Facile synthesis of 6-aryl 5-N-substituted pyridazinones: Micro wave-assisted Suzuki-Miyaura cross coupling of 6-chloropyridazinones

Article abstract of DOI:10.1021/jo801097v

(Chemical Equation Presented) A facile synthesis of 5-dialkylamino-6-aryl- (2H)-pyridazin-3-one from 5,6-dichloropyridazinone was carried out by using a palladium-catalyzed Suzuki-Miyaura cross coupling of 6-chloro-5- dialkylaminopyridazinone 1 with various arylboronic acids (3 equiv) as the key transformation. The Suzuki-Miyaura cross-coupling reaction proceeded smoothly under microwave irradiation at 135-140°C for 30 min with 5 mol % of Pd catalyst in moderate to good isolated yields. The use of a CombiPhos Pd6 mixture catalyst system and a single Pd-SPhos catalyst system was evaluated.

Full text of DOI:10.1021/jo801097v

Facile Synthesis of 6-Aryl 5-N-Substituted Pyridazinones:
Microwave-Assisted Suzuki-Miyaura Cross Coupling of
6-Chloropyridazinones
Ping Cao,* Junya Qu, George Burton, and Ralph A. Rivero
GlaxoSmithKline Pharmaceuticals, 1250 South CollegeVille Rd, CollegeVille, PennsylVania 19426
ping_2_cao@gsk.com
ReceiVed May 22, 2008
A facile synthesis of 5-dialkylamino-6-aryl-(2H)-pyridazin-3-one from 5,6-dichloropyridazinone was
carried out by using a palladium-catalyzed Suzuki-Miyaura cross coupling of 6-chloro-5-dialkylami-
nopyridazinone 1 with various arylboronic acids (3 equiv) as the key transformation. The Suzuki-Miyaura
cross-coupling reaction proceeded smoothly under microwave irradiation at 135-140 °C for 30 min
with 5 mol % of Pd catalyst in moderate to good isolated yields. The use of a CombiPhos Pd6 mixture
catalyst system and a single Pd-SPhos catalyst system was evaluated.
SCHEME 1. Conventional Synthesis of
5-Dialkylamino-6-arylpyridazinones
Introduction
The pyridazine nucleus and its 3-oxo derivative pyridazinones
are recognized as versatile scaffolds with a wide range of biological
activities that can also be used to support other pharmacophoric
groups.1-6 Most syntheses of 6-aryl 5-N-substituted pyridazinones
V proceed via the traditional methods, involving condensation of
hydrazine with appropriate substituted lactones or 1,4-dicarbonyl
compounds II or III.6 However, the major drawback of these
synthetic routes is the necessity to “custom make” the required
dicarbonyl components II or III (Scheme 1). Herein, we report
the results of our approach leading to an efficient synthetic route
(1) Frank, H.; Heinisch, G. Pharmacological Active Pyridazines. Part 1. In
Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.; Elsevier:
Amsterdam, The Netherlands, 1990; Vol. 27, p 1.
(2) (a) Tajaka, M.; Sato, M.; Terashina, K.; Tanizawa, H.; Maki, Y. J. Med.
Chem. 1979, 22, 53. (b) Montero-Lastres, A.; Nuria, L.; Reyes, C. E.; Estervez,
I.; Ravina, E. Biol. Pharm. Bull. 1999, 22, 1376–1379.
(3) (a) Thyes, M.; Lehmann, H. D.; Griess, J.; Ko¨nig, H.; Kretzschmar, R.;
Kunze, J.; Lebku¨cher, R.; Lenke, D. J. Med. Chem. 1983, 26, 800–807. (b) Slater,
R. A.; Howson, W.; Swayne, T. G.; Taylor, E. M.; Reavill, D. R. J. Med. Chem.
1988, 31, 345–351. (c) Demirayak, S.; Karaburun, A. C.; Beis, R. Eur. J. Med.
Chem. 2004, 39, 1089–1095.
(4) (a) Schoenafinger, K.; Hoelder, S.; Will, D. W.; Matter, H.; Muller, G.;
Bossart, M. PCT Int. Appl. WO2005085230 A1, 2005. (b) Schoenafinger, K.;
Hoelder, S.; Will, D. W.; Matter, H.; Muller, G.; Bossart, M. PCT Int. Appl.
WO2005085231 A1, 2005.
(5) Dal Piaz, V.; Aguilar Izquierdo, N.; Buil Albero, M. A.; Garrido Rubio,
Y.; Giovannoni, M. P.; et al. PCT Int. Appl. WO2005949581 A1, 2005.
(6) Estevez, I.; Ravina, E.; Sotel, E. J. Heterocycl. Chem. 1998, 35, 1421–
1427.
from which a large number of analogues with variable substitutions
at the N-2, C-5, and C-6 positions of the pyridazinone ring can be
readily prepared.
As depicted in Scheme 2, our synthesis employs a very
efficient microwave (MW) promoted Suzuki-Miyaura cross
7204 J. Org. Chem. 2008, 73, 7204–7208
10.1021/jo801097v CCC: $40.75 2008 American Chemical Society
Published on Web 08/08/2008

Facile Synthesis of 6-Aryl 5-N-Substituted Pyridazinones
SCHEME 2. Route to
5-Dialkylamino-6-aryl-(2H)-pyridazin-3-one
Results and Discussion
Microwave-assisted chemical methods have been proven to
be a powerful technique for increasing the throughput of
chemical synthesis.9 Microwave heating was chosen for the
cross-coupling reaction in Scheme 2 to achieve the synthesis
in short reaction time without the requirement of special reaction
conditions such as inert gas. An initial attempt to couple
6-chloro-5-piperidylpyridazinone (5a) with phenylboronic acid,
using Combiphos Pd610 catalyst in dioxane and Cs2CO3 as the
base, at a temperature of 130 °C under microwave irradiation,
gave no desired product. We suspected that the free N-H of
pyridazinone interfered with the catalyst, as repeating the
reaction with the N-benzyl-protected pyridazinone 1a under the
same conditions gave the desired coupling product (entry 1,
Table 1). To define the conditions for the Suzuki-Miyaura cross
coupling of 6-chloropyridazinones 1 with use of CombiPhos
Pd6,11 an intensive screening of reaction variables was under-
taken, using 1-benzyl-6-chloro-5-piperidyl-(2H)-pyridazin-3-one
(1a) and phenylboronic acid as representative substrates. It was
uncovered that the cross coupling can proceed smoothly when
a mixture of 1 equiv of 1a and 3 equiv of phenyl boronic acid
in 1,4-dioxane was irradiated under microwave conditions for
30 min at 135 °C in the presence of 4 equiv of Cs2CO3 and
3-15 mol % of palladium catalyst (Combiphos Pd6). At least
3 mol % Pd catalyst is required to achieve complete conversion.
In addition to Cs2CO3, K2CO3 was identified as an alternative
base providing similar results for the C-C bond formation.
SCHEME 3. Preparation of Key Intermediate 1a
a Reagents and conditions: (a) TMG (1,1,3,3-tetramethylguanidine) or
PS-BEMP (polystyrene supported 2-tert-butylimino-2-diethylamino-1,3-
dimethylperhydro-1,3,2-diazaphosphorine), BnBr and dioxane as solvent,
microwave, 100 °C, 10 min, quantitative yield; (b) DIEA, ethanol,
microwave, 150 °C, 10-25 min, quantitative yields; (c) DIEA (diisopro-
pylethylamine), ethanol, microwave, 150°C, 10-25 min, quantitative yields;
(d) TMG or PS-BEMP, dioxane, microwave, 100 °C, 10 min, quantitative
yield.
(9) (a) MicrowaVes in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH:
Weinheim, Germany, 2002. (b) MicrowaVe Synthesis: Chemistry at the Speed
of Light; Hayes, B. L., Ed.; CEM Publishing: Matthews, NC, 2002. (c) Kappe,
C. O. Controlled Microwave Heating in Modern Organic Synthesis. Angew.
Chem., Int. Ed. 2004, 43, 6250–6284. (d) MicrowaVe Assisted Organic Synthesis;
Tierney, J. P., Lidstrom, P., Eds.; Blackwell Scientific: Boca Raton, FL, 2005.
(e) MicrowaVes in Organic and Medicinal Chemistry; Kappe, O. C., Alexande,S.,
Eds.; Wiley-VCH: Weinheim, Germany, 2005.
(10) CombiPhos-Pd6 is a mixture of POPd, POPd1, POPd2, POPd3, POPd4,
POPd5, POPd6, POPd7, PXPd, PXPd2, PXPd3, PXPd4, PXPd6, PXPd7, and
PXPd2-Br in equal mole amounts:
coupling between 6-chloro-5-dialkylaminopyridazinones 1 and
arylboronic acids as the key transformation in the preparation
of 6-aryl-5-dialkylamino-(2H)-pyridazin-3-one 2. This method
is attractive since it adds the aryl group toward the end of the
synthesis, allowing one to take advantage of a wide selection
of aryl boronic acids available from commercial sources.
Although there are several reports on the preparation of
pyridazinones using a Suzuki-Miyaura cross-coupling reaction,7
there are no discussions on the synthesis of 5-dialkylamino-6-
aryl-(2H)-pyridazin-3-one 2 with this transformation.
In addition, the key intermediate 6-chloro-5-dialkylaminopy-
ridazinones 1 can be prepared in high yield in two steps starting
from 5,6-dichloropyridazinone 38 (Scheme 3). The synthesis of
the intermediate 1 involved the nucleophilic substitution of
amines at the C5 position to introduce the first diversity element,
followed by an N-alkylation at N-2 to introduce the second
diversity point or vice versa (Scheme 3).
(7) (a) Coelho, A.; Sotelo, E.; Este´vez, I.; Ravina, E. Synthesis 2001, 871–
876. (b) Tapolcsa´nyi, P.; Maes, B. U. W.; Monsieurs, K.; Guy, L. F.; Lemie`re,
G. L. F.; Riedl, Z.; Hajo´s, G.; Driessche, B.; Dommisse, R. A.; Ma´tyus, P. M.
Tetrahedron 2003, 59, 5919–5926. (c) Salives, R.; Dupas, G.; Ple´, N.; Que´guiner,
G.; Turck, A. J. Comb. Chem. 2005, 7, 414–420. (d) Ohkuchi, M.; Kyotani, H.;
Shigyo, H.; Yoshizaki, H.; Koshi, T. PCT Int. Appl. WO9944995 A1, 1999. (e)
Hoelder, S.; Naumann, T.; Schoenafinger, K.; Will, D. W.; Matter, H. PCT Int.
Appl. WO2004046117 A1, 2004.
.
(11) (a) Li, G. Y. J. Organomet. Chem. 2002, 653, 63–68. (b) Li, G. Y. J.
Org. Chem. 2002, 67, 3643–3650.
(8) Obtained from Key Organics Ltd. http://www.keyorganics.co.uk/.
J. Org. Chem. Vol. 73, No. 18, 2008 7205

Cao et al.
TABLE 1. Comparison of Catalyst Systems for Palladium-Catalyzed Suzuki Coupling of 6-Chloropyridazinone 4a
product byproduct 6a
product byproduct
entry
[Pd] (5 mol %)
Pd6
POPd2
PXPd2
PXPd
POPd6
PXPd6
Pd2(dba)3/PPh3
base + solvent
(%)b
(%)
entry
[Pd] (5 mol %)
base + solvent
(%)b
6a (%)
1
2
3
4
5
6
7
8
9
Cs2CO3/dioxane
Cs2CO3/dioxane
Cs2CO3/dioxane
Cs2CO3/dioxane
Cs2CO3/dioxane
Cs2CO3/dioxane
Cs2CO3/dioxane
77
44
88
88
55
84
90
43
50
97
13
14
12
12
21
16
10
12
10
3
11
12
13
14
15
16
17
18
19
20
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS
Pd6
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS KF/dioxane
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS
Pd2(dba)3/SPHOS KF/DMF
Cs2CO3/THF
64
97
36
3
Cs2CO3/DMF
Cs2CO3/toluene
K2CO3/dioxane
K2CO3/dioxane
K3PO4/dioxane
48
30
42
0
93
7
83
1
100
49
0
5
Pd2(dba)3/xanthphos Cs2CO3/dioxane
Pd2(dba)3/dppf
Pd2(dba)3/SPHOS
KOH/dioxane
CsF/dioxane
Cs2CO3/dioxane
Cs2CO3/dioxane
50
2
10
100
0
a All reactions were carried out in 2.5 mL Biotage reaction process vials. The reaction mixture consists of 100 µmol of 6-chloropyridazinone 1a and 5
mol % Pd catalyst, 3 equiv of phenylboronic acid, 4 equiv of base, and 1 mL of dioxane as solvent. The reaction mixture was irradiated at 135 °C for
30 min. Personal Chemistry (now Biotage) Smith Synthesized was used. b The conversion and yield of byproduct 6a was detected by LC/MS.
DMF also can be a good alternative solvent in addition to
dioxane. Some dehalogenation product of 6-chloropyridazinone
6a was also detected (entry 1, Table 1).
otherwise identical conditions as for the microwave reaction,
i.e., CombiPhos Pd6, at a temperature of 110 °C, for a period
of 14 h. Although this thermal reaction took longer, it also gave
complete conversion accompanied by the generation of around
10% dehalogenation product 6a.
By weighing the pros and cons of the reaction systems, two
sets of experimental conditions were selected as the cross-coupling
method for the synthesis of 6-aryl 5-N-substituted pyridazinones.
One set uses a mixture Pd catalyst Combiphos Pd6 and the other
uses a Pd-Sphos catalyst system. In a typical experiment, a mixture
of 1 equiv of 1a and 3 equiv of phenylboronic acid in 1,4-dioxane
was irradiated under microwave conditions for 30 min at 135 °C
in the presence of 4 equiv of Cs2CO3 and 5 mol % of palladium
catalyst (CombiPhos Pd6 or Pd-Sphos). No starting material (100%
conversion to products) was detected by LC/MS analysis. It was
found that at least 3 mol % of Pd catalyst was required to achieve
complete conversion.
Under the typical microwave coupling conditions described
above, the scope of cross coupling was investigated for the
reaction between 6-chloropyridazinone 1 and arylboronic acids
with CombiPhos Pd6 as catalyst for the synthesis of a diverse
set of 6-aryl-5-dialkylaminopyridazinones 2. The results are
summarized in Table 2. Analysis of the crude reaction mixtures
by LC/MS showed complete conversion in most cases (entries
1, 6-11, and 13, Table 2). Following preparative HPLC
purification, satisfactory isolated yields were obtained though
slightly lower than expected due to the generation of 6-23%
dehalogentation product (Table 2).
The side chain effect at C5 of the pyridazinone was explored
with different dialkylamino substitutions. Substrate 1b, with a five-
membered pyrrolidine side chain at C5, led to increased dehalo-
genation product (20% by LC/MS, entry 2, Table 2) compared
with that of the piperidine side chain (13% by LC/MS. entry 1,
Table 2). A significant reduction in the yield was observed with
both substrate 1c, bearing dimethylamine side chain, and 1d,
bearing the seven-membered ring hexamethyleneimine side chain
at C5. These low yields were due to incomplete conversion (70%
1c consumed by LC/MS for entry 3 and 86% by LC/MS for entry
4, Table 2) and to more profound dehalogenation product genera-
tion (23% by LC/MS for entry 3, 15% by LC/MS for entry 4,
The scope and limitation of using a palladium complex mixture
as catalyst was also investigated. The activity of the individual
catalysts (PXPd, POPd, PXPd2, POPd2, PXPd6, and POPd6)
consisting of Combiphos Pd6 was examined for Suzuki coupling
between 1-benzyl-6-chloro-5-piperidyl-(2H)-pyridazin-3-one (1a)
and phenylboronic acid. The results are summarized in Table 1.
The Palladium-phosphinic acid complexe catalysts are less reactive
with 58% conversion for POPd2 (entry 2, Table 1) and 76%
conversion for POPd6 (entry 5, Table 1). Palladium phosphinous
chloride complexe catalysts are more reactive with 100% conver-
sion for PXPd2, PXPd, and PXPd6 (entries 3, 4, and 6, Table 1).
With a 90% conversion for Combiphos Pd6 catalyst, the less active
catalysts POPd2 and POPd6 in the mixture did not interfere with
the performance of the more active catalysts PXPd, PXPd2, and
PXPd6. However, an observed limitation associated with using a
mixture of catalysts, Combiphos Pd6, for Suzuki-Miyaura cou-
pling is the dehalogenation of the 6-chloropyridazinone 1a (deha-
logenated product 6a). To minimize and hopefully eliminate the
undesirable dehalogenation reaction, a variety of palladium-
phosphine complexes as catalysts were also investigated. A
significant improvement on reducing dehalogenation side reaction
was achieved when using palladium-2-(2′,6′-dimehtoxybiphenyl)
dicyclohexylphosphine (Sphos12) as catalyst (100% conv., 3% 6a,
entry 10, Table 1). Further optimization of condition variables led
to the optimal catalyst system that minimized dehalogenation by
using KF as base in Dioxane (entry 17, Table 1). Improvement
also was observed for Combiphos Pd6 when K2CO3 was used as
base in dioxane. However, the reaction proceeded much slower
compared to that with Cs2CO3 as base (entry 15, Table 1). In
contrast, only sluggish reactivity was observed for the Pd-Sphos
catalyst system with K2CO3 as base (30% conv., entry 14, Table
1).
For comparison, the reaction of 1a with phenylboronic acid
was also conducted with use of a preheated oil bath under
(12) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew
Chem., Int. Ed. 2004, 43, 1871–1876. (b) Barder, T. E.; Buchwald, S. L. Org.
Lett. 2004, 6, 2649–2652.
7206 J. Org. Chem. Vol. 73, No. 18, 2008

Facile Synthesis of 6-Aryl 5-N-Substituted Pyridazinones
TABLE 2. Suzuki-Miyaura Cross Coupling of 6-Chloropyridazinones with Arylboronic Acids Catalyzed by Combiphos Pd6a
a All reactions were carried out in 2.5 mL Biotage reaction process vials. The reaction mixture consisted of 100 µmol of 6-chloropyridazinone 1 and 5
mol % Combiphos Pd6, 3 equiv of arylboronic acid, and 4 equiv of Cs2CO3 as base, and 1 mL of dioxane as solvent. The reaction mixture was
irradiated at 135 °C for 30 min. Personal Chemistry (now Biotage) microwave reactor Smith Synthesizer was used. 100% conversion was obtained for
entries 1, 6-11, and 13. b Isolated yield by reverse HPLC. c Percent 6 is from LC/MS analysis of the reaction mixture. d 52% by LC/MS e 39% by
LC/MS.S f Yield by LC/MS.
Table 2). The coupling of 6-chloropyridazinones proceeded well
with boronic acids containing meta- and para-substituted electron-
donating groups (entries 5-9, Table 2). Arylboronic acids with a
strong electron-withdrawing group at the para-position and meta-
position such as 3-nitro and 4-nitrobenzene boronic acids were
unreactive even when 10% Pd catalyst was used (data not shown).
The coupling with the heterocyclic 3-thienylboronic acid gave 30%
isolated yield of the desired product 2 (entry 12, Table 2); this
low yield resulted from incomplete conversion (39% 1a consumed).
No cross coupling occurred with other heterocyclic boronic acids,
e.g., 2-furylboronic acid or 2-thienylboronic acid. The coupling
reactions between ortho-substituted aryl boronic acids such as
2-methoxy and 2-fluorobenzene boronic acids were shown to be
less successful giving 11% and 15% conversion by LC/MS (entries
14 and 15, Table 2).
6-chloropyridazinone 1a and arylboronic acids bearing meta- or
para-substituted electron-donating groups such as 4-OMe, 3-OMe-
,and 4-Me (entries 2, 4, and 5, Table 3). However, the cross-
coupling reaction of 4-phenoxybenzeneboronic acid only gave 67%
conversion, with 35% reductive dehalogenation product 6 and 32%
isolated yield after HPLC purification (entry 10, Table 3). A low
isolated yield was also observed when using the biphenylboronic
acid substrate (100% conversion and 50% 6 by LC/MS, entry 7,
Table 3). Similarly to the CombiPhos Pd6 catalyst system, the
heterocyclic boronic acids such as 2-furanyl- or 2-thienylboronic
acids and arylboronic acids with strong electron-withdrawing
groups, like 3-nitrobenzeneboronic acid, did not give any of the
desired products.
The mixture catalyst system CombiPhos Pd6 showed limited
success for cross coupling due to the significant reductive deha-
logenation reaction (6-23% by LC/MS). Employing much im-
proved conditions with the Pd-SPhos catalyst system, cross
coupling of 5-chloropyridazinones 1a with various boronic acids
proved to be more efficient. These results are summarized in Table
3. The Pd-SPhos catalyst gave excellent reactivity with ortho-
substituted boronic acids, e.g., 2-methoxy- and 2-fluorobenzenebo-
ronic acids (entries 8-9, Table 3): 100% conversion and dehalo-
genation free was achieved for both substrates. The Pd-SPhos
catalyst system was also conducive for cross coupling between
Conclusions
In conclusion, applying a Pd-catalyzed Suzuki-Miyaura cross
coupling of 6-chloro-5-dialkylaminopyridazinones as the key
transformation, we have developed a facile synthesis of 6-aryl-5-
dialkylaminopyridazin-3-ones. Two catalyst systems have been
described. The preferred method utilized a Pd-SPhos complex as
catalyst, 1,4-dioxane as solvent, KF as the base, and microwave
irradiation as the heating source. The cross-coupling reaction
proceeded efficiently at 135-140 °C with 3-5 mol % of Pd
catalyst to form 6-aryl-5- dialkylaminopyridazinone in good yields.
J. Org. Chem. Vol. 73, No. 18, 2008 7207

Cao et al.
TABLE 3. Suzuki-Miyaura Cross Coupling of 6-Chloropyridazinones with Arylboronic Acids Catalyzed by the Pd-SPhos Catalyst Systema
a All reactions were carried out in 2.5 mL Biotage reaction process vials. The reaction mixture consisted of 300 µmol of 6-chloropyridazinone 1a and
5 mol % Sphos-Pd catalyst, 3 equiv of arylboronic acid and 4 equiv of base KF, and 2 mL of dioxane as solvent. The reaction mixture was purged with
N2 and irradiated at 140 °C for 30 min. Personal Chemistry (now Biotage) microwave reactor Smith Synthesizer was used. b Isolated yield by reverse
HPLC. c 76% conv. by LC/MS. d 100% conv. 50% dehalogenation product 6 by LC/MS. e 67% conv. and 35% dehalogenation product 6 by LC/MS.
The crude was subjected to reverse-phase HPLC purification to give
the desired product 43 mg, yield 61%.
Additionally, we also demonstrated the possibility of using a
mixture catalyst system consisting of CombiPhos Pd6, Cs2CO3 as
base in dioxane to promote the Suzuki-Miyaura cross-coupling
reaction. The catalyst system gave limited success due to the
significant reductive dehalogenation reaction. However, the Com-
biphos Pd6 method allows quick access to many of the desired
cross-coupling products of interest.
The Suzuki-Miyaura cross-coupling synthetic route described
herein allowed the addition of diversity at the C6 position of the
pyridazinone ring at a late stage in the synthesis. Further, this
Suzuki-Miyaura cross-coupling-based procedure, used in conjunc-
tion with the efficient alkylation and nucleophilic substitution
chemistries described for the preparation of 1, offers a simple
method to introduce a wide range of functional groups at N-2, C-5,
and C-6 positions, which permits a rapid pharmaco-modulation of
the pyridazinone scaffold. The results presented in this paper
represent a significant improvement in the 5,6-disubstituted py-
ridazinone synthesis.
(b) A typical experimental procedure with Pd-SPhos is as follows:
A Biotage Process Vial (2-5 mL) was charged with 5 mol % of SPhos
(6.15 mg, 15 umol), 2.5 mol % of Pd2(dba)3 (6.9 mg, 7.5 umol), chloro-
2-(phenylmethyl)-5-(1-piperidinyl)-3(2H)-pyridazinone (1a) (91.0 mg,
0.3 mmol), phenylboronic acid (110 mg, 0.9 mmol), and KF (70 mg,
1.2 mmol). The vial was charged with 2 mL of anhydrous 1,4-dioxane,
stirred at room temperature for 10 min, and then irradiated at 140 °C
for 30 min, using the microwave reactor Smith Synthesizer. After
irradiation, the sample was cooled, filtered, and purified by reverse-
phase HPLC to give the desired product (98.2 mg, yield 95%).
6-Phenyl-2-(phenylmethyl)-5-(1-piperidinyl)-3(2H)-pyridazino-
ne, 2a1. 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 2H), 7.25-7.48 (m,
8H), 6.64 (s, 1H), 5.35 (s, 2H), 2.89 (m, 4H), 1.50 (m, 6H). 13C NMR
(100 MHz, CDCl3) δ 162.06, 154.52, 144.26, 136.03, 135.80, 129.03,
128.80, 128.50, 128.44, 127.85, 127.46, 107.83, 55.08, 50.62, 24.74,
23.31. MS m/z 346.2 [M+ + H]. HRMS (ES+) calcd for C22H24N3O1
(M+ + H) 346.1914, found 346.1915.
Acknowledgment. We thank Victoria Magaard, Walter Johnson,
Chad Quinn, and Jacques Briand for analytical support and Dr.
George Li, at Combiphos Catalysts, Inc., Princeton, NJ, for helpful
discussions
Experimental Section
General Procedures for the Palladium-Catalyzed Synthesis
of 6-Aryl 5-N-Substituted Pyridazinones. (a) A Biotage Process
Vial (2-5 mL) was charged with chloro-2-(phenylmethyl)-5-(1-
piperidinyl)-3(2H)-pyridazinone (1a) (45.5 mg, 0.15 mmol), 3 mol %
Combiphos Pd6 (3.4 mg, 4.5 umol), phenylboronic acid (55 mg, 0.45
mmol), and Cs2CO3 (195 mg, 0.6 mmol) in anhydrous 1,4-dioxane (2
mL). The resulting mixture was irradiated at 135 °C for 30 min on a
microwave Smith Synthesizer. After irradiation, the sample was filtered
through a thin pad of silica gel, washed with DCM, and concentrated.
Supporting Information Available: Experimental proce-
dures and characterization data for 5-aminopyridazinone 1 and
Suzuki-Miyaura cross-coupling products 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO801097V
7208 J. Org. Chem. Vol. 73, No. 18, 2008