Synthesis of highly functionalized 2(1H)-pyrazinone 3-carboxamide scaffolds

Article abstract of DOI:10.1021/ol801664v

(Chemical Equation Presented) Synthesis of highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives is reported. A one-pot, two-step process including the base-mediated reaction of N,N-disubstituted aminoacetonitrile derivatives 18 with 3,5-dihalo

Full text of DOI:10.1021/ol801664v

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4473-4476
Synthesis of Highly Functionalized
2(1H)-Pyrazinone 3-Carboxamide
Scaffolds
Sonalika V. Pawar, Vijaykumar G. Pawar, Wim Dehaen,
and Wim M. De Borggraeve*
Molecular Design and Synthesis, Department of Chemistry, Katholieke UniVersiteit
LeuVen, Celestijnenlaan 200F, 3001 LeuVen, Belgium
wim.deborggraeVe@chem.kuleuVen.be
Received July 22, 2008
ABSTRACT
Synthesis of highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives is reported. A one-pot, two-step process including the base-
mediated reaction of N,N-disubstituted aminoacetonitrile derivatives 18 with 3,5-dihalo-2(1H)-pyrazinones 1 afforded substituted aminoacetonitrile
pyrazinone derivative 19, which on subsequent oxidation followed by transamidation of the resulting intermediate with primary or secondary
amines gave the corresponding highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives 21.
Since 1983, 3,5-dihalo-2(1H)-pyrazinones 1 have proven to
be versatile scaffolds in organic synthesis,1 and an efficient
synthesis for 3,5-dihalo-2(1H)-pyrazinones has been devel-
oped in our laboratory.2 Different methods have been studied
to functionalize this heterocyclic scaffold1,3 which can now
be functionalized with various substituents.
scaffold drew our attention in the framework of peptidomi-
metic research going on in the group.
This pyrazinone scaffold has the ability to stabilize peptide
conformations (e.g., ꢀ-sheet and ꢀ-turn) or reduce the
peptidyl features of peptide-like compounds.
One of the functionalizations that was so far not straight-
forward to achieve was the functionalization of the 3-position
with a carboxamide function (scaffold 2, Figure 1). This
(1) Pawar, V. G.; De Borggraeve, W. M. SynthesissStuttgart 2006,
2799–2814.
(2) Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocycl. Chem.
1983, 20, 919–923.
(3) Azzam, R.; De Borggraeve, W. M.; Compernolle, F.; Hoornaert,
G. J. Tetrahedron 2005, 61, 3953–3962.
(4) Hopkins, C. R.; Neuenschwander, K.; Scotese, A.; Jackson, S.;
Nieduzak, T.; Pauls, H.; Liang, G. Y.; Sides, K.; Cramer, D.; Cairns, J.;
Maignan, S.; Mathieu, M. Bioorg. Med. Chem. Lett. 2004, 14, 4819-
4823.
(5) Reiner, J. E.; Siev, D. V.; Araldi, G.-L.; Cui, J. J.; Ho, J. Z.; Reddy,
K. M.; Mamedova, L.; Vu, P. H.; Lee, K.-S. S.; Minami, N. K. Bioorg.
Med. Chem. Lett. 2002, 12, 1203–1208.
(6) Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.; Newton,
C. L.; Pellicore, J. M.; Rittle, K. E.; Selnick, H. G.; Stauffer, K. J.; Vacca,
J. P.; Williams, P. D.; Bohn, D.; Clayton, F. C.; Cook, J. J.; Krueger, J. A.;
Kuo, L. C.; Lewis, S. D.; Lucas, B. J.; McMasters, D. R.; Miller-Stein, C.;
Pietrak, B. L.; Wallace, A. A.; White, R. B.; Wong, B.; Yan, Y.; Nantermet,
P. G. J. Med. Chem. 2004, 47, 2995–3008.
Figure 1
. 3,5-Dihalo-2(1H)-pyrazinone 1, pyrazinone with car-
boxamide function 2, and Merck’s L-870810 integrase inhibitor 3.
10.1021/ol801664v CCC: $40.75
Published on Web 09/18/2008
2008 American Chemical Society

Similar pyrazinone scaffolds have been used successfully
in tryptase inhibitors,4 thrombin inhibitors,5-7 and caspase-3
inhibitors.8
Scheme 2. General Synthesis of Pyrazinone Derivative 2
These pyrazinones have very interesting structural similarity
with Merck’s L-870810 integrase inhibitor (3)9,10 as shown in
Figure 1.
To synthesize this pyrazinone scaffold 2, we wanted to
use 3,5-dihalo-2(1H)-pyrazinones 1 as the starting point since
this synthesis should allow us to introduce diverse substit-
uents at different positions of the scaffold 2. A variety of R1
and R6 substituents of scaffold 2 could be introduced while
synthesizing pyrazinone 1 (Scheme 1). Moreover, the ap-
Scheme 1. Retrosynthesis of Pyrazinone Scaffold 2
Thus, it was necessary to develop a new and more efficient
method which would provide us with carboxamidepyrazinone
scaffold 2.
In the case of 3,5-dihalo-2(1H)-pyrazinones 1, we could
take advantage of the highly electrophilic C3 carbon of
pyrazinone 1. Thus, we envisioned the insertion of carboxa-
mide at C3 by using the “umpolung concept” which could
lead us to generate pyrazinone scaffold 2 directly from
dihalopyrazinone 1. This could be achieved by applying the
well-known Stork method.11
Our first attempt was the use of N,N-disubstituted ami-
noacetonitrile derivative 7 as a synthon for amides of general
composition 8 (Figure 2). The two-step process12consisting
propriate halogen atom at position 5 could allow us to
introduce different substituents by using palladium-catalyzed
reactions,3 and this synthetic route could be very useful to
synthesize a focused library of druglike compounds.
A general way to get this carboxamide functionality at
position 3 of pyrazinones 1 is the insertion of a cyano group
followed by hydrolysis of the cyano group and the coupling
of an amine with the resulting carboxylic acid (Scheme 2).
The hydrolysis of the cyano group to the pyrazinone
carboxylic acid 6, however, is a very low yielding synthetic
step in our experience.
Figure 2. N,N-Disubstituted aminoacetonitrile derivative 7 as a
synthon for amide of general composition 8.
of a base-mediated alkylation of the methylene moiety by
SNAr (addition-elimination) at the highly electrophilic
position C-3 of dihalo 2(1H)-pyrazinone and subsequent
oxidation could result in the generation of the desired
carboxamidopyrazinone 2 after elimination of HCN from an
intermediate cyanohydrine generated from 9 (Scheme 3).13
During the optimization of the method to provide a general
reaction procedure, KHMDS was found to be a suitable base
and -78 °C was found to be the temperature of choice that
offered a clean reaction as compared to NaH or NaHMDS
at room temperature or at lower temperature (0 to -78 °C).
When the oxidant Na2O2 is used, the product 13a was
isolated in 16% yield only (Table 1).
(7) South, M. S.; Case, B. L.; Wood, R. S.; Jones, D. E.; Hayes, M. J.;
Girard, T. J.; Lachance, R. M.; Nicholson, N. S.; Clare, M.; Stevens, A. M.;
Stegeman, R. A.; Stallings, W. C.; Kurumbail, R. G.; Parlow, J. J. Bioorg.
Med. Chem. Lett. 2003, 13, 2319–2325.
(8) Han, Y.; Giroux, A.; Colucci, J.; Bayly, C. I.; McKay, D. J.; Roy,
S.; Xanthoudakis, S.; Vaillancourt, J.; Rasper, D. M.; Tam, J.; Tawa, P.;
Nicholson, D. W.; Zamboni, R. J. Bioorg. Med. Chem. Lett. 2005, 15, 1173–
1180.
(9) Egbertson, M. S.; Moritz, H. M.; Melamed, J. Y.; Han, W.; Perlow,
D. S.; Kuo, M. S.; Embrey, M.; Vacca, J. P.; Zrada, M. M.; Cortes, A. R.;
Wallace, A.; Leonard, Y.; Hazuda, D. J.; Miller, M. D.; Felock, P. J.;
Stillmock, K. A.; Witmer, M. V.; Schleif, W.; Gabryelski, L. J.; Moyer,
G.; Ellis, J. D.; Jin, L.; Xu, W.; Braun, M. P.; Kassahun, K.; Tsou, N. N.;
Young, S. D. Bioorg. Med. Chem. Lett. 2007, 17, 1392–1398.
(10) Hazuda, D. J.; Anthony, N. J.; Gomez, R. P.; Jolly, S. M.; Wai,
J. S.; Zhuang, L.; Fisher, T. E.; Embrey, M.; Guare, J. P., Jr.; Egbertson,
M. S.; Vacca, J. P.; Huff, J. R.; Felock, P. J.; Witmer, M. V.; Stillmock,
K. A.; Danovich, R.; Grobler, J.; Miller, M. D.; Espeseth, A. S.; Jin, L.;
Chen, I. W.; Lin, J. H.; Kassahun, K.; Ellis, J. D.; Wong, B. K.; Xu, W.;
Pearson, P. G.; Schleif, W. A.; Cortese, R.; Emini, E.; Summa, V.;
Holloway, M. K.; Young, S. D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
11233–11238.
(11) Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1971, 93, 5286.
(12) Zhang, Z.; Yin, Z.; Kadow, J. F.; Meanwell, N. A.; Wang, T. J.
Org. Chem. 2004, 69, 1360–1363.
4474
Org. Lett., Vol. 10, No. 20, 2008

monosubstituted aminoacetonitriles would generate cyano-
imine derivatives 16, rather than primary amides (Figure 3).
Scheme 3. First Attempt To Synthesize Pyrazinone Derivative 2
Figure 3. N-Monosubstituted aminoacetonitrile 15, generating
cyanoimine derivative 16.
Finally, this method is low yielding. This would significantly
restrict the generation of a diverse library of druglike
compounds.
Therefore, in order to get widely substituted primary and
secondary amide pyrazinones, the amino function of structure
7 must be replaced by a leaving group. Substituted aceto-
nitriles 17 or 18 (Figure 4) could function in such way that
Table 1. Optimization of Oxidation Conditions
Figure 4. Substituted acetonitriles.
combination in the final step with any amine would give the
corresponding amide. This approach could afford pyrazinone
carboxamides 2 with differently substituted primary and
secondary amides, directly from the corresponding diha-
lopyrazinones 1.
It was anticipated that an anion generated from azole-N-
acetonitrile 17 or 18 using a strong base would react with
dichloro 2(1H) pyrazinone via SNAr reaction to form the
substituted aminoacetonitrile 19 (Scheme 4). The subsequent
oxidation of 19 to the corresponding cyanohydrins would
set the stage of elimination of HCN to afford an acylated
azole derivative 20 that as an activated carbonyl derivative
would react with an amine to provide the pyrazinone amide
21 (Scheme 4).
To a mixture of dichloro-2(1H)-pyrazinone 10a (1 mmol)
and imidazole N-acetonitrile (1.5 mmol) in dry THF was
added KHMDS (2.5 mmol) at -78 °C. The reaction was
complete within 5 h. The total conversion of dichloro 2(1H)-
pyrazinone 10 to intermediate 19 was confirmed by LCMS.
The intermediate 19 was then oxidized by subsequent
addition of m-CPBA (4 mmol) and amine (3 mmol). The
reaction mixture was stirred a further 10 h at room temper-
ature, and the expected product 13a was obtained in 60%
yield (Table 2).13
(Yield %)
R1
R6
Na2O2
CH3CO3H
m-CPBA
13a
13b
13c
13d
13e
CH2Ph
CH2CH2Ph
Ph
CH2Ph
CH2Ph
H
H
16
13
23
27
18
18
24
32
33
23
28
27
32
49
CH3
CH3
Ph(p-OMe3) 4
To further optimize the reaction conditions, a stepwise
analysis was performed. The generation of the intermediate
12 was achieved in 92% isolated yield which pointed out
the problem to be in the oxidation step. Therefore three
different oxidants were tried with five different pyrazinones
10a-e, and the results are summarized in Table 1.
From this study, m-CPBA was found to be a higher
yielding reagent than Na2O2 and CH3CO3H.
However, there are three limitations for this method. First,
in this reaction different diaminoacetonitriles would be
needed for the generation of different pyrazinone 3-carboxa-
mides. Second, the amidoacetonitriles as amide synthons are
restricted to N,N-disubstituted derivatives. The use of N-
(13) For experimental data, see the Supporting Information.
Org. Lett., Vol. 10, No. 20, 2008
4475

Scheme 4
.
Synthesis of Amides 21
Table 2. One-Pot Synthesis: Affording Primary and Secondary
3-Carboxamide Pyrazinone Derivatives 13 and 21
R1
R6
R7
R8
yielda (%)
13a CH2Ph
13b (CH2)2Ph
13c Ph
H
H
CH3
CH3
Me Me
Me Me
Me Me
Me Me
60b,24c,33d
63b
To generalize this one-pot process, a library of 12 pyrazinone
3-carboxamide derivatives was generated using six different
dihalopyrazinones and eight different primary as well as
secondary amines. The results are summarized in Table 2.
As shown in Table 2, this one-pot procedure affords
products 13a-e and 21a-g in good overall yields.
This indicates the superiority of this method over the
method using dimethylaminoacetonitrile. m-CPBA was found
to be a good oxidizing reagent which gives a clean reaction
compared to Na2O2 and CH3CO3H (entry 13a).
In summary, novel and highly functionalized derivatives
of pyrazinone carboxamide were synthesized in a single step
starting from different dihalopyrazinones by taking advantage
of its electrophilic C-3 position. Azole-N-acetonitriles deriva-
tives as carbonyl synthon allow the introduction of a wide
variety of primary and secondary amines. Thus highly
functionalized pyrazinone scaffolds could be prepared,
illustrating the wide scope of this scaffold as well as this
mild and versatile method.
74b
13d CH2Ph
13e CH2Ph
21a CH2Ph
21b CH2Ph
21c CH2Ph
21d CH2Ph
21e CH2Ph
21f CH2Ph
21g CH2Ph
67b
Ph (p-OMe) Me Me
Ph (p-OMe)
Ph (p-OMe) pyrrolidine
Ph (p-OMe) Et Et
Ph (p-OMe)
Ph (p-OMe)
Ph (p-OMe)
Ph (p-OMe)
83b
H
(CH2)2CH(CH3)2 73b
88b
72b
81b
49b
H
H
H
H
(CH2)5CH3
allyl
CH2Ph(p-OMe) 79b
CH2CH2OCH3
76b
a Isolated yield using oxidant. b mCPBA. c Na2O2. d CH3CO3H.
a postdoctoral fellowship for V.G.P. The F.W.O.-Vlaanderen
is thanked for a postdoctoral fellowship to W.M.D. and
further project support.
Supporting Information Available: General experimental
procedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the K.U. Leuven for finan-
cial support, including a doctoral fellowship for S.V.P. and
OL801664V
4476
Org. Lett., Vol. 10, No. 20, 2008