Pyrazole, pyridine and pyridone synthesis on solid support

Article abstract of DOI:10.1055/s-1999-3619

Versatile solid-phase syntheses of trisubstituted pyrazole carboxylic acids, trisubstituted pyridines and disubstituted pyridones are presented. Pyrazoles are prepared by reaction of polymer bound arylidene- or alkylidene- β-oxo esters with phenylhydrazines. Pyridines result from the Krohnke reaction of immobilised enones with 1-(2-oxo-2-arylethyl)pyridinium salts and ammonium acetate. Pyridones are obtained from polymer bound enones, 1- (methoxycarbonylmethyl)pyridinium bromide and ammonium acetate.

Full text of DOI:10.1055/s-1999-3619

SPECIAL TOPIC
1961
Pyrazole, Pyridine and Pyridone Synthesis on Solid Support
Philipp Grosche, Alexandra Höltzel, Tilmann B. Walk, Axel W. Trautwein, Günther Jung*
Institut für Organische Chemie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295560; E-mail: guenther.jung@uni-tuebingen.de
Received 19 May 1999; revised 7 July 1999
treatment with phenylhydrazines. Diaryl substituted
enones B and C served as educts for the pyridine and py-
ridone syntheses.
Abstract: Versatile solid-phase syntheses of trisubstituted pyrazole
carboxylic acids, trisubstituted pyridines and disubstituted pyrid-
ones are presented. Pyrazoles are prepared by reaction of polymer
bound arylidene- or alkylidene-ß-oxo esters with phenylhydrazines.
Pyridines result from the Kröhnke reaction of immobilised enones
with 1-(2-oxo-2-arylethyl)pyridinium salts and ammonium acetate.
Pyridones are obtained from polymer bound enones, 1-(methoxy-
carbonylmethyl)pyridinium bromide and ammonium acetate.
Pyrazoles
The pyrazole scaffold occurs in several biologically active
compounds, for example COX-2 inhibitors6 and antimi-
crobial pyrrolnitrin analogues7 and therefore represents an
interesting target for combinatorial chemistry.
Key words: pyrazoles, pyridines, pyridones, solid-phase synthesis,
combinatorial chemistry
Several solid-phase pyrazole syntheses have been previ-
ously reported.8 However, in none of these pathways are
pyrazole carboxylic acids formed, which are potential
synthons for convergent combinatorial strategies.
Introduction
Combinatorial chemistry, high-throughput synthesis and
screening have been established as key technologies in the
lead discovery and lead optimisation process.1 Recently
the combinatorial approach has also received increasing
attention in topics outside medicinal chemistry. For exam-
ple, it has been successfully applied in material science,2
heterogeneous3 and homogeneous catalysis. 4
In our approach these scaffolds were obtained by starting
from alkylidene- and arylidene-b-oxo esters 2 (Scheme
1). In the first step resin bound b-oxo esters 1 were pre-
pared either by transesterification of methyl or ethyl b-
oxo carboxylates with Wang resin in NMP under DMAP
catalysis or in the case of acetoacetic acid ester via ace-
toacetylation with diketene in CH2Cl2 under DMAP catal-
ysis. The following Knoevenagel reaction with aliphatic
and aromatic aldehydes resulted in the formation of 2-
alkylidene- and 2-arylidene-b-oxo esters 2. In the case of
aromatic aldehydes catalytic amounts of ethylenediamine
diacetate (EDDA) in DMF/pyridine (4:1) were used for
the condensation step. Milder conditions were applied for
aliphatic aldehydes, which were reacted following a pro-
tocol of Tietze et al.9 (cat. EDDA in CH2Cl2 at room tem-
The most advanced synthetic technique for preparing
compound libraries is solid-phase synthesis.1d,5 Working
on a solid support facilitates the multiple parallel synthe-
sis of both single compounds and compound collections in
the format of defined mixtures.
Due to their conformational constraints and their wide
range of properties, heterocyclic systems play an essential
role as scaffolds of potentially active compounds. Enones
represent important educts in this field since they can be
converted into a wide range of heterocycles. Therefore we
decided to use polymer bound enones as substrates for the
preparation of pyrazoles, pyridines and pyridones. Two
structurally different types of enones were used (Figure
1).
perature).
Cyclisation
with
phenylhydrazine
hydrochlorides and subsequent cleavage with TFA/
CH2Cl2 (1:3) led to trisubstituted pyrazole-4-carboxylic
acids 5 and 6.
The cyclisation step can result in the formation of two re-
gioisomers. This is due to two mechanistic pathways
(Scheme 2). Under basic conditions Michael addition of
the phenylhydrazine to the enone is favoured, followed by
a condensation and subsequent aromatisation step (4). Ba-
sic conditions (DIEA in NMP, 70 °C) were used in the
standard procedure for the regioselective synthesis of one
hundred pyrazoles 6. Some representative examples are
shown in Table 1. Figure 2 shows the structures of two
pyrazole carboxylic acids.
Figure 1
For comparative NMR studies of the two regioisomers we
also established a synthesis of regioisomer 5. A two step
procedure was used. Acidic treatment of the polymer
bound enone 2 with a phenylhydrazine hydrochloride pro-
Starting from arylidene- or alkylidene-b-oxo esters A,
trisubstituted pyrazole carboxylic acids were formed upon
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

1962
P. Grosche et al.
SPECIAL TOPIC
Scheme 1
Table 1 Solid-Phase Synthesis of Pyrazole Carboxylic Acids
Entry
6a
6b
6c
R1
CH3-
R2
R3
Method
Puritya (%)
Yieldb (%)
4-CF3-C6H4-
4-NO2-C6H4-
4-NO2-C6H4-
3-OH-4-NO2-C6H3-
3-MeO-C6H4-
EtOOC-
C6H5-
C6H5-
A
A
A
A
B
A
B
B
A
A
A
A
A
77
90
73c
84
64d
83
75
88
91
87
91
89
79
41
49
52
52
43
57
61
41
44
40
42
32
48
CH3-
CH3-
4-MeO-C6H4-
C6H4-
6d
6e
CH3-
CH3-
4-MeO-C6H5-
C6H5-
6f
CH3-
6g
6h
6i
CH3-
C6H5CH2CH2-
4-Pyridyl-
C6H5-
C2H5-
4-Cl-C6H4-
C6H5-
CH3CH2CH2-
(CH3)2CH-
(CH3)2CH-
C6H5-
3-OH-4-NO2-C6H3-
4-Br-C6H4-
6j
4-MeO-C6H4-
3,4-Me2-C6H3-
C6H5-
6k
6l
4-CF3-C6H4-
4-CF3-C6H4-
3-Pyridyl-
6m
C6H5-
4-Br-C6H4-
a determined by C18 RP HPLC at l=214 nm
b yield of the crude products based on the initial loading of the resin
c 16 % of regioisomer 5c
d 9 % of regioisomer 5e
vided the hydrazone. Cyclisation and aromatisation were
achieved by heating the hydrazone with DBU in DMF
(Scheme 2). This pathway has not been fully optimised
yet. Therefore only the data of those pyrazoles 5 which
were synthesised for the NOE experiments are shown in
Table 3.
The identity of the regioisomers 5 and 6 was proven by
NOE difference spectroscopy for compounds 5a, 5b, 6a,
and 6b. Irradiation of the resonance frequency of the pro-
tons H-2’led to the enhancement of the signal of the pro-
Figure 2
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Pyrazole, Pyridine and Pyridone Synthesis on Solid Support
1963
Table 2 High Resolution ES-FT-ICR-MS Analysis of Pyrazole Carboxylic Acids
Entry
6a
6b
6c
Molecular Formula
C18H13F3N2O2
C17H13N3O5
m (M+H)calculated
347.100180
324.097872
354.108435
340.092786
339.133922
275.102623
307.144093
328.084721
368.124084
415.065168
403.162777
409.115829
420.034204
m (M+H)measured
347.100934
324.098406
354.108835
340.093374
339.134232
275.102657
307.144086
328.084668
368.124820
415.064605
403.161771
409.115941
420.033174
Dm
ppm
Hits
1
0.000754
0.000534
0.000400
0.000588
0.000310
0.000034
0.000007
0.000053
0.000736
0.000563
0.001030
0.000112
0.001030
2.172
1.648
1.130
1.729
0.914
0.124
0.023
0.162
1.999
1.356
2.495
0.274
2.452
1
C18H15N3O5
1
6d
6e
C17H13N3O5
1
C19H18N2O4
1
6f
C14H14N2O4
1
6g
6h
6i
C19H18N2O2
2
C17H14ClN3O2
C19H17N3O5
2
1
6j
C20H19BrN2O3
C22H21N2O2
9
6k
6l
2
C23H15F3N2O2
C21H14BrN3O2
2
6m
8
Table 3 Selective Formation of Regioisomers 5
Entry
5a
R1
R2
R3
Puritya (%)
Regioisomer 6 (%)
Yieldb (%)
CH3-
CH3-
4-CF3-C6H4-
4-NO2-C6H4-
C6H5-
C6H5-
62
64
3
9
71
67
5b
a determined by C18 RP HPLC at l=214 nm
b yield of the crude products based on the initial loading of the resin
Figure 3a
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

1964
P. Grosche et al.
SPECIAL TOPIC
Figure 3b
tons H-2’’ in the case of regioisomers 5 (Figure 3a), very low sample consumption, high throughput analysis,
whereas for regioisomers 6 an enhancement of the signal high resolution, high mass accuracy and the possibility to
of the methyl protons Me-5 was observed (Figure 3b).
determine the molecular formula of the analysed com-
pound.10 A further advantage is that the elemental compo-
sition of crude products can be determined, so that a time
consuming purification step is not necessary. In the case
of the pyrazoles 6 the proof of the elemental composition
by FT-ICR-MS data was exemplified. The results are
summarised in Table 2. The hits represent the number of
possible molecular formulae by taking the exclusion rules
(nitrogen rule, double bound rule, valences) into account.
All compounds were analysed by analytical HPLC and
ES-FT-ICR-MS. ES-FT-ICR-MS offers the advantages of
Postmodification of Immobilised Pyrazoles
Additional structural diversity was introduced via acyla-
tion, sulphonylation or alkylation of suitable polymer
bound pyrazoles. For this purpose nitrophenyl or pyridyl
substituted pyrazoles are applicable. The nitro group was
reduced with 2 M SnCl2∑2H2O in DMF and the resulting
amino function was acylated or sulfonylated with carbox-
ylic acid chlorides or sulfonyl chlorides, respectively, at
room temperature in dichloromethane in the presence of
pyridine as base. As an example the reduction and acyla-
tion of polymer bound 5-methyl-3-(4’-nitrophenyl)-1-
phenylpyrazole-4-carboxylic acid 4b is shown (Scheme
3).
Pyridinium substituted pyrazoles 8 were obtained by
treatment of 4n with alkylating reagents in DMF at 70 °C
Scheme 2
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Pyrazole, Pyridine and Pyridone Synthesis on Solid Support
1965
Pyridines
Dihydropyridines and pyridines have recently attracted
the attention of solid-phase chemists.11 In the second part
of our contribution we present a novel three step solid-
phase pyridine synthesis following the route first de-
scribed by Kröhnke,12 which includes the Michael type
addition of 1-(2-oxo-2-arylethyl)pyridinium salts to
enones followed by cyclisation with ammonium acetate
under formation of the pyridine ring. In each reaction step
a variable substituent is introduced via commercially
available or easily accessible building blocks. From a
combinatorial point of view, this reaction allows the prep-
aration of a complex and diverse pyridine library. Further-
more, diaryl substituted pyridones13 were obtained by
treatment of polymer bound enones with 1-(methoxycar-
bonylmethyl)pyridinium bromide and ammonium acetate.
Scheme 3
The synthesis was performed using Wang Bromo PS in
the case of hydroxy functionalised educts or Rink Amide
PS in the case of carboxy functionalised educts. In order
to increase the diversity of the enones two pathways were
followed (Scheme 5). Path A uses polymer bound ace-
tophenones 9 which were condensed with aromatic and
heteroaromatic aldehydes to afford enones 10. The Kno-
evenagel condensation was performed in THF using
NaOMe (0.5 M in MeOH) as base at room temperature.14
Reaction time and base concentration were adapted to the
electronic properties of the corresponding building
blocks. Path B utilises immobilised aldehydes 12 which
were converted in a Wittig reaction into enones 13 upon
treatment with 1-(2-oxo-2-arylethyl)triphenylphosphoni-
um bromide and sodium methylate. The phosphonium
bromides were obtained by reaction of a-bromo ketones
with triphenylphosphane according to a literature proce-
dure.15 Enones 10 and 13 were then reacted with pyridin-
ium salts (Scheme 5: R3 = aryl, heteroaryl) and
ammonium acetate to form pyridines 11. The pyridinium
salts were obtained by reaction of the respective a-bromo
ketones with pyridine. The pyridinium salts may also be
generated by treatment of the corresponding acetyl com-
Scheme 4
(Scheme 4). To demonstrate the possibility of this modifi-
cation we used polymer bound acetoacetic acid, pyridine-
3-carboxaldehyde and phenylhydrazine hydrochloride for
the pyrazole formation and ethyl iodide, methyl bromo-
acetate and 4-nitrobenzyl bromide for the pyridine N-
alkylation.
The results of the postmodifications are presented in Ta- pounds with iodine and pyridine.16
ble 4.
The cyclisation conditions were optimised by using resin
bound 4’-hydroxychalcone and phenacylpyridinium bro-
mide. The choice of solvent is of particular importance. In
solution phase cyclisation is commonly performed in gla-
cial acetic acid. When we performed the solid-phase reac-
tion in this solvent almost no product was formed, even
after heating for 24 h at 90 °C. Changing to neat DMF as
solvent led to nearly complete conversion of the interme-
diate Michael adduct 14 to a byproduct 15 which is
formed through cleavage of the benzoyl residue (Scheme
6). The best results were obtained with a mixture of DMF
and acetic acid (5:3) (Table 5). After cleavage from the
resin with TFA/CH2Cl2 2,4,6-trisubstituted pyridines
were obtained in good purity. Table 6 shows some repre-
sentative results of the solid-phase Kröhnke reaction.
Table 4 Alkylation and Acylation/Sulfonylation of Pyrazole
Derivatives
Entry
Educt Acylation/Sulfonylation/
Alkylating reagent
Puritya Yieldb
(%)
(%)
7a
7b
7c
8a
8b
8c
4b
4b
4b
4n
4n
4n
pivaloyl chloride
benzoyl chloride
methanesulfonyl chloride
ethyl iodide
methyl bromoacetate
4-nitrobenzyl bromide
83
70
82
83
85
74
58
52
63
44c
44c
47c
a determined by C18 RP HPLC at l=214 nm
b yield of the crude products based on the initial loading of the resin
c trifluoroacetate as anion
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

1966
P. Grosche et al.
SPECIAL TOPIC
, r.t.
Scheme 5
Table 5 Influence of the Solvent in the Solid-Phase Kröhnke
Pyridine Synthesis
Solvent
Educt
(%)
Pyridine 11
(%)
By-product15
(%)
HOAc
79
54
38
10
2
9
36
54
82
91
88
11
–
–
–
1
1
HOAc/DMF 3:1
HOAc/DMF 5:3
HOAc/DMF 1:1
HOAc/DMF 3:5
HOAc/DMF 1:3
DMF
1
–
2
65
Figure 4
Bipyridines are accessible via two pathways. The first
pathway starts from polymer bound enones 10 which are
then converted to bipyridines upon treatment with 1-[2-
oxo-2-(pyrid-2’-yl)ethyl]pyridinium iodide. This com-
pound was synthesised in an Ortoleva-King reaction16 of
2-acetylpyridine.
In a second approach resin bound aldehydes were treated
with 1-[2-oxo-2-(pyrid-2’-yl)ethyl]phosphonium bromide
in a Wittig reaction resulting in pyridyl substituted
enones. This phosphonium bromide was synthesised by
bromination of 2-acetylpyridine18 and subsequent substi-
tution with triphenylphosphane. The following Kröhnke
reaction with 1-(2-oxo-2-arylethyl)pyridinium salts pro-
vided bipyridines. Figure 4 shows two representative
structures of the bipyridine syntheses. The use of 1-[2-
oxo-2-(pyrid-2'-yl)ethyl]pyridinium iodide led to the for-
mation of terpyridines. Two examples are shown in Fig-
ure 5.
Scheme 6
Bipyridines and Terpyridines
Table 7 shows representative results of the bi- and terpy-
ridine synthesis.
Bipyridines and terpyridines are well known as ligands of
metal ions.17 Both classes of compounds can be obtained
via our solid-phase pyridine synthesis described above.
We also applied the Kröhnke pyridine synthesis to the
modification of polymer bound amino acids. Fmoc-amino
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Pyrazole, Pyridine and Pyridone Synthesis on Solid Support
1967
Table 6 Solid-Phase Synthesis of Pyridines
Entry
11a
11b
11c
11d
11e
11f
R1, R5
R2, R4
R3
Path
A
Puritya
77
Yieldb
4-OH-3-MeO-C6H3-
4-OH-C6H4-
3-OH-C6H4-
4-NO2-C6H4-
4-Cl-C6H4-
4-Cl-C6H4-
3-MeO-C6H4-
C6H5-
2-Thienyl-
3,4-Cl2-C6H3-
4-F-C6H4-
2,5-(MeO)2-C6H3-
C6H5-
74
78
74
82
78
72
85
72
68
4-NO2-C6H4-
A
89
3,4,5-(MeO)3-C6H2-
4-(CONH2)-C6H4-
3-(CONH2)-C6H4-
3-OH-C6H4-
A
78
B
92
C6H5-
B
97
C6H5-
B
96
11g
11h
11i
2-OH-3-MeO-C6H3-
3,5-Cl2-2-OH-C6H2-
4-OH-3,5-(MeO)2-C6H2-
C6H5-
B
87
C6H5-
B
88
2-Naphthyl-
C6H5-
B
89
a determined by C18 RP HPLC at l=214 nm
b yield of the crude products based on the initial loading of the resin
Figure 5
acids were coupled to Rink Amide PS resin using DIC,
HOBt in DMF. After cleavage of the Fmoc-group the ami-
no function was acylated with 3- or 4-carboxybenzalde-
hyde. The following steps were performed as described
above. Table 8 shows the corresponding results. Figure 6
shows a lysine based bis(bipyridine).
Figure 6
Table 7 Solid-Phase Synthesis of Bipyridines and Terpyridines
Entry
11j
R1
R2
R3
2-Pyridyl-
2-Pyridyl-
2-Pyridyl-
3-MeO-C6H4-
C6H5-
Path
Puritya
Yieldb
69
2-Pyridyl-
2-Pyridyl-
2-Pyridyl-
2-Pyridyl-
2-Pyridyl-
2-Pyridyl -
2-OH-C6H4-
2-OH-C6H4-
4-OH-3-MeO-C6H3-
4-OH-3,5(MeO)2-C6H2-
2-OH-3,5-Cl2-C6H2-
3-CONH2-C6H4-
4-OH-3-MeO-C6H3-
3-OH-C6H4-
B
B
B
B
B
B
A
A
A
85
95
95
88
94
98
90
91
76
11k
11l
54
81
11m
11n
11o
11p
11q
11r
64
71
2-OH-3,5-Cl2-C6H2-
4-CF3-C6H4-
C6H5-
79
2-Pyridyl-
2-Pyridyl-
2-Pyridyl-
71
4-MeO-C6H4-
71
2-Thienyl-
65
a determined by C18 RP HPLC at l=214 nm
b yield of the crude products based on the initial loading of the resin
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

1968
P. Grosche et al.
SPECIAL TOPIC
Table 8 Solid-Phase Pyridine Synthesis Based on Immobilized Amino Acids
Entry
11s
Amino Acid
Phe
R1
R2
R3
Puritya
Yieldb
75
3-OC-C6H4-
3-OC-C6H4-
4-OC-C6H4-
4-OC-C6H4-
C6H5-
C6H5-
91
90
92
88
11t
Ile
4-Cl-C6H4-
3-MeO-C6H4-
C6H5-
4-MeO-C6H4-
4-Cl-C6H4-
2-Pyridyl-
70
11u
11v
e-Ahx
Lysc
85
84
a determined by C18 RP HPLC at l=214 nm
b yield of the crude products based on the initial loading of the resin
c both amino functions were modified
Pyridones
bound educts. Pyrazole-4-carboxylic acids were obtained
in good regioselectivity and purity from the reaction of
Enones 13 were also used for the solid-phase synthesis of phenylhydrazines with alkylidene- or arylidene-b-oxo es-
4,6-disubstituted pyridones. Treatment of enones 13 with ters. This synthetic strategy allows the production of large
1-(methoxycarbonylmethyl)pyridinium bromide and am- libraries of a pharmacologically interesting scaffold. Py-
monium acetate in DMF/acetic acid (5:3) afforded pyri- ridines and pyridones were synthesised according to the
dones 16 (Scheme 7). Repetition of the reaction was Kröhnke procedure starting from immobilised diaryl sub-
necessary for a satisfying conversion of the educt. The re- stituted enones. Our procedures also offer access to bi-
action conditions were applied to a range of enones. Table and terpyridines which possess interesting metal chelating
9 shows some representative results of the pyridone syn- properties.
thesis.
1H and 13C NMR spectra of all compounds except 5a, 5b, 6a, and
1
6b were recorded on a Bruker AC250 spectrometer at 297 K. H
NMR and NOE difference spectra of compounds 5a, 5b, 6a, and 6b
were acquired on a Bruker AMX2-600 spectrometer at 300 K. NMR
samples were solutions of the compounds in DMSO-d6. Chemical
shifts were measured in d (ppm) and coupling constants J in Hz. The
spectra were referenced to the signal of the solvent at d(1H) = 2.50
and d(13C) = 39.5.
Reagents were purchased from Aldrich, Fluka, Lancaster, Novabio-
Scheme 7
chem and Rapp Polymere and used without further purification. An-
alytical HPLC was performed using a reversed phase Nucleosil C18
(5 mm) column (250 x 2 mm) (Grom, Herrenberg, Germany), 214
nm detection, gradient 10–100% B (A = Water/0.1% TFA;
B = ACN/0.1% TFA) over 45 min, flow = 0.3 ml/min. ES-FT-ICR-
MS measurements were performed on a Bruker-Daltonic Apex II
spectrometer which was connected to a Hewlett Packard HP 1100
HPLC.
Conclusions
In summary we have established the solid-phase synthe-
ses of three heterocyclic systems. The common feature of
these strategies is the use of enones as versatile polymer
Polymer Bound b-Oxo Esters 1; General Procedure
Wang PS (1% DVB) resin (100 mg, capacity:1.13 mmol/g) was sus-
pended in NMP (800 µL). DMAP (4.4 mg, 0.045 mmol) and b-oxo
ester (1.13 mmol) were added and the mixture was stirred for 20 h
at 105 °C. The resin was washed with DMF, MeOH, CH2Cl2 and
Et2O and dried under vacuum.
Table 9 Representative Results of the Pyridone Synthesis
Entry R1
R2
Puritya Yieldb
16a
16b
16c
16d
16e
16f
4-OH-C6H4-
4-OH-3-MeO-C6H3-
C6H5-
C6H5-
73
75
69
75
75
78
74
76
71
73
Polymer Bound Acetoacetic Ester 1
Wang PS (1% DVB) resin (100 mg, capacity:1.13 mmol/g) was sus-
pended in CH2Cl2 (1000 µL). DMAP (4.4 mg, 0.045 mmol) was
added and the suspension was cooled to –21 °C. A solution of
diketene (60 µL, 0.791 mmol) in CH2Cl2 (500 µL) was added in
small portions over a period of 15 min. After shaking at r.t. for 2 h
the resin was washed with DMF, MeOH, CH2Cl2 and Et2O and
dried under vacuum.
4-OH-3,5-(MeO)2-C6H2- 4-Cl-C6H4-
3-OH-C6H4-
4-Cl-C6H4-
3-OH-C6H4-
3-MeO-C6H4- 76
2-Naphthyl- 67
2-OH-3-MeO-C6H3-
a determined by C18 RP HPLC at l=214 nm
b yield of the crude products based on the initial loading of the resin
Polymer Bound Arylidene-b-oxo Ester 2; General Procedure
Polymer bound b-oxo ester 1 (0.113 mmol) was suspended in DMF/
pyridine (4:1) (800 µL). Ethylenediamine diacetate (4.1 mg, 0.023
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Pyrazole, Pyridine and Pyridone Synthesis on Solid Support
1969
mmol) and aldehyde (0.226 mmol) were added and the mixture was
stirred for 16 h at 70 °C. The resin was washed and dried as de-
scribed above. Ethyl glyoxylate was also reacted following this pro-
cedure.
acid chloride (0.565 mmol) were added and the mixture was shaken
for 6 h at r.t. The resin was washed and cleavage was performed as
described above (6).
3-(N-Alkylpyridyl)-5-methyl-1-phenylpyrazole-4-carboxylic
Acid (8); General Procedure
Polymer Bound Alkylidene-b-oxo Ester 2; General Procedure
Polymer bound b-oxo ester 1 (0.113 mmol) was suspended in
CH2Cl2 (1000 µL). Ethylenediamine diacetate (8.2 mg, 0.046
mmol) and aldehyde (0.565 mmol) were added and the mixture was
shaken for 3 h at r.t. The resin was washed and dried as described
above.
Polymer bound 4n (0.113 mmol) was shaken with a solution of
DIEA (50 µL) in DMF (1000 µL) for 20 min at r.t. and then washed
with DMF. The resin was suspended in DMF (1000 µL) and the
alkylating reagent (0.452 mmol) was added. The mixture was
stirred for 4 h at 70 °C. The resin was washed and cleavage was per-
formed as described above (6).
Trisubstituted Pyrazole Carboxylic Acids 6; General Procedure
Method A: Polymer bound arylidene-b-oxo ester 2 (0.113 mmol)
was treated with a solution of phenylhydrazine hydrochloride
(0.226 mmol) and DIEA (34.8 µL, 0.203 mmol) in NMP(2mL). Af-
ter stirring the mixture at 70 °C for 7 h the resin was washed with
DMF, MeOH and CH2Cl2. The resin was then treated with CH2Cl2/
HOAc for 0.5 h and washed with CH2Cl2. Cleavage was performed
with TFA/CH2Cl2 (1:3) for 45 min. This step was repeated once.
The solution was concentrated to dryness to provide the crude pyra-
zole which was then lyophilised twice from t-BuOH/H2O (4:1).
Loading of Wang Bromo PS with Hydroxyacetophenones and
Hydroxybenzaldehydes 9/12; General Procedure
Wang Bromo PS (1% DVB) resin (50 mg, capacity: 1.1 mmol/g)
was treated with the hydroxy component (0.275 mmol), Cs2CO3
(35.8 mg, 0.11 mmol) and DMF (500 µL). After stirring for 3 h at
80 °C the resin was washed and dried.
Loading of Rink Amide PS with Carboxylic acids; General Pro-
cedure
Fmoc Rink Amide PS (1% DVB) resin (50 mg, capacity: 0.78
mmol/g) was deprotected by treatment with piperidine/DMF (1:1)
(2x). After washing with DMF a solution of carboxylic acid (0.117
mmol), HOBt (17.9 mg, 0.117 mmol) in DMF (800 µL) was added
followed by DIC (18.1 µL, 0.117 mmol). The mixture was shaken
at r.t. until the Kaiser test was negative, followed by a washing and
deprotection step.
Method B: Method B follows the procedure described under Meth-
od A with the difference that 1.2 equiv phenylhydrazine hydrochlo-
ride (0.136 mmol) and 1.1 equiv DIEA (21.2 µL, 0.124 mmol) were
used.
5-methyl-1-phenyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-
4-carboxylic Acid (6a)
1H NMR (600.13 MHz): d = 2.54 (s, 3H, Me-5), 7.53 (t, 1H,
Jbc = 7.2 Hz, H-4'), 7.59 (dd, 2H, Jbc = 7.2 Hz, Jab = 8.3 Hz, H-3'),
7.62 (d, 2H, Jab = 8.3 Hz, H-2'), 7.77 (d, 2H, Jab = 8.3 Hz, H-2''),
7.87 (d, 2H, Jab = 8.3 Hz, H-3''), 12.60 (br, 1H, COOH).
In the case of carboxybenzaldehyde, the mixture of aldehyde, HOBt
and DIC in DMF was shaken for 30 min at r.t. before adding to the
resin.
5-Methyl-3-(4’-(nitrophenyl)-1-phenylpyrazole-4-carboxylic
Acid (6b)
Enone 10 Synthesis by Condensation of Acetophenones with Al-
dehydes
Resin 9 was suspended in THF (650 µL). 0.5 M NaOMe in MeOH
(650 µL) and aldehyde (0.55 mmol) were added and the mixture
was stirred at r.t. for 72 h. After washing the resin was dried.
1H NMR (600.13 MHz): d = 2.54 (s, 3H, Me-5), 7.54 (t, 1H,
Jbc = 7.2 Hz, H-4’), 7.59 (dd, 2H, Jbc = 7.2 Hz, Jab = 8.3 Hz, H-3’),
7.62 (d, 2H, Jab = 8.3 Hz, H-2’), 7.94 (d, 2H, Jab = 8.8 Hz, H-2’’),
8.27 (d, 2H, Jab = 8.8 Hz, H-3’’), 12.68 (br, 1H, COOH).
The enone used for the synthesis of pyridine 11b was synthesised
via a slightly modified procedure:
Trisubstituted Pyrazole Carboxylic Acid (5); General Proce-
dure
The resin was suspended in THF (890 µL). 0.5 M NaOMe in MeOH
(110 µL) and aldehyde (0.55 mmol) were added and the mixture
was stirred at r.t. for 24 h. After washing, the resin was dried.
Polymer bound arylidene-b-oxo ester 2 (0.113 mmol) was treated
with a solution of phenylhydrazine hydrochloride (32.6 mg, 0.226
mmol) in DMF/HOAc (2:1) (1500 µL). After shaking for 4 h at r.t.
the resin was washed. A solution of DBU (50 µL) in DMF (1000
µL) was added and the mixture was stirred at 70 °C for 4 h. The res-
in was washed and cleavage was performed as described above.
Enone 13 Synthesis by Wittig Reaction
Resin bound aldehydes 12 were treated with 1-(2-aryl-2-oxoeth-
yl)triphenylphosphonium bromide (0.385 mmol), THF (650 µL)
and 0.5 M NaOMe in MeOH (650 µL). After stirring for 2 d at 60 °C
the resin was washed and dried.
3-Methyl-1-phenyl-5-[4’-(trifluoromethyl)phenyl]pyrazole-4-
carboxylic Acid (5a)
1H NMR (600.13 MHz): d = 2.48 (s, 3H, Me-3), 7.20 (d, 2H,
Jab = 6.5 Hz, H-2’), 7.33 (m, 3H, H-3’ and H-4’), 7.51 (d, 2H,
2,4,6-Trisubstituted Pyridines (11); General Procedure
Resin bound enone 10/13 (0.055 mmol) was treated with 1-(2-aryl-
2-oxoethyl)pyridinium salt (0.22 mmol) and a solution of NH4OAc
(84.7 mg, 1.1mmol) in DMF/HOAc (5:3) (1000 µL) was added. Af-
ter 24 h at 90 °C the resin was washed and cleavage was performed
as described above. The solution was concentrated to dryness to
provide the crude pyridine which was then lyophilised twice from
t-BuOH/H2O (4:1).
Jab = 8.3 Hz, H-2’’), 7.70 (d, 2H, Jab = 8.3 Hz, H-3’’), 12.30 (broad,
1H, COOH).
3-Methyl-5-(4'-nitrophenyl)-1-phenylpyrazole-4-carboxylic
Acid (5b)
1H NMR (600.13 MHz): d = 2.48 (s, 3H, Me-3), 7.21 (d, 2H,
Jab = 6.5 Hz, H-2’), 7.34 (m, 3H, H-3’ and H-4’), 7.59 (d, 2H,
Jab = 8.8 Hz, H-2’’), 8.17 (d, 2H, Jab = 8.8 Hz, H-3’’), 12.39 (broad,
1H, COOH).
2-(3’,4’-Dichlorophenyl)-6-(4’’-hydroxy-3’’-methoxyphenyl)-4-
(thien-2’’’-yl)pyridine (11a)
1H NMR (250.13 MHz): d = 3.92 (s, 3H), 6.94 (d, 1H, J = 8.4 Hz),
7.28 (dd, 1H, J = 5.0 Hz, J = 3.7 Hz), 7.74 (dd, 1H, J = 8.4 Hz,
J = 2.1 Hz), 7.77 to 7.84 (m, 3H), 8.04 (d, 1H, J = 1.2 Hz), 8.11 (dd,
1H, J = 3.7 Hz, J = 1.1 Hz), 8.14 (d, 1H, J = 1.2 Hz), 8.31 (dd, 1H,
J = 8.4 Hz, J = 2.1 Hz), 8.54 (d, 1H, J = 2.1 Hz), 9.44 (br, 1H).
5-Methyl-1-phenyl-3-(N-acyl (or sulfonyl)-4-aminophe-
nyl)pyrazol-4-carboxylic Acid (7); General Procedure
Polymer bound 4b (0.113 mmol) was shaken with 2 M SnCl2◊2 H2O
in DMF (1000 µL) at r.t.. for 15 h. After washing the resin was sus-
pended in CH2Cl2 (1000 µL). Pyridine (73 µL, 0.904 mmol) and
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

1970
P. Grosche et al.
SPECIAL TOPIC
13C NMR (62.90 MHz): d = 55.84, 110.95, 114.09, 114.56, 115.68,
120.15, 126.93, 127.29, 128.38, 128.47, 128.69, 129.52, 130.87,
131.66, 131.86, 139.16, 140.59, 143.07, 147.83, 148.38, 153.65,
156.91.
c) Combinatorial Peptide and Nonpeptide Libraries; Jung, G.,
Ed.; VCH: Weinheim, 1996.
d) Combinatorial Chemistry; Jung, G., Ed.; Wiley-VCH:
Weinheim, 1999.
(2) Xiang, X. D.; Sun, X.; Briceno, G.; Lou, Y.; Wang, K. A.;
Chang, H.; Wallace-Freedman, W. G.; Chen, S. W.; Schultz,
P. G. Science 1995, 268, 1738.
(3) Senkan, S. M.; Ozturk, S. Angew. Chem. Int. Ed. 1999, 38,
791.
(4) Burgess, K.; Lim, H.-J.; Porte, A. M.; Sulikowski, G. A.
Angew. Chem. Int. Ed. Engl. 1996, 35, 220.
(5) a) Früchtel, J. S.; Jung, G.; Angew. Chem. Int. Ed. Engl. 1996,
35, 17.
2-(4’-Fluorophenyl)-6-(4’-hydroxyphenyl)-4-(4’-nitrophenyl)-
pyridine (11b)
1H NMR (250.13 MHz): d = 6.93 (d, 2H, J = 8.7 Hz), 7.37 (t, 2H,
J = 8.9 Hz), 8.12 to 8.24 (m, 4H), 8.28 to 8.44 (m, 6H), 9.84 (br,
1H).
13C NMR (62.90 MHz): d = 115.34, 115.50, 115.67, 123.93,
128.44, 128.73, 129.07, 129.19, 129.28, 135.10, 144.23, 147.12,
147.78, 155.40, 156.82, 158.91, 163.03.
4-(3’-Carboxamidophenyl)-2-(4’-chlorophenyl)-6-phenylpyri-
dine (11e)
b) Balkenhohl, F.; von dem Bussche-Hünnefeld, C.; Lansky,
A.; Zechel, C. Angew. Chem. Int. Ed. 1996, 35, 2288.
c) Thompson, L. A.; Ellman J. A. Chem. Rev. 1996, 96, 555.
d) Hermkens, P. H. H.; Ottenheijm H. C. J.; Rees D. C.
Tetrahedron 1997, 53;5643.
1H NMR (250.13 MHz): d = 7.45 to 7.72 (m, 7H), 8.02 (d, 1H,
J = 7.9 Hz), 8.23 (d, 2H, J = 7.9 Hz), 8.30 (d, 2H, J = 2.0 Hz), 8.34
(dd, 2H, J = 7.9 Hz, J = 1.5 Hz), 8.40 (d, 2H, J = 8.6 Hz), 8.46 (t,
1H, J = 1.5 Hz).
e) Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees,
D. C. Tetrahedron 1998, 54, 15385.
13C NMR (62.90 MHz): d = 116.62, 116.91, 125.93, 126.94,
128.59, 128.72, 129.14, 129.32, 130.11, 134.11, 135.07, 137.48,
138.56, 149.11, 155.27, 156.67, 167.47.
f) Lam, K. S.; Lebl, M.; Krchnak V. Chem. Rev. 1997, 97, 411.
g) Brown, R. Contemp. Org. Syn. 1997, 216.
(6) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha,
J. W.; Miyashiro, J. M., Rogers, R. S.; Rogier, D. J.; Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S.
A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen,
A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40,
1347.
(7) Cecchi, L.; Melani, F.; Palazzino, G.; Filacchoni, G. Il
Farmaco, Ed. Sc. 1984, 39, 953.
(8) a) Marzinzik, A. L.; Felder, E. R. Tetrahedron Lett. 1996, 37,
1003.
Pyridones (16); General Procedure
Resin bound enone 13 (0.055 mmol) was treated with a solution of
1-(methoxycarbonylmethyl)pyridinium bromide (54.5 mg, 0.22
mmol) and NH4OAc (84.7 mg, 1.1 mmol) in DMF/HOAc (5:3)
(1000 µL). After 24 h at 90 °C, the resin was washed and the reac-
tion step was repeated once. Cleavage was performed as described
above. The solution was concentrated to dryness to provide the
crude pyridone which was then lyophilised twice from t-BuOH/
H2O (4:1).
4-(3’-Hydroxyphenyl)-6-(3’-methoxyphenyl)pyrid-2-one (16e)
1H NMR (250.13 MHz): d = 3.85 (s, 3H), 6.55 (d, 1H, J = 1.4 Hz),
6.87 (ddd, 1H, J = 7.9 Hz, J = 2.3 Hz, J = 1.1 Hz), 6.91 (s, br, 1H),
7.03 (ddd, 1H, J = 7.8 Hz, J = 2.4 Hz, J = 1.4 Hz), 7.12 (t, 1H,
J = 1.8 Hz), 7.20 (dt, 1H, J = 7.9 Hz, J = 1.4 Hz), 7.28 (t, 1H,
J = 7.8 Hz), 7.35 to 7.49 (m, 3H), 9.66 (br, 1H).
13C NMR (62.90 MHz): d = 56.22, 104.66, 105.38, 111.16, 127.29,
128.59, 128.86, 133.93, 134.17, 137.22, 147.43, 148.22, 152.05,
163.70.
b) Watson, S. P.; Wilson, R. D.; Judd, D. B.; Richards, S. A.
Tetrahedron Lett. 1997, 38, 9065.
c) Wilson, R. D.; Watson, S. P.; Richards, S. A. Tetrahedron
Lett. 1998, 39, 2827.
d) Marzinzik, A. L.; Felder, E. R. J. Org. Chem. 1998, 63, 723.
(9) Tietze, L. F.; Hippe, T.; Steinmetz, A. Synlett 1996, 1043.
(10) Walk, T. B.; Trautwein, A. W.; Richter, H.; Jung, G. Angew.
Chem. Int. Ed., in print.
(11) a) Gordeev, M. F.; Patel, D. V.; Wu, J.; Gordon, E. M.
Tetrahedron Lett. 1996, 37, 4643.
b) Chiu, C.; Tang, Z.; Ellingboe, J. W. J. Comb. Chem. 1999,
1, 73.
(12) Kröhnke, F. Synthesis 1976, 1.
(13) Kröhnke, F.; Schnalke, K. E.; Zecher, W. Chem. Ber. 1970,
103, 322.
(14) Hollinshead, S. P. Tetrahedron Lett. 1996, 36, 9157.
(15) Kuchar, M.; Kakac, B.; Nemecek, O. Collect. Czech. Chem.
Commun. 1972, 37, 3950.
6-(4’-Chlorophenyl)-4-(4’-hydroxy-3’,5’-dimethoxyphenyl)-
pyrid-2-one (16c)
1H NMR (250.13 MHz): d = 3.86 (s, 6H), 6.72 (d, 1H, J = 1.4 Hz),
7.05 (s, 2H), 7.09 (s, br, 1H), 7.56 (d, 2H, J = 8.6 Hz), 7.95 (d, 2H,
J = 8.6 Hz), 8.75 (very br, 1H).
13C NMR (62.90 MHz): d = 55.25, 104.59, 111.95, 112.61, 113.51,
115.72, 116.31, 117.58, 119.23, 129.79, 129.99, 135.82, 138.84,
148.03, 151.96, 157.78, 159.44, 163.55.
(16) King, L. C. J. Am. Chem. Soc. 1944, 66, 894.
(17) a) Mukkala, V. M.; Helenius, M.; Hemmilä, I.; Kankare, J.;
Takalo, H. Helv. Chim. Acta 1993, 76, 1361.
b) Lawrence, D. S.; Jiang, T.; Levett, M. Chem. Rev. 1995, 95,
2229.
Acknowledgement
This work was supported by the BMBF grant “Automatisierte Kom-
binatorische Chemie” 03D0037A7.
(18) Barlin, G. B.; Davies, L. P.; Ireland, S. J.; Ngu, M. M. L. Aust.
J. Chem. 1987, 42, 1735.
References
(1) a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P.
A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233.
Article Identifier:
1437-210X,E;1999,0,11,1961,1970,ftx,en;Z04199SS.pdf
b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P.
A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385.
Synthesis 1999, No. 11, 1961–1970 ISSN 0039-7881 © Thieme Stuttgart · New York