Synthesis of symmetrical and unsymmetrical pyrazines

Article abstract of DOI:10.1021/jo061935m

(Chemical Equation Presented) Opening of representative epoxides with 1,2-amino alcohols delivered the amino diols. The product amino diols were then oxidized under Swern conditions. The amino diketones so prepared were not isolated, but were condensed directly with hydroxylamine to give the substituted pyrazines.

Full text of DOI:10.1021/jo061935m

Epoxide Opening. It is important to note that the hydrogen-
bonded amino alcohol is much less nucleophilic, perhaps due
to intramolecular hydrogen bonding, than is an isolated amine.
We initially had difficulty finding conditions for the epoxide
opening. We heated cyclohexene oxide and 2-amino-3-phenyl-
1-propanol under solvent-free conditions, but after 7 days only
starting materials were visible by TLC. While LiClO4 and BF3·
OEt2 failed to activate the epoxide, the addition of a catalytic
amount of Yb(OTf)3 to the reaction6 facilitated an easy
transformation to the amino diol. This is thought to be due to
the oxophilicity of the early lanthanides. Further investigations
later showed that identical loading of LiBr7 under solvent-free
conditions effected an even faster transformation to the amino
diol.
Synthesis of Symmetrical and Unsymmetrical
Pyrazines
Douglass F. Taber,* Peter W. DeMatteo,
and Karen V. Taluskie
Department of Chemistry and Biochemistry, UniVersity of
Delaware, Newark, Delaware 19716
taberdf@udel.edu
ReceiVed September 19, 2006
When an activated epoxide such as 1b was used (entries 3
and 4, Table 1), additions were carried out without catalyst.
Indeed, if catalysts were added, an increased amount of the
undesired regioisomer was observed.
Oxidation and Pyrazine Formation. We carried out our
initial investigations with 2,2′-bis(cyclohexanol)amine (3e). This
amino diol provided a fine platform for the elucidation of
oxidation strategies. Amino diol 3e was readily prepared by
Taguchi’s procedure,8 combining cyclohexene oxide and aque-
ous ammonia.
Opening of representative epoxides with 1,2-amino alcohols
delivered the amino diols. The product amino diols were then
oxidized under Swern conditions. The amino diketones so
prepared were not isolated, but were condensed directly with
hydroxylamine to give the substituted pyrazines.
The Jones reagent,9a Dess-Martin periodinane,9b and the
Swern reaction with trifluoroacetic anhydride9c each failed to
produce the desired amino diketone. The Swern reaction utilizing
oxalyl chloride10 gave some promising results, but incomplete
conversion of amino diols (indicated by the presence of amino
diol by TLC after workup) proved to be troublesome. When
the oxidations were performed at or near the upper temperature
limit of -10 °C with an excess of oxidant, the reactions went
to completion.
The organic extract from the workup of the oxidation was
dried over Na2SO4, then directly added to a refluxing solution
of ethanolic NH2OH‚HCl. The reaction flask was fitted with
an air condenser that allowed the CH2Cl2 to distill out over the
course of the cyclization. The brown mixture so produced could
then be subjected to acid/base extraction, or evaporated directly
onto silica gel for chromatography, to give the product pyrazines
(Table 1).
Pyrazines are important as intermediates for fragrances,1
pharmaceuticals,2 and agricultural chemicals.3 Remarkably,
given the importance of other aromatic heterocycles in medicinal
chemistry, there are fewer than 100 trialkyl-substituted pyrazines
in the SciFinder database. This is due, not to lack of interest on
the part of the pharmaceutical community, but to limited
methods for their preparation.4
In the course of other work, we had occasion to briefly
explore the coupling of epoxides with 1,2-aminodiols. The
coupled products could then be oxidized under Swern conditions
and condensed with NH2OH to give pyrazines.5 Herein we report
our results.
(1) Maga, J. A.; Sizer, C. E. J. Agric. Food Chem. 1973, 21, 22.
(2) (a) Nie, S. Q.; Kwan, C. Y.; Epand, R. M. Eur. J. Pharmacol. Mol.
Pharmacol. Sect. 1993, 244, 15. (b) Palacios, F.; Retana, A. M. O.; Munain,
R. L. Org. Lett. 2002, 14, 2405. (c) McCullough, K. L. In Heterocyclic
Compounds. Rodd’s Chemistry of Carbon Compounds, 2nd ed., 2nd
supplement; Sainsbury, M., Ed.; Elsevier: Amsterdam, The Netherlands,
2000; Vol. 4, Parts I-J, p 99. (d) Urban, S.; Hickford, S. J. H.; Blunt,
J. W.; Munro, M. H. G. Curr. Org. Chem. 2000, 4, 765. (e) Ohta, A.;
Aoyagi, Y. ReV. Het. Chem. 1998, 18, 141. (f) Sato, N. I. ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Boulton, A. J.,
Eds.; Elsevier: Oxford, UK, 1996; Vol. 6, p 233.
(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. (d) Brown, W. V.; Moore, B. P. Insect Biochem. 1979, 9,
451. (e) 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. (f) Oldham, N. J.; Morgan, E. D. J. Chem.
Soc., Perkin Trans. 1 1993, 2713.
(4) For leading references to methods for the preparation of alkyl-
substituted pyrazines, see: (a) Ohta, A.; Itoh, R.; Kaneko, Y.; Koike, H.;
Yuasa, K. Heterocycles 1989, 29, 939. (b) Heathcock, C. H.; Smith, S. C.
J. Org. Chem. 1994, 59, 6828. (c) Guo, C.; Bhandaru, S.; Fuchs, P. L.
J. Am. Chem. Soc. 1996, 118, 10672. (d) Drogemuller, M.; Flessner, T.;
Jautelat, R.; Scholz, U.; Winterfeldt, E. Eur. J. Org. Chem. 1998, 2811. (e)
Elmaaty, T. A.; Castle, L. W. Org. Lett. 2005, 7, 5529. (f) Buchi, G.;
Galindo, J. J. Org. Chem. 1991, 56, 2605.
Alternatively, it was not necessary to purify the intermediate
amino diol. The amino alcohol 2a was coupled with the epoxide
1a. The crude amino diol 3a was carried directly to Swern
oxidation, followed by condensation with NH2OH‚HCl. The
overall yield of the pyrazine 4a from 2a was slightly improved
(10.1% vs 7.8%) and the procedure was easily scaled.
(6) Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M.
Tetrahedron Lett. 1994, 35, 433.
(7) Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem.
2004, 3597.
(8) Taguchi, T.; Hayashida, K. J. Am. Chem. Soc. 1958, 80, 2522.
(9) (a) Mueller, R. H.; DiPardo, R. M. J. Org. Chem. 1977, 42, 3210.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Omura,
K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976, 41, 957.
(10) Mancuso, A. J.; Huang, S.; Swern, D. J. Org. Chem. 1978, 43, 2480.
(11) Vitzthum, O. G.; Werkhoff, P. J. Agric. Food Chem. 1975, 23, 510.
(12) Suzuki, H.; Kawaguchi, T.; Takaoka, K. Bull. Chem. Soc. Jpn. 1986,
59, 665.
(13) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d”,
from methylene and quaternary carbons as “u”.
(5) Higasio, Y. S.; Shoji, T. Appl. Catal., A 2001, 221, 197.
10.1021/jo061935m CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/24/2007
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J. Org. Chem. 2007, 72, 1492-1494

TABLE 1. Preparation of Pyrazines
(m, 2H), 1.69 (m, 2H), 1.94 (m, 2H), 2.38 (m, 1H), 2.60 (m, 1H),
3.23 (m, 1H), 3.48 (m, 2H); 13C NMR (CD3OD)13 δ d 10.12, 11.03,
58.36, 59.06, 61.88, 62.32, 74.72, 75.02; u 24.13, 25.62, 25.79,
26.38, 31.65, 32.00, 35.21, 35.30, 62.68, 64.81; HRMS calcd for
C10H21NNaO2 210.147, obsd 210.147 [M + Na].
Pyrazine 4b. Oxalyl chloride (2.13 g, 14.0 mmol) diluted to 10
mL with CH2Cl2 was added to a 100-mL round-bottomed flask in
a -40 °C bath. To this was added DMSO (1.31 g, 16.9 mmol,
diluted to 10 mL with CH2Cl2) over the course of 1 min (gas
evolution). Amino diols 3b (200 mg, 1.07 mmol, in 10 mL of CH2-
Cl2) were then added. The reaction was allowed to proceed with
the temperature being kept between -20 and -40 °C. After 2 h, 5
mL of triethylamine (35.8 mmol) was added (exotherm) to give a
turbid yellow solution. The mixture was allowed to warm to 0 °C
over the course of 30 min, and the mixture was then partitioned
between water and CH2Cl2. The combined organic extract was dried
over Na2SO4. TLC indicated the absence of amino diols 3b. The
CH2Cl2 solution was decanted into a 250-mL round-bottomed flask,
to which was added 20 mL of absolute EtOH and NH2OH‚HCl
(88 mg, 1.27 mmol). The round-bottomed flask was fitted with a
distillation apparatus and the mixture was heated until the bulk of
the CH2Cl2 had distilled out. The mixture was then kept at reflux
for 2 h with an air condenser. The brown mixture was then
concentrated onto flash silica gel and chromatographed on flash
silica gel with a MTBE/PE gradient to give 88 mg of crude pyrazine
4b. This was then further purified via TLC mesh chromatography
(1:1 MTBE/PE) to give 25 mg of analytically pure pyrazine 4b as
a pale yellow oil, 15% yield overall from 3b. TLC Rf 0.43 (MTBE);
1
IR 2937, 1651, 1463, and 1386 cm-1; H NMR (CD3OD) δ 1.26
(t, J ) 7.6 Hz, 3H), 1.88 (m, 4H), 2.73 (q, J ) 7.6 Hz, 2H), 2.89
(m, 4H), 8.16 (s, 1H); 13C NMR (CD3OD) δ d 14.03, 140.44; u 22.69,
28.46, 31.55, 31.97, 149.95, 151.84, 155.29; HRMS calcd for
C10H15N2 163.124, obsd 163.123 [M+].
Telescoped Procedure: Pyrazine 4a. In a 25-mL sealed tube,
S-(-)-2-amino-3-phenyl-1-propanol (2a) (3.0 g, 20 mmol) was
combined with cyclohexene oxide (1a) (3.9 g, 40 mmol). LiBr (50
mg) was added and the flask was sealed. The reaction was
maintained at 80 °C for 4 days, at which point the mixture was
cooled to room temperature. NMR of the reaction mixture indicated
complete consumption of 2a. A 2.0-g portion of the reaction mixture
was dissolved into 15 mL of CH2Cl2 and carried on to the oxidation/
cyclization protocol.
Oxalyl chloride (6.87 mL, 80 mmol) was added to 100 mL of
CH2Cl2 in a 250-mL round-bottomed flask at -78 °C. DMSO
(7 mL, 90 mmol diluted to 20 mL with CH2Cl2) was added over
the course of 3 min with gas evolution and apparent exotherm.
The crude reaction mixture 3a (2.0 g in 15 mL of CH2Cl2) was
then added over the course of a minute. The reaction was allowed
to proceed with the temperature being kept between -20 and
-40 °C. After 2 h, the reaction was taken back to -78 °C and
triethylamine (20 mL, 143 mmol) was then added with accompany-
ing exotherm to give a turbid yellow solution. The mixture was
kept at -78 °C for 15 min, then allowed to warm to 0 °C over the
course of 30 min, at which point the mixture was then partitioned
between 75 mL of a 1:1:1 (saturated NaCl, H2O, 15% NaOH)
solution and CH2Cl2. The combined organic extract was dried over
Na2SO4. TLC indicated the absence of amino diols 3a. The CH2-
Cl2 solution was decanted into a 250-mL round-bottomed flask, to
which was added 25 mL of absolute EtOH and NH2OH‚HCl (880
mg, 12.7 mmol). The round-bottomed flask was fitted with a
distillation apparatus and the mixture was heated until the bulk of
the CH2Cl2 had distilled out. The mixture was then kept at reflux
overnight with an air condenser. The resulting black solution was
then concentrated onto flash silica gel and filtered through a plug
of flash silica gel with 100 mL of MTBE to give 240 mg of crude
pyrazine 4a. This was then subjected to kugelrohr distillation
(130 °C, 200 mbar) and the bottoms were chromatographed with a
TLC mesh column (10-40% MTBE/PE, 50 mL/10% increment)
a Reference 11. b Reference 8. c Reference 12.
In conclusion, we have developed what appears to be a
versatile route to symmetrical and unsymmetrical pyrazines. It
is particularly noteworthy that the Swern oxidation of the
aminodiols can be carried out without protection of the basic
amines.
Experimental Section
Amino Diols 3b. In a 25-mL round-bottomed flask, (R)-(-)-2-
amino-1-butanol (2b) (2.00 g, 23.5 mmol) was added to cyclohex-
ene oxide (1a) (2.31 g, 23.6 mmol). To this was then added LiBr
(102 mg, 5 mol %). The flask was sealed and the reaction was
heated to 70 °C for 2 days, and then subjected to bulb-to-bulb
distillation (100 °C, 2 mmHg) to remove unreacted amino alcohol
and epoxide. The residue was chromatographed over basic alumina
with a gradient of acetone in CH2Cl2 (0-60% in 20% increments)
that had been saturated with NH4OH. The eluent was dried over
Na2SO4, filtered with CH2Cl2, and concentrated to give the
diastereomeric mixture of amino diols 3b (3.12 g, 70% yield) as a
viscous, pale yellow oil. TLC: Rf 0.43 (5:44:1 MeOH/CH2Cl2/NH4-
OH); IR (film) 3364, 2931, 2858, and 1450 cm-1; 1H NMR (CD3-
OD) δ 0.93 (t, J ) 7.41 Hz, 3H), 1.11 (m, 1H), 1.27 (m, 3H), 1.52
J. Org. Chem, Vol. 72, No. 4, 2007 1493

to give 103 mg of pyrazine 4a as a pale yellow oil, 10.1% yield
overall from the starting amino alcohol 2a.
Acknowledgment. This work was supported by the National
Institutes of Health (GM 42056). We thank John Dykins of the
University of Delaware for high-resolution mass spectroscopic
analysis.
TLC Rf 0.56 (MTBE); IR (film) 2936, 1454, 1387, and 1126
1
cm-1; H NMR (CDCl3) δ 1.73 (m, 4H), 2.75 (m, 4H), 3.93 (s,
Supporting Information Available: General experimental
procedures, experimental details, and spectra for all new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
2H), 7.10 (m, 5H), 7.99 (s, 1H); 13C NMR (CDCl3) δ d 126.39,
128.47, 128.64, 128.76, 141.08; u 22.43, 29.52, 31.34, 31.78, 41.51,
138.52, 150.17, 151.95, 152.59; HRMS calcd for C15H15N2 223.124,
obsd 223.124 [M - H].
JO061935M
1494 J. Org. Chem., Vol. 72, No. 4, 2007