Effective synthesis of 3,5-diaryl-(1H)-pyrazin-2-ones via microwave mediated ring closure

Article abstract of DOI:10.1016/j.tetlet.2013.05.095

In this study we report on a flexible straight forward synthesis toward novel 3,5-diaryl-(1H)-pyrazin-2-ones. Our synthetic strategy involved an acyclic di-keto derivative as key intermediate. The final pyrazin-2-one ring closure reaction was yield-optimized by using a microwave mediated procedure and ammoniumacetate as nitrogen source. Our method is a suitable alternative to palladium-catalyzed coupling reactions for the 3,5-diaryl decoration of the (1H)-pyrazin-2-one scaffold. Since the (1H)-pyrazin-2-ones is present as scaffold in a number of biologically active compounds the reported synthetic platform is a useful approach to generate a set of highly diverse 3,5-diaryl-(1H)-pyrazin-2-one compounds.

Full text of DOI:10.1016/j.tetlet.2013.05.095

Accepted Manuscript
Effective synthesis of 3,5-diaryl-(1H)-pyrazin-2-ones via microwave mediated
ring closure
Eugen Johannes, Rebecca Horbert, Joachim Schlosser, Dorian Schmidt,
Christian Peifer
PII:
S0040-4039(13)00874-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.095
TETL 42995
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 March 2013
16 May 2013
22 May 2013
Please cite this article as: Johannes, E., Horbert, R., Schlosser, J., Schmidt, D., Peifer, C., Effective synthesis of 3,5-
diaryl-(1H)-pyrazin-2-ones via microwave mediated ring closure, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.05.095
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Tetrahedron Letters
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Effective synthesis of 3,5-diaryl-(1H)pyrazin-
2-ones via microwave mediated ring closure
Eugen Johannes, Rebecca Horbert, Joachim Schlosser, Dorian Schmidt, and Christian Peifer
MW

Tetrahedron Letters
1
Tetrahedron Letters
journal hom epag e: www.elsevier.com
Effective synthesis of 3,5-diaryl-(1H)-pyrazin-2-ones via microwave mediated ring
closure
Eugen Johannesa, Rebecca Horberta, Joachim Schlossera,b, Dorian Schmidta, and Christian Peifera∗
a Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany
bInstitute of Pharmacy, University of Tübingen, Auf der Morgenstelle 8b, D-72076 Tübingen, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
In this study we report on a flexible straight forward synthesis towards novel 3,5-diaryl-(1H)-
pyrazin-2-ones. Our synthetic strategy involved an acyclic di-keto derivative as key
intermediate. The final pyrazin-2-one ring closure reaction was yield-optimized by using a
microwave mediated procedure and ammoniumacetate as nitrogen source. Our method is a
suitable alternative to palladium-catalysed coupling reactions for the 3,5-diaryl decoration of the
(1H)-pyrazin-2-one scaffold. Since the (1H)-pyrazin-2-ones is present as scaffold in a number of
biological active compounds the reported synthetic platform is a useful approach to generate a
set of highly diverse 3,5-diaryl-(1H)-pyrazin-2-one compounds.
Received in revised form
Accepted
Available online
Keywords:
3,5-Diaryl-(1H)-pyrazin-2-ones
Microwave reaction
Aryl-α-ketoamines
2013 Elsevier Ltd. All rights reserved.
Aryl-glyoxylic acids
Protein kinase inhibitors
∗ Corresponding author. Tel.: +49-431-880-1137; fax: +49-431-880-1352; e-mail: cpeifer@pharmazie.uni-kiel.de

Tetrahedron Letters
2
The (1H)-pyrazin-2-one scaffold is present in a number of
natural derived compounds showing interesting biological
activities. These natural products include marine alkaloids such
as ma´edamines1, dragmacidines2, JBIR-56/573, leuvaline,
phevaline, tyrvalin4, and hamacanthines5,6 (Figure 1). Moreover,
the (1H)-pyrazin-2-one is the central core in further
pharmacologically active compounds, e.g. µ-receptor agonists7,
corticotropin-releasing factor receptor-1 antagonists8, non-
nucleoside HIV-1 reverse transcriptase inhibitors9,10, mast-cell
tryptase inhibitors11, TF/VIIa inhibitors12, protein kinase
inhibitors13, and in marketed drugs such as Olbetam14,
Alphagan15, and Ximovan16.
Several methods are available for the preparation of
substituted (1H)-pyrazin-2-ones either from heterocyclic
intermediates or from acyclic precursors17-20. Among these, the
palladium catalysed coupling using 3,5-dichloro-(1H)-pyrazin-2-
one as starting material is a common approach10. Another
strategy involves (1H)-pyrazin-2-one ring closure by refluxing
di-ketoamides in ammonia21,22
.
These methods often involve drawbacks such as expensive
catalysts, prolonged reaction times, tedious work-up procedures,
producing low yields, or limited availability of starting material
with desired substitution. In the present paper we report on a
flexible straight forward preparation method towards 3,5-diaryl-
(1H)-pyrazin-2-ones using an acyclic di-keto precursor accessible
from readily available starting materials. The final pyrazin-2-one
ring closure reaction between the respective benzylic carbonyl
oxygens consists of a microwave mediated procedure using
ammoniumacetate as nitrogen source (Scheme 1). The reaction
1
2
tolerates
a variety of aromatic glyoxylic acids and α-
aminoketones containing electron donating and electron
withdrawing substituents as well as several heteroaromatic
systems. By this general method we produced novel 3,5-diaryl-
(1H)-pyrazin-2-ones (Table 1) suitable for our medicinal
chemistry programme.
4
3
5
or
6
I
II
7
Figure 1. Examples of marine alkaloids possessing the (1H)-
pyrazin-2-one scaffold. 1 Ma´edamine A; 2 Dragmacidin D; 3 JBIR-
56; 4 leuvalin; 5 phevalin; 6 tyrvalin; 7 Hamacanthin B.
III
8
9
In the course of our work to develop novel protein kinase (PK)
inhibitors possessing the central 3,5-diaryl-(1H)-pyrazin-2-one
core, we became particularly interested in hamacanthins, a family
of marine-sponge derived alkaloids which have been reported to
act as human- and bacterial-PK inhibitors. All PK of the
“kinome” use ATP as cofactor for the phosphorylation of
proteins in signal transduction pathways. Thus, they share a
highly conserved ATP binding pocket which is the molecular
binding site of most PK inhibitors. In the active site of PK small
molecular differences in amino acid identity provide selectivity
filters for the specificity of inhibitors.. Therefore, we aimed to
establish a straight forward and flexible synthetic platform to
develop potent and specific 3,5-diaryl-(1H)-pyrazin-2-ones as PK
inhibitors.
10
IV
Scheme 1. General synthetic11procedure towards targeted 3,5-
diaryl-(1H)-pyrazin-2-ones (D). arylglyoxylic acids (8) by
I
oxidation of acetophenons using SeO2; II α–ketoamines (9) from
acetophenons or aryl-acids; III amides (10) coupling via CDI; IV
(1H)-pyrazin-2-ones (11) ring closure via microwave conditions and
ammoniumacetate as nitrogen source.
Table 1. Synthesis of 3,5-diaryl-(1H)-pyrazin-2-one derivatives 12 - 35 produced via general synthetic method (as referred to in Scheme 1)
arylglyoxylic acid
α-ketoamine
diketo-precursor
3,5-diaryl-(1H)-pyrazin-2-one
Yield
H
O
N
54%
N
N
H
12a
12b
12c
12
H
N
R
O
R
20%
N
N
H
N
H
N
H
N
H
13a
13b
13c
13

Tetrahedron Letters
3
H
N
R
O
R
15%
19%
58%
N
N
H
N
H
14a
14b
14c
14
H
N
R
O
R
N
N
H
F
N
H
F
15a
15b
15c
16c
17c
15
H
N
R
O
R
N
O
N
H
N
H
O
16a
16b
16
H
R
O
R
O
N
N
O
51%
N
H
O
N
H
O
17a
17b
17
H
N
O
O
R
R
O
O
O
S
N
37%
S
O
O
18a
18b
18c
18
H
N
O
O
R
R
O
O
O
O
O
60%
N
O
O
19a
19b
19c
19
H
R
R
O
N
N
10%
12%
30%
N
O
H
N
H
O
20a
20b
20c
20
H
N
R
O
O
O
R
N
H
N
N
H
O
O
O
O
21a
21b
21c
21
H
N
R
O
R
N
N
N
H
N
H
O
N
O
22a
22b
22c
22
H
N
R
R
O
54%
N
O
O
23a
23b
23c
23
R
H
N
O
R
16%
N
N
H
N
H
O
O
24a
24b
24c
24

Tetrahedron Letters
4
R
H
N
O
R
85%
N
N
H
O
N
H
O
25a
25b
25c
25
H
R
O
N
R
54%
66%
87%
88%
39%
N
N
H
N
H
F
F
26a
26b
27b
28b
29b
26c
27c
28c
29c
30c
26
R
H
N
O
R
N
N
H
N
H
27a
27
H
N
R
O
R
R
R
R
N
N
H
N
H
28a
28
H
N
O
N
N
H
N
H
N
29a
29
H
N
R
O
N
N
N
H
N
N
H
30a
30b
30
H
N
O
53%
N
N
H
N
H
N
31a
31b
31c
31
R
78%
N
H
32a
32b
32c
33c
34c
32
33
34
H
N
R
O
R
R
R
91%
N
S
N
H
S
N
H
33a
33b
H
N
R
O
63%
S
N
N
H
S
N
H
34a
34b
H
N
O
R
55%
N
N
H
N
H
35a
35b
35c
35

Tetrahedron Letters
5
Regarding the (1H)-pyrazin-2-one ring closure mechanism
from the acyclic di-keto precursors it is noteworthy that in our
hands only the benzylic carbonyl moieties reacted towards the 6-
membered ring closure, keeping the lactam moiety present in the
final product. Thus, under our reported conditions the reaction
mechanism does not involve the amide carbonyl of the di-keto
precursors. In line with this notion we did not observe the
formation of 5-membered imidazoles (aryl-(4-aryl-1H-imidazole-
2-yl)methanones).
Synthesis of arylglyoxylic acids was performed by oxidizing
the respective acetophenone with SeO2 in pyridine23. Synthesis of
α-ketoamines was either achieved by Delépine reaction from
acetophenones24 or by using aryl acids25 as starting material.
Figure 2. ORTEP of compound 15 determined by Xray
crystallography showing the atom numbering scheme.
Typical procedure for CDI-mediated coupling to produce
diketoamide 12c: 1 equiv. of arylglyoxylic acid 12a was
dissolved in 2 ml NMP and 1.1 equiv. of CDI were added. The
mixture was stirred at rt for 1h followed by addition of 1 equiv.
of α-ketoamine 12b. After stirring at rt over night water was
added slowly to precipitate diketoamide 12c which was filtered
off and washed with methanol and diethylether. Alternatively, the
diketoamide was extracted by ethylacetate and purified by Flash
chromatography.
Acknowledgments
The authors thank Martin Schütt and Dr. Ulrich Girreser for
excellent technical assistance during synthesis and analytical
characterization at the Institute of Pharmacy, Kiel. The help of
Dr. Dieter Schollmeyer, Institute of Organic Chemistry,
University of Mainz, Germany for Xray structure determination
is gratefully acknowledged.
Typical procedure for the synthesis of compound 12: a
microwave vial (5ml) was equipped with 100 mg (1 equiv.) of
diketoamide 12c, 252 mg (10 equiv.) of ammoniumacetate and 3
ml acetic acid. The vial was sealed and stirred at max. radiation
power (200 W) limited by 160°C reaction temperature for 4 min
in a microwave synthesizer (CEM Discover). The reaction vessel
was then air-cooled to rt and water was added to precipitate the
crude pyrazinone 12 which was filtered off. Analytical samples
of pyrazinones (10-50 mg) were chromatographed by preparative
HPLC on RP column to afford ≥ 98% purity.
Supplementary Material
Supplementary data including relevant H/13C-NMR, IR, MS
and HPLC for all compounds and CCDC-numbers for
compounds 15, 18, 19 - 21, and 23 associated with this paper can
be found in the online version at http://(to be inserted)
1
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1
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