Facile regiocontrolled synthesis of trialkyl-substituted pyrazines

Article abstract of DOI:10.1021/ol0523751

(Chemical Equation Presented) α-Nitro ketones can be transformed selectively into trialkyl-substituted pyrazines via reaction with α-amino ketones using octyl viologen as an electron-transfer reagent. The new synthetic method, and the optimal reaction conditions that allow for the regiochemical control, are described.

Full text of DOI:10.1021/ol0523751

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5529-5530
Facile Regiocontrolled Synthesis of
Trialkyl-Substituted Pyrazines
Tarek Abou Elmaaty and Lyle W. Castle*
Department of Chemistry, Idaho State UniVersity, Campus Box 8023,
Pocatello, Idaho 83209
castlyle@isu.edu
Received September 30, 2005
ABSTRACT
r
-Nitro ketones can be transformed selectively into trialkyl-substituted pyrazines via reaction with
r
-amino ketones using octyl viologen as
an electron-transfer reagent. The new synthetic method, and the optimal reaction conditions that allow for the regiochemical control, are
described.
Alkylpyrazines have been known as flavor components in
foods,1 as versatile synthetic intermediates,2 and as phero-
mones in various insect species.3 From the perspective of
chemical ecology, which we are interested in, alkylpyrazines
have been recognized as the components of trail laying4 or
alarm pheromones5,6 in various species of ants.
Substituted alkylpyrazines are challenging targets, and
previous methods developed to synthesize this class of
compounds regioselectively were unsatisfactory for one
reason or the other. To date, the methods used to overcome
this problem either use thermal electrocyclization-aroma-
tization, which requires the use of specialist high-temperature
short contact pryolysis equipment,7 or expensive zirconium-
mediated complexes.8 Sato9 et al. developed a method where
2,5-dimethylpyrazines are alkylated yielding unsymmetrical
trialkylpyrizines; however, this method limits the substitution
at the 2,5 position to methyl groups.
The synthetic strategy of this method is based on reacting
R-nitro ketone with R-amino ketone protected as the hydro-
chloride salt under reducing conditions, where octylviologen
is used as the reducing agent. The use of classic reducing
agents to reduce the nitro group of the nitro ketone such as
zinc, tin, or iron in the presence of an acid gave a mixture
of regioisomers, and in some cases, the reaction stopped at
intermediate stage, yielding hydrazines. Octylviologen was
chosen on the basis of the work by Hu,10 where octylviologen
was used to reduce a series of substituted nitrobenzenes to
substituted anilines.
Alkylpyrazines are produced chiefly by self-condensation
of R-amino carbonyl compounds and the combination of
R-diketones with vicinal diamines followed by dehydrogena-
tion.2a Those methods failed in the preparation of unsym-
metrical substituted pyrazines because they afford mixtures
of regioisomers.
* To whom correspondence should be addressed. Tel: (208) 282-4006.
Fax: (208) 282-4373.
(1) (b) Maga, J. A.Pyrazine in Foods. An Update; Furia, T. E., Ed.; CRC
Critical Reviews In Food Sciences And Nutrition: Boca Raton, FL, 1982;
Vol. 16, pp 1-48. (b) Brophy, J. J.; Cavill, G. W. K. Heterocycles 1980,
14, 477. (c) Seeman, J. I.; Ennis, D. M.; Secor, H. V.; Claweson, L.; Palen,
J. Chem. Senses 1989, 14, 395.
(2) (a) Barlin, G. B. The Chemistry of Heterocyclic Compounds; Wiley:
New York, 1982; Vol. 41. (b) Hasegawa, M.; Katsumata, T.; Ito, Y.; Saigo,
K.; Iitaka, Y. Macromolecules 1988, 21, 3134.
(3) (a) Fales, H. M.; Blum, M. S.; Southwick, E. W.; William, D. L.;
Roller, P. P.; Don, A. W.Tetrahedron 1988, 44, 5045. (b) Tecle, B.; Sun,
C. M.; Borphy, J. J.; Toia, R. F. J. Chem. Ecol 1987, 13, 1811. (c) Wheeler,
J. W.; Avery, J.; Olubajo, O.; Shamim, M. T.; Storm, C. B. Tetrahedron
1982, 38, 1939.
(6) Oldham, N. J.; Morgan, E. D. J. Chem. Soc., Perkin Trans. 1 1993,
2713.
(4) Cross, J. H.; Byler, R. C.; Ravid, U.; Silverstein, R. M.; Robinson,
S. W.; Baker, P. M.; DeOliveira, J. S.; Jutsum, A. R.; Cherrett, J. M. J.
Chem. Ecol. 1979, 5, 187.
(7) Buchi, G.; Galindo, J. J. Org. Chem. 1991, 56, 2605.
(8) Guram, A. S.; Jordan, R. F.J. Org. Chem. 1992, 57, 5994.
(9) Sato, N.; Matsuura, T. J. Chem. Soc., Perkin Trans. 1 1996, 2345.
(10) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 919.
(5) Brown, W. V.; Moore, B. P. Insect Biochem. 1979, 9, 451.
10.1021/ol0523751 CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/01/2005

In this method, the R-nitro ketones11 (4) are reacted with
suitable R-amino ketones12 (5) in the presence of octyl-
viologen and hydrogen sulfite (see Scheme 1), where
Unequivocal proof of structure for 6a was accomplished
through the concerted interpretation of the 1H, 13C, gHMQC,
and gHMBC NMR spectra. The three key long-range
correlations that unequivocally prove the regiochemistry are
those of H-6, which resonates at δ 8.19, the 3-methyl protons
resonating at δ 2.53, and the 1′ protons of the butyl group
resonating at δ 2.77 with the resonance at δ 152.93
corresponding to C-2 (see Table 1).
Scheme 1. Synthesis of Trialkylpyrazines 6a-d
Table 1. 1H and 13C NMR Assignments and GHMBC
Correlations for 6a
position
1H (δ)
gHMBC correlations
13C (δ)
2
3
5
6
152.93
150.98
149.92
141.12
21.83
8.19
2.53
149.92, 152.93
150.98, 152.93
3-CH3
5-CH3
2.49
149.92, 141.12
21.24
1′
2′
3′
4′
5′
6′
2.77
152.93, 150.98, 29.92
a
a
a
34.83
1.30 (m)
1.30 (m)
1.30 (m)
1.30 (m)
0.88
29.49b
28.65b
31.91b
22.80
a
22.80, 31.91
14.29
octylviologen serves as the electron-transfer agent. Addition
of the R-amino ketone along with the hydrogen sulfite
solution to that of the R-nitro ketone and octylviologen
solution using a syringe pump ensures that only one
regioisomer is formed. Optimization, by systematically
changing addition times and rates, revealed that simultaneous
addition over 25 min affords a much cleaner product.
However, it also revealed that addition of the amino ketone
must begin and end 1 min before that of the hydrogen sulfite/
potassium carbonate mixture in order to obtain a pure
product. Delaying addition of the amino ketone by 1 min
ensures that the amino ketone is always in excess, thus
preventing reduction and self-condensation of the nitroketone,
which would result in a mixture of alkylpyrazines. The use
of the syringe pump, which allows for the simultaneous
addition of precise quantities of both the R-amino ketone
and the hydrogen sulfite solutions over precisely controlled
times, is crucial to this method.
a Correlations are ambiguous due to chemical shift overlap. b These
chemical shift assignments are interchangeable; the 13C chemical shift for
4′ was assigned on the basis of correlation with 6′ protons.
In conclusion, a new one-pot synthesis of trialkylpyrazines
using readily available starting materials has been developed
and proceeds with complete control of regioselectivity. Also,
the regiochemistry has been unequivocally established using
2D-NMR methods.
Acknowledgment. We thank the NSF for funds for the
purchase of the NMR (Grant No. 9980793) and Idaho State
University and the Fulbright commission of Egypt for
providing expenses for T.A.E.
Supporting Information Available: Selected spectral
data including H NMR, 13C NMR, gCOSY, gHMBC, and
gHMQC for the synthesized compounds. Detailed experi-
mental procedures and spectral/physical data are also in-
cluded. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
(11) The R-amino ketones were prepared by a modified chromate
oxidation procedure that minimized reaction time and is scaleable: Elmaaty,
T. A.; Castle, L. W. Molecules 2005, in press.
(12) Yinglin, H.; Hongwen, H. Synthesis 1990, 615.
OL0523751
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