Diversity-oriented synthesis of 1-substituted 4-aryl-6-oxo-1,6- dihydropyridine-3-carboxamides.

Article abstract of DOI:10.1021/co3000709

A simple five-step diversity-oriented synthesis of 1-substituted 4-aryl-6-oxo-1,6-dihydropyridine-3-carboxamides was developed. Treatment of dimethyl 2-((dimethylamino)methylidene)-3-oxopentanedioate with twenty primary amines gave 1-substituted methyl 4-hydroxy-6-oxo-1,6-dihydropyridine-3- carboxylates. Transformation into the corresponding 4-tosyloxy and 4-chloro derivatives, followed by Suzuki-Miyaura arylations gave a series of eleven N-substituted methyl 4-aryl-6-oxo-1,6-dihydropyridine-3-carboxylates. Combinatorial screening was employed to establish suitable reaction conditions for Suzuki-Miyaura arylation of N-alkylpyridones. Hydrolysis of the esters followed by parallel solution-phase amidation of the corresponding carboxylic acids with primary and secondary amines furnished a library of seventeen final products.

Full text of DOI:10.1021/co3000709

Research Article
pubs.acs.org/acscombsci
Diversity-Oriented Synthesis of 1‑Substituted 4‑Aryl-6-oxo-1,6-
dihydropyridine-3-carboxamides.
Jernej Baskovc,† Georg Dahmann,‡ Amalija Golobic,† Uros Groselj,† Drago Kocar,† Branko Stanovnik,†
̌
̌
̌
̌
̌
̌
and Jurij Svete*,†
†Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ask
̌
erce
̌
va 5, P.O. Box 537, 1000 Ljubljana, Slovenia
‡Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry, 88397 Biberach, Germany.
S
* Supporting Information
ABSTRACT: A simple five-step diversity-oriented synthesis of 1-substituted
4-aryl-6-oxo-1,6-dihydropyridine-3-carboxamides was developed. Treatment of
dimethyl 2-((dimethylamino)methylidene)-3-oxopentanedioate with twenty
primary amines gave 1-substituted methyl 4-hydroxy-6-oxo-1,6-dihydropyr-
idine-3-carboxylates. Transformation into the corresponding 4-tosyloxy and 4-
chloro derivatives, followed by Suzuki−Miyaura arylations gave a series of
eleven N-substituted methyl 4-aryl-6-oxo-1,6-dihydropyridine-3-carboxylates. Combinatorial screening was employed to establish
suitable reaction conditions for Suzuki−Miyaura arylation of N-alkylpyridones. Hydrolysis of the esters followed by parallel
solution-phase amidation of the corresponding carboxylic acids with primary and secondary amines furnished a library of
seventeen final products.
KEYWORDS: parallel synthesis, cyclization, pyridones, Suzuki−Miyaura arylation, amidation
Within our long-term studies on enaminones as versatile
reagents in heterocyclic synthesis,13 a part of our research has
been focused on the synthesis of fused pyridones14 from
pyridineacetic acid derivatives13,15 and on the synthesis of 1,4-
dihydropyridines16 by cyclocondensations of bis-enaminones
with primary amines13,17 including parallel solution-phase
approach.15,18 For the synthesis of dihydropyridine derivatives,
dimethyl acetone-1,3-dicarboxylate (1)19 has been found as
particularly useful starting material.17a,b,d,18 Recently, we
reported a simple one-pot transformation of 1 with ammonia
and aliphatic primary amines into methyl 1-alkyl-4-hydroxy-6-
oxo-1,6-dihydropyridine-3-carboxylates.20 In extension, we
focused our attention on parallel preparation and trans-
formations of 6-oxo-1,6-dihydropyridine derivatives with 4-
aryl-6-oxo-1,6-dihydropyridine-3-carboxamides 11 as target
compounds. Herein, we report a novel five-step synthesis of
11 (Scheme 1) comprising a enaminone-based preparation of
methyl 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylates 4
from primary amines 3{1−20} (Figure 1), transformations
into the corresponding tosylates 5 and chloro analogues 6,
Suzuki−Miyaura arylation of 5 and 6 with arylboronic acids
7{1−4} (Figure 2), followed by hydrolysis of methyl 4-aryl-6-
oxo-1,6-dihydropyridine-3-carboxylates 8, and parallel amida-
tions of the so-formed carboxylic acids 9 with aliphatic amines
3{20−27} (Figure 1) to furnish title carboxamides 11 (Scheme
1).
INTRODUCTION
■
Heterocyclic compounds are important scaffolds for the
preparation of compound libraries for medicinal and
pharmaceutical applications.1−4 Within this context, the 2-
pyridone system is a useful core for derivatization and, hence,
preparation of biologically active compounds. For example, 2-
pyridone containing compounds have recently been prepared
as MCH1R antagonists,5 11β-hydroxysteroid dehydrogenase 1
inhibitors,6 P2X7 purinoceptor modulators,7 inhibitors of
cyclooxygenases and 5-lipoxygenase,8 dopamine D3 receptor
antagonists,9 and antibiotics.10 Therefore, synthesis of libraries
of novel 2-pyridone derivatives and their fused analogues is of
particular interest.
Nicotinamide (vitamin B3) is an important pyridine
derivative and a large number of its derivatives and analogues
have been prepared, so far. However, 1,4-disubstituted 6-oxo-
1,6-dihydropyridine-3-carboxamides that are unsubstituted at
positions 2 and 5 are almost unexplored group of nicotinamide
derivatives. To the best of our knowledge, only two compounds
of this particular type are known.11,12 The first one is N′-
functionalized 2-(5-carbamoyl-2-oxo-4-(trifluoromethyl)-
pyridin-1(2H)-yl)acetic acid, that has been prepared as
chemokine modulator quite routinely by a three step
derivatization of commercially available 6-hydroxy-4-trifluor-
omethylnicotinic acid.11 The second one, N′-substituted 4-(3-
chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxa-
mide, has been prepared as farnesyltransferase inhibitor in five-
step synthesis including pyridone ring formation. The synthesis
comprises Heck-type arylation of diethyl glutaconate, for-
mylation, cyclization with methylamine, hyrolysis of the ester,
and amidation.12a
Received: June 28, 2012
Revised: August 5, 2012
© XXXX American Chemical Society
A
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ACS Combinatorial Science
Research Article
Scheme 1. General Synthetic Route
Figure 1. Diversity reagents 3{1−20} used for cyclization of enaminone 2 and diversity reagents 3{20−27} used for amidation of carboxylic acids 9.
nopyridine (DMAP) at 95 °C furnished the corresponding
tosylates 5{1,3,8,9,13,16,18−20} in 18−87% yield. Similarly,
parallel chlorination of the pyridones 4{18−20} in refluxing
phosphorus oxychloride afforded the chloro analogues 6{18−
20} in 60−57% yield (Scheme 2, Table 1). It is noteworthy,
that triflates and bromides should be better coupling partners in
subsequent Suzuki−Miyaura reactions than the corresponding
tosylates 5 and chlorides 6. Unfortunatelly, attempts to obtain
the corresponding triflate and bromide from pyridone 4{18}
failed. [Simplicity and cost-effectiveness of the cross-coupling
method were also important to us. Preparation of triflates and
bromides was not studied further for the following reasons: (a)
the reagents, Tf2O and POBr3, are approximately ten times
more expensive than TsCl and POCl3; (b) the solid TsCl is
much easier to handle than Tf2O, which is a moisture-sensitive
liquid; (c) excess POCl3 (bp 106 °C) is easily removable by
evaporation using a diaphragm pump, while POBr3 (bp 192
°C) is not; (d) tosylates are more convenient to use, since they
are usually crystalline and hydrolytically more stabile than
triflates.]
Figure 2. Diversity reagents 7{1−4} used for Suzuki−Miyaura
arylations.
RESULTS AND DISCUSSION
■
Following modified literature procedures,18,20 commercially
available dimethyl acetone-1,3-dicarboxylate (1) was first
transformed with N,N-dimethylformamide dimethylacetal
(DMF-DMA) into the enaminone 2. Acid-catalyzed parallel
treatment of 2 with primary amines 3{1−20} gave the
intermediates 2′{1−20},18 which were directly (without
isolation) cyclized into 4 by treatment with methanolic
potassium hydroxide. Acidification and evaporation of the
reaction mixtures followed by extraction of the products 4 from
the solid residues with a 2:5 mixture of methanol and ethyl
acetate, filtration, and evaporation furnished analytically pure
methyl 1-aryl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxy-
lates 4{1−20} in 40−80% yield. Further parallel treatment of
4-hydroxypyridones 4{1,3,8,9,13,16,18−20} with tosyl chloride
in DMF in the presence of triethylamine and 4-dimethylami-
Suzuki−Miyaura cross-coupling of the corresponding
tosylates 5 with arylboronic acids 7 (Figure 2) was then
studied. Reaction conditions were first optimized for the
reaction of 1-phenyltosylate 5{16} with phenylboronic acid
7{1} and Pd(PPh3)4 as catalyst. Reaction in refluxing tert-
butanol in the presence of potassium phosphate afforded the
corresponding cross-coupling product 8{16/1} in 10% yield.
B
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ACS Combinatorial Science
Research Article
a
a
Scheme 2. Synthesis of Compounds 4−6
Scheme 3. Synthesis of 1,4-Diarylpyridones 8 (Method A)
a
Reaction conditions: (i) R2B(OH)2 7 (chemset 7), Pd(PPh3)4 (cat.),
Cs2CO3, DMF−H2O, 90 °C.
a
Table 2. Experimental Data on 1,4-Diarylpyridones 8
entry compound
R1
R2
yield (%)
63
1
2
3
4
5
6
8{3/1}
4-methylpyridin-2-yl
Ph
Ph
Ph
b
8{8/1}
4-nitrophenyl
82
b
8{16/1}
8{16/2}
8{16/3}
8{16/4}
Ph
Ph
Ph
Ph
72
b
4-cyanophenyl
3-chlorophenyl
pyridin-4-yl
67
b
58
b
50
a
All compounds were obtained in ≥80% purity (determined by LC-
b
1
MS and H NMR). Analytical purity was determined by elemental
analysis. The found values for C, H, and N were within 0.4% range
with respect to the theoretical values.
Next, reaction in aqueous DMF in the presence of cesium
carbonate at 65 °C gave 8{16/1} in 47% yield, while at 90 °C
8{16/1} was obtained in 72% yield. Under microwave-
irradiation at 90 °C, the yield was almost identical (71%).
Next, parallel cross-coupling of the representative 1-phenyl-
tosylate 5{16} with arylboronic acids 7{1−4} and reactions of
5{3} and 5{8} with phenylboronic acid 7{1} was performed.
Reactions were carried out in aqueous DMF, Pd(PPh3)4 as
catalyst, and cesium carbonate at 90 °C followed by extraction
and purification of the crude products by filtration through a
short plug of silica gel to give 1,4-diarylpyridones 8 in 50−82%
yield. Out of six pyridones 8, five were analytically pure, while
a
Reaction conditions: (i) DMF-DMA, MeOH, r.t. (ref 18); (ii)
R1NH2 3{1−20}, MeOH, 37% HCl (1 equiv.), r.t. (ref 18); (iii) KOH,
MeOH, reflux; (iv) TsCl, DMF, Et3N, DMAP (cat.), 95 °C; (v)
POCl3, reflux.
a
Table 1. Experimental Data on Compounds 4−6
yield (%)
entry
compound
R1
4
5
6
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
1
1
4{1}, 5{1}
4{2}
pyrazinyl
58
63
65
60
54
80
50
50
46
45
45
45
60
48
63
54
40
60
57
46
47
compound 8{3,1} was also >80% pure according to H NMR
and LC-MS (Method A, Scheme 3, Table 2).
2
pyridin-2-yl
b
3
4{3}, 5{3}
4{4}
4-methylpyridin-2-yl
5-methylpyridin-2-yl
3-hydroxypyridin-2-yl
5-chloropyridin-2-yl
5-nitropyridin-2-yl
4-nitrophenyl
4-fluorophenyl
2-iodophenyl
4-hydroxyphenyl
4-methylphenyl
4-methoxyphenyl
3-nitrophenyl
2-methoxyphenyl
Ph
52
To our surprise, neither the 1-alkyl tosylates 5{18−20}, nor
the chloropyridones 6{18−20}, underwent cross-coupling with
phenylboronic acid 7{1}. Several attempts to carry out these
reactions by variation of reaction conditions (substrate, solvent,
base, and catalyst) were futile as well. To prepare the 1-alkyl
substituted pyridones 8, extensive combinatorial screening for
suitable reaction conditions with respect to the substrate,
solvent, base, and catalyst was performed. A series of 320
Suzuki−Miyaura cross-coupling reactions were carried out,
comprising combinations of one reagent 7{1}, two substrates
5{18} and 6{18}, five solvents 1−5, four bases I−IV, and eight
catalysts A−H. Parallel screening reactions were carried out at
60 °C on a 12 × 0.1 mmol scale in 2 mL glass vials using a
standard magnetic stirrer/heater equipped with aluminum
block with 12 positions and temperature controller. The
reactions were monitored by TLC and by change of color. In
the two successful cross-couplings, progress of the reaction was
detected when the initially orange-brown reaction mixture
turned dark green with precipitation of colloidal palladium
black (Scheme 4).
4
5
4{5}
6
4{6}
7
4{7}
b
b
8
4{8}, 5{8}
4{9}, 5{9}
4{10}
87
18
9
10
11
12
13
14
15
16
17
18
19
20
4{11}
4{12}
b
b
4{13}, 5{13}
4{14}
36
4{15}
4{16}, 5{16}
4{17}
75
H
b
b
b
b
4{18}−6{18}
4{19}−6{19}
4{20}−6{20}
Me
45
29
35
62
75
60
1-propyl
2-methoxyethyl
a
All compounds were obtained in ≥80% purity (determined by LC-
b
1
MS and H NMR). Analytical purity was determined by elemental
analysis. The found values for C, H, and N were within 0.4% range
with respect to the theoretical values.
Out of 320 reactions, just two of them gave the desired cross-
coupling product 8{18/1}: (a) reaction of the chloride 6{18} in
DMF, with KOH−MeOH as base, and PdCl2/P(p-tolyl)3 as
C
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Scheme 4. Screening for Reaction Conditions for Arylation of 1-Alkylpyridones 5 and 6
a
Scheme 5. Synthesis of 1-Alkyl-4-arylpyridones 8 (Method
B)
Scheme 6. Synthesis of Compounds 9 and 11
a
a
Reaction conditions: (i) R2B(OH)2 7, Cs2CO3, DMF−H2O,
Pd(PPh3)4−[PdCl(allyl)]2 (cat.), 55−65 °C.
a
Table 3. Experimental Data on 1-Alkyl-4-arylpyridones 8
a
entry
compound
R1
R2
yield (%)
Reaction conditions: (i) 1 M KOH−MeOH, reflux; (ii) Et3N, BPC,
MeCN, r.t.; (iii) R3R4NH 3{20−27}, Et3N, MeCN, r.t.
b
1
2
3
4
8{18/1}
8{18/3}
8{19/1}
8{20/3}
Me
Me
Ph
73
3-chlorophenyl
Ph
49
61
45
1-propyl
and 8{20/3} were obtained in 45−73% yield and in >80%
purity (determined by LC-MS and 1H NMR)(Method B,
Scheme 5, Table 3).
Although our primary goal was to obtain the 4-arylpyridones
8, several attempts were also made to prepare the 4-alkyl and
the 4-alkyenyl substituted compounds 8 by cross-coupling of
5{16} and 6{18} with butyl-, isobutyl-, cyclopentyl-, and trans-
styrylboronic acid, yet without success. Even under microwave
irradiation formation of the corresponding cross-coupling
products was not observed.
2-methoxyethyl
3-chlorophenyl
a
All compounds were obtained in ≥80% purity (determined by LC-
b
1
MS and H NMR). Analytical purity was determined by elemental
analysis. The found values for C, H, and N were within 0.4% range
with respect to the theoretical values.
catalyst and (b) reaction of the chloride 6{18} in DMF,
Cs2CO3 as base, and combination of Pd(PPh3)4 and [PdCl-
(allyl)]2 as the catalyst (Scheme 3). However, only the latter
reaction was reproducible and, consequently, these conditions
were finally employed for the preparation of five 1-alkyl-4-aryl
pyridones 8. In this manner, compounds 8{18/1,3}, 8{19/1},
Finally, transformation of the esters 8 into the corresponding
carboxamides 11 was performed (Scheme 6). Hydrolysis of the
esters 8 was carried out in parallel with 1 M KOH in methanol
D
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a
Table 4. Experimental Data on Compounds 9
entry
compound
R1
R2
yield (%)
1
2
3
4
5
6
7
8
9
9{8/1}
4-nitrophenyl
Ph
Ph
95
80
9{16/1}
9{16/2}
9{16/3}
9{16/4}
9{18/1}
9{18/3}
9{19/1}
9{20/3}
Ph
b
Ph
4-cyanophenyl
3-chlorophenyl
pyridin-2-yl
Ph
83
b
Ph
83
b
Ph
65
b
Me
98
b
Me
3-chlorophenyl
Ph
94
b
n-Pr
74
b
MeO(CH2)2−
3-chlorophenyl
82
a
All products were obtained in ≥80% purity (determined by LC-MS
b
and 1H NMR). Analytical purity was confirmed by elemental analysis.
The found values for C, H, and N were within 0.4% range with
respect to the theoretical values.
Figure 3. Molecular structure of compound 4{20}.
under reflux to afford analytically pure carboxylic acids 9 in 76−
98% yield upon simple filtration workup (Scheme 6, Table 4).
Carboxylic acids 9{16/1,3} and 9{18/1,3} and amines
3{20,21,23} were chosen as model substrates for parallel
amidation. In addition, five other amidations of the acids
9{16,18/1} and 9{20/3} with amines 3{22,24−27} were
performed as well. The acids 9 were activated with
bis(pentafluorophenyl) carbonate (BPC) to give the penta-
fluorophenyl esters 10, followed by treatment with aliphatic
amines 3{20−27} (Figure 1) to furnish title compounds 11 in
48−98% yield. Since BPC-mediated amidation affords only
volatile byproduct, it allows simple evaporative workup. Thus,
all seventeen title compounds 11 were primarily isolated just by
filtration of the reaction mixtures (to remove the precipitated
ammonium salts) followed by thorough evaporation of the
filtrates at 100 °C/0.01 Torr (Workup A). Ten products,
compounds 11{16/1/20,23}, 11{16/3/20,21,23}, 11{18/1/
a
Table 5. Experimental Data on Compounds 11
a
b
1
All products were obtained in ≥80% purity (determined by LC-MS and H NMR). Analytical purity was confirmed by elemental analysis. The
found values for C, H, and N were within 0.4% range with respect to the theoretical values.
E
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ACS Combinatorial Science
Research Article
N(1), C(4), and the carboxy group in the 6-oxo-1,6-
dihydropyridine-3-carboxylic acid core. Hence, it offers an
easy access to 1-substituted 4-aryl-6-oxo-1,6-dihydropyridine-3-
carboxamides 11 and could also serve as a useful tool for the
preparation of novel compound libraries for pharmaceutical and
other practical applications.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, characterization data, and
the representative spectra for chemsets 4−6, 8, 9, and 11. This
information is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
Figure 4. Molecular structure of compound 8{18/1}.
*Tel.: +386 1 2419 100. Fax: +386 1 2419 220. E-mail: jurij.
svete@fkkt.uni-lj.si.
Author Contributions
20,21}, and 11{18/3/20,21,23} were obtained in this way in
83−98% yield and in 80−98% purity. The purity of seven other
products, 11{16/1/21,26}, 11{18/1/22−25}, and 11{20/3/
27} was not satisfactory upon Workup A. These crude products
were further purified by trituration with 1 M hydrochloric acid
followed by extraction with ethyl acetate (Workup B) to give
the corresponding purified products 11 in 48−92% yield and in
87−100% purity. Of the seventeen final library members 11,
seven were ≥95% pure as confirmed also by elemental analyses
for C, H, and N (Scheme 6, Table 5).
The structures and purities of novel compounds in chemsets
4−6, 8, 9, and 11 were determined by spectroscopic methods
(IR, NMR, MS, HRMS), by LC-MS, and by elemental analyses
for C, H, and N. Physical and spectral data for known
compounds 4{17} and 4{18} were in agreement with the
literature data.18 Characterization data for all compounds of
chemsets 4−6, 8, 9, and 11 are given in the Supporting
Information.
The manuscript was written with contributions from all
authors. All authors have given approval to the final version
of the manuscript.
Funding
The financial support from Boehringer-Ingelheim Pharma
(Biberach, Germany) and from the Slovenian Research Agency
through grant P1-0179 is gratefully acknowledged. We
acknowledge with thanks the financial contributions of
pharmaceutical companies Krka d.d. (Novo mesto, Slovenia)
and Lek d.d. a Sandoz Company (Ljubljana, Slovenia), which
made the purchase of Mettler-Toledo Bohdan MiniBlock
Compact Shaking and Washing Station and Vacuum Collection
Base possible.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
The structures of compounds 4{20} and 8{18/1} were
determined by X-ray diffraction (Figures 3 and 4, see also the
Supporting Information).
BPC, bis(pentafluorophenyl) carbonate; DMAP, 4-dimethyla-
minopyridine; DMF, N,N-dimethylformamide; DMF-DMA,
N,N-dimethylformamide dimethylacetal; TLC, thin layer
chromatography
CONCLUSION
■
A five-step parallel solution-phase synthesis of 1-substituted 4-
aryl-6-oxo-1,6-dihydropyridine-3-carboxamides 11 from di-
methyl 3-oxopentanedioate (1) was developed. The synthesis
starts with one-pot preparation of methyl 4-hydroxy-6-oxo-1,6-
dihydropyridine-3-carboxylates 4. O-tosylation or nucleophilic
chlorination of 4-hydroxypyridines 4, followed by Suzuki−
Miyaura cross-coupling of the corresponding tosyloxy- 5 or
chloro derivatives 6 with arylboronic acids 7 gave 4-aryl-6-oxo-
1,6-dihydropyridine-3-carboxylates 8 as the key-intermediates.
Combinatorial screening was crucial for determining of the
optimal reaction conditions for the synthesis of 1-alkyl-4-
arylpyridones 8. Hydrolysis of the esters 8 followed by BPC-
mediated parallel solution-phase amidation of the acids 9 gave
the title compounds 11 in good yields and purities. Typical
overall yield of the final carboxamides 11 obtained from the
representative amines 3{20,21,23} and 1-arylcarboxylic acids
9{16/1,3} (∼20%, R1 = Ph, R2 = Ar) and 8{18/1,3} (∼15%, R1
= Me, R2 = Ar) shows that the method is somewhat more
efficient for the preparation of the 1-aryl- that for the 1-alkyl
substituted compounds. In summary, this method allows
introduction of diverse substituents at three different positions:
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