Silica-supported aluminum chloride-assisted solution phase synthesis of pyridazinone-based antiplatelet agents

Article abstract of DOI:10.1021/co100017h

A solution phase protocol that enabled the synthesis of three diverse libraries of pyridazin-3-ones incorporating α,-unsaturated moieties at position 5 of the heterocyclic core has been developed using silica-supported aluminum trichloride as a heterogene

Full text of DOI:10.1021/co100017h

LETTER
pubs.acs.org/acscombsci
Silica-Supported Aluminum Chloride-Assisted Solution Phase
Synthesis of Pyridazinone-Based Antiplatelet Agents
Abdelaziz El Maatougui,†,§ Jhonny Azuaje,†,§ Eddy Sotelo,†,‡,§ Olga Caama~no,†,‡ and Alberto Coelho*,†,§
†Combinatorial Chemistry Unit (COMBIOMED), Institute of Industrial Pharmacy (IFI), ‡Department of Organic Chemistry,
Faculty of Pharmacy, and §Center for Research in Biological Chemistry and Molecular Materials, University of Santiago de Compostela,
Santiago de Compostela 15782, Spain
S Supporting Information
b
ABSTRACT: A solution phase protocol that enabled the synthesis of three diverse
libraries of pyridazin-3-ones incorporating R,β-unsaturated moieties at position 5 of
the heterocyclic core has been developed using silica-supported aluminum trichlor-
ide as a heterogeneous and reusable catalyst. This robust procedure has facilitated
the hit to lead process for these series of compounds and allowed the identification of
new potent derivatives that elicit antiplatelet activity in the low micromolar range.
KEYWORDS: supported reagents, Knoevenagel and Claisen-Schmidt condensations, platelet aggregation inhibitors, chalcones,
solution phase synthesis
ontemporary Organic Synthesis is faced with the challenge
of developing new, efficient, atom economical, and eco-friendly
reliable and useful in the synthesis of fine chemicals,8 hetero Diels-
Alder reactions,10 and particularly in the preparation of compounds
of biological significance.11
C
processes that enable the preparation of diverse structures in a rapid
and cost-effective manner.1 While solid phase organic synthesis has
been the method of choice for the production of large libraries since
the early days of combinatorial chemistry, solution phase synthesis
has recently gained importance, particularly in the context of the
parallel synthesis of focused libraries. Solution phase library genera-
tion has been fuelled by the development of successful concepts such
as solid-supported reagents, catalysts, and scavengers. Indeed, this
approach has emerged as the leading strategy for library generation
because it combines the advantages of both solid phase organic
synthesis and solution phase chemistry (e.g., the ease of monitoring
the progress of the reactions by liquid chromatography-mass spectro-
metry (LC-MS), thin layer chromatography (TLC), or standard
NMR techniques).2 In addition to its efficacy and robustness, a
major requirement of novel supported reagents concerns their
reusability, a factor that has significant environmental and economic
impact since the most costly components in a chemical reaction are
often not the starting materials but the catalyst.3
Knoevenagel and Claisen-Schmidt condensations occupy a
prominent position within the carbon-carbon bond formation syn-
thetic armamentarium,4-6 with both transformations catalyzed by a
wide range of highly diverse reagents.7,8 The development of novel
heterogeneous catalytic systems for these reactions is a highly active
research area. Advances in this field not only increase the reliability
and general interest of these transformations, but more importantly
have enabled the implementation of environmentally friendly syn-
thetic methods.9 Both transformations are widely documented to be
In the context of a Medicinal Chemistry program,12,13 we
recently reported the discovery of novel families of potent platelet
aggregation inhibitors derived from the pyridazin-3-one scaffold and
incorporating diverse R,β-unsaturated residues at position 5 of the
heterocycle (Figure 1). It was found that compounds derived from
chemotypes A, B, and C (Figure 1) elicited the highest antiplatelet
activity, with the regioisomeric chemotypes B and C being particu-
larly attractive since they can be considered as pyridazinone/
chalcone hybrid structures. We describe here the development of a
silica-supported aluminum chloride-assisted solution phase protocol
that enables the synthesis of focused libraries derived from previously
identified chemotypes. A preliminary account of the pharmacological
data obtained during this process is also presented.
Knoevenagel and Claisen-Schmidt condensations have proven
successful with a highly diverse set of catalysts and experimental
conditions (e.g., diverse bases, Lewis acids, non-conventional ther-
mal sources and supported reagents), but these experimental proto-
cols are generally not readily amenable to the parallel approach. In
the context of a program aimed at optimizing previously identified
hit structures (Figure 1), it was necessary to develop an efficient,
robust, and simple experimental protocol that would be capable of
delivering libraries of the target chemotypes. These requirements
led to the choice of aluminum chloride as a reagent as it is superior to
Received: September 27, 2010
Published: November 9, 2010
r
2010 American Chemical Society
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ACS Combinatorial Science
LETTER
Figure 1. Representative pyridazin-3-ones as platelet aggregation inhibitors.
established preparative methods in both the Knoevenagel and the
Claisen-Schmidt transformations, and results were experimentally
validated during the early phases of the project.13 In spite of the
excellent reactivity profile observed, several drawbacks that are
usually associated with the use of this reagent were experienced.
For example, aluminum chloride readily undergoes hydrolysis when
exposed to moisture, tends to dimerize when dissolved, and often
forms a suspension of Al(OH)3 during reaction workup. It was
therefore decided to evaluate the applicability of polymer-supported
aluminum chloride (e.g., Si-AlCl3) during the synthesis of target
arrays. In comparison with conventional aluminum chloride, the
silica-bound equivalent offers several advantages over the free
catalyst14 (e.g., a milder acidity, superior shelf life, and the ability
to conduct non-aqueous work-ups)15 or the polystyrene-supported
version (such as no swelling and ability to carry out reactions in polar
solvents). Accordingly, for library production purposes the use of
Si-AlCl3 was assessed. The preparative applications of this reagent
have been reported previously, and it proved to be particularly
effective in Friedel-Crafts alkylations and acylations16 and in ether
synthesis.17 To the best of our knowledge, however, the application
of this material as a catalyst in Knoevenagel and Claisen-Schmidt
condensations remains unexplored.
The synthetic pathways developed to access the target pyr-
idazinone arrays are based on the assembly of the exocyclic R,β-
unsaturated framework through either the Knoevenagel (chemo-
type A) or the Claisen-Schmidt (chemotypes B or C) con-
densations (Scheme 1), with silica-supported aluminum chloride
employed as a catalyst. The synthetic strategy and building blocks
employed were both designed to achieve our aim of preparing a
diverse library to enable the preliminary assessment of the
structural determinants for antiplatelet activity in these series
(e.g., electronic, steric, and lipo-/hydrophilic features). Thus, the
reactive groups [e.g., formyl (A1-6) or acetyl (B1-6)] present
in the heterocyclic precursors were readily transformed into the
corresponding R,β-unsaturated system (Scheme 1) by reaction
with a diverse range of activated methylene compounds (C1-8),
acetophenones (D1-8), or carboxaldehydes (E1-8). Optimized
experimentalconditionsforthe three libraries (chemotypesA-C)
are given in Scheme 1.
The 5-formylpyridazinones A1 and A4 and activated methy-
lene compounds C1 and C4 were selected as model substrates
for process optimization during the preliminary study into the
synthesis of chemotypes A. The main experimental parameters
explored were the catalyst ratio [catalytic (0.1 or 0.4 equiv) vs
stochiometric conditions], the solvent (THF, MeCN, dioxane,
or EtOH) and the temperature (25-120 °C). Preliminary
investigations identified the optimal conditions for the Knoeve-
nagel reactions on the tested substrates, with the use of EtOH as
solvent at 110 °C and 0.4 equiv of Si-AlCl3 found to give the best
results. These conditions were used for library production
starting from building blocks A and C. A remarkable feature of
these conditions concerns robustness, as the required 5-alkyli-
dene pyridazinones were successfully obtained regardless of the
reactivity profile of the starting malonate partners (i.e., C4-C8)
(Table 1).
Two representative 5-formylpyridazinones (A1, A4) and
5-acetylpyridazinones (B1, B4), as well as benzaldehyde (E1)
and acetophenone (D1), were employed as model substrates for
the synthesis of libraries of chemotypes B and C (Tables 2, 3). As
for the Knoevenagel reaction, the catalyst ratio [catalytic (0.1 or
0.4 equiv) vs stochiometric conditions], solvents (dioxane, tetra-
hydrofuran (THF), EtOH, and dimethylformamide (DMF)) and
temperatures (25-120 °C) were assessed. Preliminary screening
highlighted the critical influence that the solvent and temperature
had on the reaction behavior. The optimal solvent was found to be
ethanol for compounds of chemotype B and dioxane for the
regioisomeric series (chemotype C). Satisfactory yields were
obtained on working at 80 and 110 °C, respectively. The use of
higher temperatures (>100 °C) during the synthesis of enones B
led to side reactions.
The screening of the optimal catalyst ratio during the study of
the Claisen-Schmidt condensation on 5-formyl- or 5-acetylpyr-
idazin-3-ones incorporating a methoxymethyl group at position 2
of the heterocyclic core (e.g., A6 and B6, Scheme 1, Tables 2, 3)
provided additional evidence for the robustness of this versatile
reagent (Scheme 1). Thus, it was verified that, in clear contrast to
the results obtained on employing aluminum chloride, the use of a
large excess (up to 10 equiv) of the supported Lewis acid afforded
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ACS Combinatorial Science
LETTER
Scheme 1. Synthesis of Target Pyridazin-3-one Libraries18
Table 1. Structures and Isolated Yields of Representative Knoevenagel-Type Compounds
cmpd
R2
R6
W
Z
yield (%)
cmpd
R2
R6
W
Z
yield (%)
A1C1
A1C4
A1C5
A1C7
A1C8
A2C1
A2C4
A2C5
A2C6
A2C7
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
H
H
H
CN
CN
87
60
68
86
85
86
64
77
66
68
A4C1
A4C3
A4C5
A4C6
A4C7
A5C5
A5C3
A5C4
A5C6
A5C7
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CN
CN
80
82
74
76
72
78
87
67
88
88
COOMe
COOEt
COOtBu
COOtBn
CN
COOMe
COOEt
COOtBu
COOtBn
CN
H
CN
COOEt
COOEt
COOiPr
COOiBu
COOEt
COOEt
COOMe
COOiPr
COOtBu
H
COOEt
COOiPr
COOiBu
COOEt
CN
H
H
Me
Me
Me
Me
Me
COOMe
COOEt
COOiPr
COOtBu
COOMe
COOEt
COOiPr
COOtBu
COOMe
COOiPr
COOtBu
the target structures without promoting cleavage of the methoxy-
methyl protecting group. In addition to the catalytic efficacy
observed during the Knoevenagel and Claisen-Schmidt con-
densations, a remarkable feature of the synthetic protocol
documented here concerns the recyclability of silica-supported
aluminum chloride. Once the reaction had finished, the polymer-
supported reagent was separated from the reaction mixture by
filtration, submitted to a washing protocol (dioxane, CH2Cl2,
diethyl ether), and then dried under vacuum for 12 h. The
recovered polymeric material was routinely reused (at least three
times) during library production without significant loss of
activity and with the average yield maintained within the series
for substrates of similar reactivity (e.g., A2D1: 54%, A4D1: 55%
and B1E1: 50%, B2E1: 55%, B4E1: 56%).
Preliminary biological data from thrombin-induced aggrega-
tion studies on human platelets19 performed on representative
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ACS Combinatorial Science
Table 2. Structures and Isolated Yields of Representative 1-Aryl-3-(2,6-substituted-3-oxo-pyridazin-5-yl)-2-propen-1-ones
LETTER
cmpd
R2
R6
Y
yield (%)
cmpd
R2
Ph
R6
Y
yield (%)
A1D1
A1D2
A1D3
A1D4
A1D5
A1D6
A1D7
A1D8
A2D1
A2D2
A2D3
A2D4
A2D5
A2D6
A2D7
A2D8
A3D1
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
57
56
55
60
58
56
54
57
58
52
58
58
57
60
52
54
56
A3D2
A3D3
A3D4
A3D5
A3D6
A3D7
A3D8
A4D1
A4D2
A4D3
A4D4
A4D5
A4D6
A4D7
A4D8
A5D1
A6D1
H
Ph-4-OMe
Ph-4-Br
58
55
57
60
62
54
56
62
46
56
57
50
58
51
59
68
68
Ph-4-OMe
Ph-4-Br
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
Ph-4-Cl
Ph-4-Cl
H
Ph-2,4-Cl
Ph-3,4,5-(OMe)3
2-Furyl
Ph-2,4-Cl
Ph-3,4,5-(OMe)3
2-Furyl
H
H
H
2-Thienyl
Ph
2-Thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph-4-OMe
Ph-4-Br
Ph-4-OMe
Ph-4-Br
H
H
Ph-4-Cl
Ph-4-Cl
H
Ph-2,4-Cl
Ph-3,4,5-(OMe)3
2-Furyl
Ph-2,4-Cl
Ph-3,4,5-(OMe)3
2-Furyl
H
H
H
2-Thienyl
Ph
2-Thienyl
Ph
Me
MOM
Ph
Table 3. Structures and Isolated Yields of Representative 3-Aryl-1-(2,6-substituted-3-oxo-pyridazin-5-yl)-2-propen-1-ones
cmpd
R2
R6
Y
yield (%)
cmpd
R2
Ph
R6
Y
yield (%)
B1E1
B1E2
B1E3
B1E4
B1E5
B1E6
B1E7
B1E8
B2E1
B2E2
B2E3
B2E4
B2E5
B2E6
B2E7
B2E8
B3E1
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
52
55
67
55
50
59
60
52
62
52
68
51
52
59
52
51
62
B3E2
B3E3
B3E4
B3E5
B3E6
B3E7
B3E8
B4E1
B4E2
B4E3
B4E4
B4E5
B4E6
B4E7
B4E8
B5E1
B6E1
H
Ph-4-OMe
Ph-4-Br
60
53
55
50
58
50
54
60
56
56
50
48
58
57
60
58
64
Ph-4-OMe
Ph-4-Br
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
Ph-4-Cl
Ph-4-Cl
H
Ph-2,4-Cl
Ph-3,4,5-(OMe)3
2-Furyl
Ph-2,4-Cl
Ph-3,4,5-(OMe)3
2-Furyl
H
H
H
2-Thienyl
Ph
2-Thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph-4-OMe
Ph-4-Br
Ph-4-OMe
Ph-4-Br
H
H
Ph-4-Cl
Ph-4-Cl
H
Ph-2,4-Cl
Ph-3,4,5-(OMe)3
2-Furyl
Ph-2,4-Cl
Ph-3,4,5-(OMe)3
2-Furyl
H
H
H
2-Thienyl
Ph
2-Thienyl
Ph
Me
MOM
Ph
compounds are given in Table 4. Comparison of the activity data
for hit compounds (Figure 1) with the data obtained for the
novel derivatives prepared in this work (Table 4) demonstrates
the improvements that can be achieved in the antiplatelet activity
through structural manipulation of model chemotypes. It can be
seen that the increase in potency is particularly remarkable on
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ACS Combinatorial Science
LETTER
Table 4. Antiplatelet Data Obtained for Representative
Pyridazin-3-one/chalcone Hybrids
’ ACKNOWLEDGMENT
This work was financially supported by the Fondo Europeo de
Desarrollo Social (FEDER) and the Galician Government. J.A.
thanks Fundayacucho (Venezuela) for a predoctoral grant. E.S. is
the recipient of a Consolidation Group Research Grant from the
Conselleria de Educaciꢀon (Xunta de Galicia). E.S. and A.C. are
researchers of the Isidro Parga Pondal program (Xunta de
Galicia, Spain).
cmpd
R2
R6
Y
IC50 (μM)a
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A4D3
A4D5
B4E3
B4E5
A1D4
A1D5
A3D2
A5D3
A2D2
A2D7
B1E8
B3E4
B3E5
H
Ph
Ph
Ph
Ph
H
4-Br-Ph
12.27 ( 0.36
3.44 ( 0.04
9.23 ( 0.84
5.51 ( 0.83
4.65 ( 0.35
3.69 ( 0.63
10.97 ( 1.58
7.64 ( 0.52
4.94 ( 0.29
11.72 ( 1.11
6.21 ( 2.65
5.56 ( 0.65
4.12 ( 1.03
509.10 ( 49.00
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, spectroscopic data, and copies of NMR and mass spectra
for representative compounds are described. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(17) Morrissey, M. M.; Mohan, R.; Xu, W. Tetrahedron Lett. 1997,
Corresponding Author
*Phone: þþ34-981-563100. Fax: þþ34-981-528093. E-mail:
38, 7337–7340.
(18) Si-AlCl3 employed in this work was purchased from Sigma-
Aldrich. Kimble vials were closed before heating without any pressurization.
albertojose.coelho@usc.es.
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LETTER
Complete description of the spectroscopic, biological and analytical data for
representative compounds is included in the Supporting Information.
(19) The platelet aggregation inhibitory activity was examined in
vitro on washed human platelets by the turbidimetric method of Born.
See: Born, G. V. R. Aggregation of Blood Platelets by Adenosine
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