer
1640 FTIR spectrophotometer. 1H-NMR spectra were obtained on Bruker
WM250 and AM300 Hz spectrometers using tetramethylsilane as internal
standard (chemical shifts are in d values, J in Hz). Mass spectra were
recorded on a Varian MAT-711 instrument. Elemental analyses were per-
formed on a Perkin-Elmer 240B apparatus at the Microanalysis Service of
the University of Santiago de Compostela. The progress of the reactions was
monitored by thin layer chromatography with 2.5 mm Merck silica gel GF
254 plates, and the purified compounds each showed a single spot; unless
otherwise stated iodine vapour and/or UV light were used for detection.
Chromatographic separations were performed on silica gel columns by flash
chromatography (Kieselgel 40, 0.040—0.063 mm).
5-Bromo-6-phenyl-3(2H)-pyridazinone (1) This compound was pre-
pared following our previously described procedure.21)
5-Bromo-2-methoxymethyl-6-phenyl-3-pyridazinone (2) Methoxy-
methyl chloride (1.28 ml, 16.9 mmol) was added to a suspension of 5-
3(2H)-pyridazinones. The biological activity of the obtained bromo-6-phenyl-3(2H)-pyridazinone
1 (1.7 g, 6.77 mmol), 4-dimethyl-

April 2003
429
aminopyridine (5 mg) and N,N-diisopropylethylamine (1.76 ml, 10.1 mmol) 5.08 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.01 mg, 0.25
in anhydrous methylene chloride (12 ml) at 0 °C. The mixture was stirred for mmol) and tributyl(1-ethoxyvinyl)tin (1.887 ml, 5.58 mmol) in anhydrous
1 h at 0 °C. The reaction was allowed to warm up to room temperature and toluene (16 ml) was heated under reflux under argon for 2 h. During the
stirred for a further 2 h. The solvent was evaporated to give a yellow oil, course of the reaction the colour changed from yellow to black and this was
which was purified by column chromatography (silica gel, ethyl acetate/ accompanied by the formation of a precipitate. The mixture was allowed to
hexane 1 : 3) to afford colourless needles (1.71 g, 85%). mp 103 °C. IR
(KBr): 1669 (CꢀO), 1053 (C–O–C) cmꢁ1 1H-NMR (CDCl3): d: 3.42 (s,
3H, OCH3), 5.45 (s, 2H, CH2O), 7.21 (s, 1H, H4), 7.40 (m, 3H, aromatics),
cool to room temperature, filtered through a pad of Celite and the filtrate was
evaporated to dryness to give a residue, which was purified by column chro-
.
matography (silica gel, ethyl acetate/hexane 2 : 1) to afford compound 8 as a
1
7.63 (m, 2H, aromatics). Anal. Calcd for C12H11BrN2O2: C, 48.84; H, 3.76; brown oil (1.42 g, 98%). IR (KBr): 1674 (CꢀO), 1053 (C–O–C) cmꢁ1. H-
Br, 27.07; N, 9.49. Found: C, 48.97; H, 3.82; N, 9.53.
2-Methoxymethyl-6-phenyl-5-vinyl-3-pyridazinone (3) A mixture of Jꢀ6.9 Hz, 1H), 4.43 (d, Jꢀ2.1 Hz, 1H), 5.48 (s, 2H, CH2O), 7.01 (s, 1H,
5-bromo-2-methoxymethyl-6-phenyl-3-pyridazinone (3.38 mmol), bis- H4), 7.37 (m, 5H, aromatics). Anal. Calcd for C11H8N2O2: C, 65.99; H, 4.03;
(triphenylphosphine)palladium(II) dichloride (1.18 mg, 0.167 mmol) and N, 13.99. Found: C, 65.97; H, 4.06; N, 14.34.
NMR (CDCl3): d: 0.81 (t, Jꢀ6.9 Hz, 3H, CH3), 3.49 (s, 3H, CH3O) 4.31 (q,
2
tributyl(vinyl)tin (1.089 ml, 3.72 mmol) in anhydrous toluene (16 ml) was
heated under reflux under argon for 2 h. During the course of the reaction the
5-Acetyl-2-methoxymethyl-6-phenyl-3(2H)-pyridazinone (9) This
compound was synthesised by treatment of 8 with 5% hydrochloric acid at
colour changed from yellow to black and this was accompanied by the for- room temperature in toluene for 12 h. The product was extracted with meth-
mation of a precipitate. The mixture was allowed to cool to room tempera- ylene chloride (3ꢂ15 ml), dried (Na2SO4) and the solvent evaporated. The
ture, filtered through a pad of Celite and the filtrate was evaporated to dry-
resulting yellow oil was purified by column chromatography (silica gel, ethyl
ness to give a yellow oily residue. The residue was purified by column chro- acetate/hexane 3 : 2) to give a colourless oil (157 mg, 90%). IR (KBr): 1718
matography (silica gel, ethyl acetate/hexane 1 : 1) to afford 3 as a yellow oil, (COCH3), 1676 (CO), 1099 (C–O–C). 1H-NMR (CDCl3): d: 2.15 (s, 3H,
which crystallized on standing; yield: 0.75 g (95%), oil. IR (KBr): 1669
CH3), 3.52 (s, 3H, OCH3), 5.50 (s, 2H, CH2), 7.43 (s, 1H, H4), 7.44 (m, 5H,
(CꢀO) cmꢁ1
.
1H-NMR (CDCl3): d: 3.48 (s, 3H, OCH3), 5.47 (s, 2H, aromatics). Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found:
CH2O), 5.50 (d, Jꢀ11.0 Hz, 1H, HCꢀCH2), 5.83 (d, Jꢀ17.7 Hz, 1H,
HCꢀCH2), 6.41 (dd, Jꢀ11.0, 17.7 Hz, 1H, HCꢀCH2), 7.04 (s, 1H, H4), 7.42
C, 65.24; H, 5.47; N, 10.89. This compound can be obtained in a one-pot
procedure by treating compound 6 with tributyl(1-ethoxyviny)tin, as de-
(s, 5H, aromatics). Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. scribed in the general procedure, followed by treatment with 5% HCl at
Found: C, 69.54; H, 5.88; N, 11.61.
room temperature for 12 h.
2-Methoxymethyl-5-formyl-6-phenyl-3(2H)-pyridazinone (4) To
solution of compound 3 (1 g, 4 mmol) in anhydrous methylene chloride
a
5-Acetyl-6-phenyl-3(2H)-pyridazinone (10) This compound was syn-
thesised by treatment of 8 with 6 N hydrochloric acid. The mixture was
(30 ml) at ꢁ78 °C was passed a slow flow of ozone for 10 min. After this heated under reflux for 12 h and the product then extracted with methylene
time, methyl sulfide (2 ml) was added and the mixture was stirred overnight chloride (3ꢂ15 ml), dried (Na2SO4) and the solvent evaporated. The result-
under a nitrogen atmosphere. Evaporation of the solvent under reduced pres- ing colourless oil was purified by column chromatography (silica gel, ethyl
sure gave a crude solid, which was purified by column chromatography (sil-
ica gel, ethyl acetate/hexane 1 : 1) to give aldehyde 4 (0.63 g, 85%). mp
79.3—81.0 °C. IR (KBr): 2720 (CHO), 1710 (CHO), 1680 (CO), 1590 (aro-
acetate/hexane 1 : 1) to afford a white solid (710 mg, 90%), which was re-
crystallized from 2-propanol. mp 188.2 °C. A one-pot preparation was also
undertaken (following the Stille coupling general procedure for compound
6), followed by treatment with 6 N HCl–a process that directly gives com-
1
matics). H-NMR (CDCl3): d: 3.38 (s, 3H, CH3), 5.39 (s, 2H, –CH2), 7.38
(s, 1H, H4), 7.55—7.47 (m, 5H, aromatics), 9.82 (s, 1H, CHO). Anal. Calcd pound 10. IR (KBr): 3100—2900 (NH), 1702 (COCH3), 1674 (CO). 1H-
for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C, 64.35; H, 4.99; N, NMR (CDCl3): d: 2.14 (s, 3H, CH3), 7.43 (s, 1H, H4), 7.44 (m, 5H, aromat-
11.58.
5-Formyl-6-phenyl-3(2H)-pyridazinone (5)
ics), 12.64 (bs, 1H, NH). Anal. Calcd for C12H10N2O2: C, 67.28; H, 4.71; N,
13.08. Found: C, 67.37; H, 4.71; N, 13.12.
A
solution of the
methoxymethyl derivative 4 (0.20 g, 1.0 mmol) in MeOH (10 ml) was treated
with 6 N HCl (7 ml) and the mixture was heated under reflux (90 °C) for
24 h. The mixture was poured onto ice and the resulting solid was recrystal-
lized from 2-propanol to give a white solid (0.15 g, 95%). mp 230.0—
5-(3ꢀ-Dimethylamino-2ꢀ-en-propionyl)-6-phenyl-3(2H)-pyridazinone
(11) A mixture of compound 10 (31 mg, 0.14 mmol) and N,N-dimethylfor-
mamide dimethyl acetal (0.036 ml, 0.27 mmol) in benzene (5 ml) was heated
under reflux during 6 h. The reaction mixture was evaporated to dryness and
231.2 °C. IR (KBr): 3180—3050 (NH), 2720 (CHO), 1720 (CHO), 1650 the residue washed with water. The product was extracted into methylen
1
(CO), 1590 (aromatics). H-NMR (CDCl3): d: 7.46 (s, 1H, H4), 7.70—7.60 chloride, dried (NaSO4) and purified by column chromatography (silica gel,
(m, 5H, aromatics), 9.87 (s, 1H, CHO), 13.82 (s, 1H, NH). Anal. Calcd for chloroform/methanol 13 : 0.5) to afford a yellow oil (35 mg, 90%). IR (KBr):
C11H8N2O2: C, 65.99; H, 4.03; N, 13.99. Found: C, 65.97; H, 4.06; N, 14.34.
5-(1ꢀ-Hydroxyethyl)-2-methoxymethyl-6-phenyl-3(2H)-pyridazinone 3.11 (s, 3H, CH3), 5.07 (d, Jꢀ9.5 Hz, 1H, HCꢀC), 6.98 (d, Jꢀ9.5 Hz, 1H,
2925 (NH), 1669 (CO), 1712 (CO). 1H-NMR (CDCl3): d: 2.78 (s, 3H, CH3),
(6) To a solution of ketone 9 (120 mg, 0.46 mmol) in MeOH (25 ml) was
added slowly sodium borohydride (26 mg, 0.69 mmol) and the suspension
was stirred at room temperature during 30 min. The reaction mixture was
treated with water (25 ml) and the solution extracted with methylene chlo-
CꢀCH), 7.26 (s, 1H, H4), 7.38 (m, 3H, aromatics), 7.53 (m, 2H, aromatics),
11.30 (bs, 1H, –NH). Anal. Calcd for C15H15N3O2: C, 66.99; H, 5.61; N,
15.60. Found: C, 66.92; H, 5.63; N, 15.64.
5-(3ꢀ-Dimethylamino-2ꢀ-propienyl)-2-methyl-6-phenyl-3(2H)-pyri-
ride, dried (Na2SO4), and the solvent removed to give a colourless oil, which dazinone (12) A suspension of compound 10 (31 mg, 0.14 mmol) in N,N-
was purified by column chromatography (silica gel, ethyl acetate/hexane dimethylformamide dimethyl acetal (2 ml, 15 mmol) was heated under reflux
1 : 2) to give the product as a colourless oil (78 mg, 65%). IR (KBr): 3235
during 6 h. The reaction mixture was evaporated to dryness and the residue
1
(OH), 1680 (CO), 1580 (aromatics), 1150 (C–O–C). H-NMR (CDCl3): d: washed with water, extracted into methylene chloride, dried (NaSO4) and
1.03 (d, 3H, CH3), 3.41 (s, 3H, OCH3), 4.66 (br s, 1H, OH), 5.38 (s, 2H,
N–CH2–O), 5.54 (q, 1H, CH), 7.10 (s, 1H, H4), 7.53 (s, 5H, aromatics).
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.70. Found: C, 64.79; (CO), 1570 (aromatics),. H-NMR (CDCl3): d: 2.76 (s, 3H, –CH3), 3.09 (s,
H, 6.27; N, 110.59.
purified by column chromatography (silica gel, chloroform/methanol
13 : 0.5) to afford a yellow oil (37 mg, 90%). IR (KBr): 1697 (CO), 1651
1
3H, CH3), 3.86 (s, 3H, N–CH3), 5.07 (d, Jꢀ11.6 Hz, 1H, HCꢀC), 6.96 (d,
Jꢀ11.6 Hz, 1H, CꢀCH), 7.36 (s, 1H, H4), 7.51 (m, 3H, aromatics), 7.52 (m,
5-(1ꢀ-Hydroxyethyl)-6-phenyl-3(2H)-pyridazinone (7) To a solution
of ketone 10 (250 mg, 1.16 mmol) in MeOH (25 ml) was added slowly 2H, aromatics). Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83.
sodium borohydride (26 mg, 1.75 mmol) and the mixture was stirred at room
temperature during 30 min. The reaction mixture was treated with water
(25 ml) and the product extracted with methylene chloride. The organic lay-
Found: C, 67.85; H, 6.05; N, 14.84.
Acknowledgements Financial support from the Xunta de Galicia (Pro-
ers were dried (Na2SO4) and the solvent was removed to give an oil, which ject XUGA 8151389) is gratefully acknowledged. We also thank the Spanish
was purified by column chromatography (silica gel, ethyl acetate/hexane Instituto de Cooperación Iberoamericana (ICI) for a Doctoral fellowship for
2 : 1) to afford the product as a colourless oil (163 mg, 65%). IR (KBr): 3255
Eddy Sotelo.
(OH), 1680 (CO), 1590 (aromatics). 1H-NMR (CDCl3): d: 1.01 (d, 3H,
CH3), 4.58 (br s, 1H, OH), 5.43 (q, 1H, CH), 6.95 (s, 1H, H4), 7.45 (m, 5H, References
aromatics), 13.00 (s, 1H, NH). Anal. Calcd for C12H12N2O2: C, 66.65; H,
5.59; N, 12.96. Found: C, 66.73; H, 5.71; N, 13.08.
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