Entry to Asymmetrically Substituted Pyrazines
SCHEME 1. Retrosynthetic Analysis for the Generation of Asymmetrically Substituted Pyrazines
of these strategies have surfaced as for example oxidative
addition of amino alcohols to epoxides,8 reaction of R-azido
ketones with R-amino methoximes,9 or treatment of R-nitro
ketones with R-amino ketones using octyl viologen.10 Although
noteworthy in their own right, these methods often result in
low yields and are insufficiently versatile for varying the
substituent pattern. An interesting approach is the 1,4-addition
of 1,2-diamines to 1,2-diaza-1,3-butadienes for the synthesis of
tetrasubstituted pyrazines.11 However, this procedure limits the
substitution pattern at the C5-position to a methyl group.
Another interesting report describes the treatment of a R-diazo-
â-ketoester with an R-amino acid to produce tetrasubstituted
pyrazines. However this method restricts the substitution
pattern at the C6-position to an ester group.12 The regio-
selective metalation of pyrazines is a useful alternative for the
synthesis of multisubstituted pyrazines,13 but this requires
already the pyrazine scaffold as starting material and selective
2,3,5,6-substitution of pyrazines still remains a major and
challenging problem. We will now report a novel and versatile
methodology for the synthesis of asymmetrically substituted
pyrazines.
that the pyrazinone framework offers a unique gateway for the
generation of asymmetrically tri- and tetrasubstituted pyrazines
(Scheme 1). The substituent in the C6-position of the pyrazinone
is determined by the aldehyde used during its construction,15
while the substituent at the C3-position could be easily
introduced via reaction of the imidoyl chloride moiety.16
Recently, Kappe and co-workers reported the arylation of
thioamides and dihydropyrimidine thiones using a modified
Liebeskind-Srogl protocol.17 As we envisaged the application
of this elegant protocol we planned to convert the pyrazinone
into the corresponding pyrazine-thione followed by hydrolysis
of the p-methoxybenzylether (PMB-ether). This should allow
a Liebeskind-Srogl cross-coupling at the C2-position giving
access to asymmetrically 2,3,6-trisubstituted pyrazines. More-
over pyrazine formation would render the hitherto unreactive
chlorine in C5-position susceptible to transition metal-catalyzed
substitution, paving the way for the synthesis of asymmetrically
2,3,5,6-tetrasubstituted pyrazines.
Results and Discussion
As a proof of concept the pyrazinones 1a,b were subjected
to the proposed procedure (Scheme 2). Both of the compounds
were methoxylated at the C3-position using sodium hydride
providing the required compounds 2a,b in quantitative yield.18
Treatment of 1a with Me4Sn under Stille conditions provided
the methylated compound 2c in 92% yield.16 Compound 2a was
treated with 1 mol of Lawesson’s reagent (LR) per mol of 2a
without any solvent, applying focused microwave irradiation
at a ceiling temperature of 130 °C and 150 W maximum power,
according to some literature protocols.19 However, no product
was formed even after 1 h of irradiation, and the majority of
starting material remained unreacted. On the contrary, when
toluene was added, keeping all other conditions unchanged,
compound 3a could be isolated in 56% yield along with
We have previously explored the application of 3,5-dichloro-
2(1H)-pyrazinones as attractive starting materials for the
synthesis of different heterocyclic compounds.14 We envisaged
(6) (a) Ohta, A.; Itoh, R.; Kaneko, Y.; Koike, H.; Yuasa, K. Heterocycles
1989, 29, 939. (b) Buchi, G.; Galindo, J. J. Org. Chem. 1991, 56, 2605.
(c)Heathcock, C. H.; Smith, S. C. J. Org. Chem. 1994, 59, 6828. (d)
Drogemuller, M.; Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeldt, E. Eur.
J. Org. Chem. 1998, 2811. (e) McCullough, K. J. In Rodd’s Chemistry of
Carbon Compounds, 2nd ed.; Sainsbury, M., Ed.; Elsevier: Amsterdam,
2000; Vol. 4 (Parts I-J), p 99.
(7) (a) Jeong, J. U.; Sutton, S. C.; Kim, S.; Fuchs, P. L. J. Am. Chem.
Soc. 1995, 117, 10157. (b) Kenning, D. D.; Mitchell, K. A.; Calhoun, T.
R.; Funfar, M. R.; Sattler, D. J.; Rasmussen, S. C. J. Org. Chem. 2002, 67,
9073. (c) Kotharkar, S. A.; Shinde, D. B. Chin. J. Chem. 2007, 25, 105.
(8) Taber, D. F.; De Matteo, P. W.; Taluskie, K. V. J. Org. Chem. 2007,
72, 1492.
(9) Guo, C.; Bhandaru, S.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118,
10672.
(10) Elmaaty, T. A.; Castle, L. W. Org. Lett. 2005, 7, 5529.
(11) Aparicio, D.; Attanasi, O. A.; Filippone, P.; Ignacio, R.; Lillini, S.;
Mantellini, F.; Palacios, F.; de los Santos, J. M. J. Org. Chem. 2006, 71,
5897.
(12) Matsushita, H.; Lee, S.-H.; Yoshida, K.; Clapham, B.; Koch, G.;
Zimmermann, J.; Janda, K. D. Org. Lett. 2004, 6, 4627.
(13) (a) Fruit, C.; Turck, A.; Ple´, N.; Mojovic, L.; Que´guiner, G.
Tetrahedron 2001, 57, 9429. (b) Buron, F.; Ple, N. J. Org. Chem. 2005,
70, 2616.
(14) Topics in Heterocyclic Chemistry; Van der Eycken, E., Kappe, C.
O., Eds.; Springer: Berlin, Germany, 2006; Vol. 1, p 267.
(15) Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocycl. Chem.
1983, 20, 919.
(16) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der Eycken,
E. Mol. DiVersity 2003, 7, 125.
(17) Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6, 771. (b) Prokopcova,
H.; Kappe, C. O. J. Org. Chem. 2007, 72, 4440. (c) Pisani, L.; Prokopcova,
H.; Kremsner, J. M.; Kappe, C. O. J. Comb. Chem. 2007, 9, 415.
(18) Buysens, K. J.; Vandenberghe, D. M.; Toppet, S. M.; Hoornaert,
G. J. J. Chem. Soc., Perkin Trans. 1 1996, 231.
(19) (a) Varma, R. S.; Kumar, R. D. Org. Lett. 1999, 1, 697. (b) Jesberger,
M.; Davis, T. P.; Barner, L. Synthesis 2003, 13, 2003. (c) Ozturk, T.; Ertas,
E.; Mert, O. Chem. ReV. 2007, 107, 5210.
J. Org. Chem, Vol. 73, No. 6, 2008 2383