A new method for the synthesis of symmetrical disubstituted pyrazines

Article abstract of DOI:10.1002/jhet.1748

Through the self-condensation of α-amino aldehydes, the synthesis of symmetrical disubstituted pyrazines was achieved in a three-step one-pot reaction. The α-amino aldehydes were easily obtained by treating methyl esters of natural α-amino acids with diisobutylaluminium hydride.

Full text of DOI:10.1002/jhet.1748

982
A New Method for the Synthesis of Symmetrical Disubstituted Pyrazines
Vol 50
*
Nora Rojas, Yvonne Grillasca, Alejandrina Acosta, Irene Audelo, and Gustavo García de la Mora
Departamento de Química Orgánica, DEP, Facultad de Química, Universidad Nacional Autónoma
de México, Ciudad Universitaria 04510 México Distrito Federal, México
*
E-mail: garciadm@servidor.unam.mx
Received January 20, 2012
DOI 10.1002/jhet.1748
Published online 2 July 2013 in Wiley Online Library (wileyonlinelibrary.com).
Through the self-condensation of a-amino aldehydes, the synthesis of symmetrical
disubstituted pyrazines was achieved in a three-step one-pot reaction. The a-amino
aldehydes were easily obtained by treating methyl esters of natural a-amino acids with
diisobutylaluminium hydride.
J. Heterocyclic Chem., 50, 982 (2013).
INTRODUCTION
was our goal, the reaction mixture was worked-up as indi-
cated in the experimental; however, when an oxidation agent
as oxone was added, the reaction mixture was cleaner and
easier to work up to produce pyrazines [15b] (Scheme 1).
Although we attempted to isolate the formed a-amino
aldehyde precursors, the auto condensation occurs spontane-
ously, leading to dehydropyrazines undergoing consequent
oxidation to the corresponding pyrazines 1–6 (Fig. 1).
The three-step one-pot reaction yielded about 50%
overall yield. In Table 1, we present the yield and the
physical properties.
Pyrazines are essential components for the flavor and odor
of foods and some wines such as Cabernet Sauvignon [1–3]
as well as the pheromones of some insect species [4]. In me-
dicinal chemistry, pyrazines are important intermediates [5].
In nature, pyrazines are enzymatically produced through
amino acids, and they are common units of a great variety
of natural marine products with cytotoxic and antitumor
properties [6–8]. In the production of potassium Clavulanate,
an important b-lactamases inhibitor is necessary to account
for standards of some pyrazines to determine and prove the
purity level of the pharmaceutical drug; as a consequence,
the synthesis of these heterocycles, therefore, is required [9].
There are several methods for the synthesis of pyrazines
in the laboratory, such as the condensation of 1,2-diamines
with vicinal dicarbonyl compounds followed by oxidation
[10,11a,b] and the condensation of a-amino carbonyls
[12,13]. The main problem with those methods consists
in the necessary chemical steps to obtain the starting
materials and mainly a-amino aldehydes [14].
1
The structures were easily characterized by H NMR,
13C NMR, as well as mass spectrometry. As an example,
the 2,5-dibenzylpyrazine 1 shows the signal for the
aromatic protons of the heterocycle in 1H NMR at
8.38ppm and the signals for carbons 3,6 and carbons 2,5
in 13C NMR at 142.8 and 153.6 ppm, respectively. All other
pyrazines give very similar spectra as shown in Table 2.
CONCLUSIONS
It is well known that the diisobutylaluminium hydride
(DIBAL-H) is a very good reducing agent to transform all
kinds of carbonyl groups to the corresponding alcohol, but
at low temperatures, however, esters are cleanly reduced to
the corresponding aldehydes used for our transformation [15].
We are presenting a short and easy method for the synthe-
sis of symmetrical disubstituted pyrazines. The three-step
one-pot reaction gave more than 50% overall yield, which
represents an average of 80% yield for each step. This
method can be applied to almost any a-amino ester.
EXPERIMENTAL
RESULTS AND DISCUSSION
General.
All reagents were obtained from commercial
Herein, we are reporting a straightforward method
to obtain a-amino aldehydes by the DIBAL-H reduction of
a-amino methyl esters from natural a-amino acids [16].
The reduction occurred very rapidly, and several products
were observed by TLC. Because the formation of pyrazines
sources. Silica gel plates (0.25 mm, 60F254) were used for
analytical TLC. Chromatographic purifications were performed
using silica gel (60 mm, 40–63 mesh) according to the method of
1
Still [17]. Yields are reported for isolated compounds. H NMR
and 13C NMR spectra were recorded using a Varian UNITY
© 2013 HeteroCorporation

July 2013
A New Method for the Synthesis of Symmetrical Disubstituted Pyrazines
983
Scheme 1
Figure 1. Chemical structures of pyrazines.
Table 1
Synthesis of symmetrical disubstituted pyrazines (Scheme 1).
General procedure for the synthesis of 2,5-bis disubstituted
pyrazines (1–6). The a-amino acid methyl ester (0.1 g,
0.6 mmol) and toluene (10 mL) were added to a three-neck flask
under nitrogen atmosphere and a magnetic stirring bar. The
solution was cooled to À78ꢀC, and then, a 1.5 M solution of
DIBAL-H in toluene (6 mmol) was added. When the reaction
was completed (2 h), the reaction mixture was treated with a
mixture of AcOEt/H2O (9:1) 10 mL and stirred for an additional
1 h at room temperature. The suspension was filtered through
celite, and the solution was washed with a saturated aqueous
solution of NaCl (2 Â 5 mL), dried over Na2SO4, and the
solvent was removed under reduced pressure. The residue was
purified by flash column chromatography.
Compound
Yield (%)
53
Features
2,5-Dibenzylpyrazine 1
Colorleess solid
mp 51–52ꢀC
Yellow oil
Yellow oil
Yellow oil
2,5-Diisopropylpyrazine 2
2,5-Di-sec-butylpyrazine 3
2,5-Bis(2-(methylthio)ethyl)
pyrazine 4
52
53
50
2,5-Bis((1H-indol-3-yl)methyl)
pyrazine 5
2,5-Bis(4-hydroxybenzyl)pyrazine 6
50
49
Reddish solid mp
160–162ꢀC
White solid mp
210–212ꢀC
2,5-Dibenzylpyrazine (1).
This compound was obtained
from phenylalanine methyl ester as a colorless solid; 0.038 g
1
(53%), mp 51–52ꢀC; H NMR (deuteriochloroform): d 4.12 (s,
4H, CH2), 7.21–7.33 (m, 10H, phenyl), 8.38 (s, 2H pyrazine);
13C NMR (deuteriochloroform): 41.5 (CH2), 126.7, 128.7,
129.0, 138.3 (CH and C phenyl), 143.7 (CH, pyrazine), 153.6
(C, pyrazine); ms: m/z 260 (55), 259 (100), 115 (35), 91 (23),
65 (8). Anal. Calcd for C18H16N2: C, 83.04; H, 6.19; N, 10.76.
Found: C, 82.87; H, 6.16; N, 10.80.
Table 2
1H NMR and 13C NMR data for pyrazines (ppm).
1H NMR 13C NMR 13C NMR
Compound
CH
CH
quaternary
2,5-Diisopropylpyrazine (2).
This compound was obtained
2,5-Dibenzylpyrazine 1
2,5-Diisopropylpyrazine 2
2,5-Di-sec-butylpyrazine 3
2,5-Bis(2-(methylthio)
ethyl)pyrazine 4
2,5-Bis((1H-indol-3-yl)
methyl)pyrazine 5
2,5-Bis(4-hydroxybenzyl)
pyrazine 6
8.38
8.39
8.37
8.42
142.8
141.8
142.8
144.0
153.6
159.3
158.6
153.3
from valine methyl ester as an oil; 0.032 g (52%),1H NMR
(deuteriochloroform): d 1.32 (d, 12H, CH3, J= 6 Hz), 3.08
(sep, 2H, CH, J= 6.9 Hz), 8.39 (s, 2H, pyrazine); 13C NMR
(deuteriochloroform): 22.2 (CH3), 33.5 (CH), 141.8 (CH, pyrazine),
159.3 (C, pyrazine); ms: m/z 164 (30), 149 (100), 136 (35).
8.45
8.36
143.0
143.3
153.8
154.0
2,5-Di-sec-butylpyrazine (3). This compound was obtained
from isoleucine methyl ester as an oil; 0.035 g (50%),1H NMR
(deuteriochloroform): d 0.85 (t, 6H, CH3, J = 7.4 Hz), 1.31 (d,
6H, CH3, J = 6.9 Hz), 1.82 and 1.61 (m, 4H, CH2), 2.8 (sex, 2H,
CH, J = 6.9 Hz), 8.37 (s, 2H, pyrazine); 13C NMR
(deuteriochloroform): 12.1 (CH3), 20.0 (CH3), 29.7 (CH2), 40.7
(CH), 142.8 (CH, pyrazine), 158.6 (C, pyrazine); HRMS (esi:
m/z) Calcd for C12H20N2 192.1621. Found: 192.1526.
INOVA 300 MHz spectrometer in a solution of CDCl3, DMSO-
d6, and CD3OD. Chemical shifts are reported in parts per
million (ppm d), relative internal Me4Si (d 0.00) for 1H, and
internal chloroform (d 77.0) and DMSO (d 39.5) for 13C;
coupling constants are reported in Hertz (Hz). Mass spectra
were obtained on a Thermo-Electron spectrometer. Elemental
analysis was obtained on a Perkin Elmer PE2400 instrument.
2,5-Bis(2-(methylthio)ethyl))pyrazine (4).
This compound
was obtained from methionine methyl ester as an oil; 0.035 g
(50%),1H NMR (deuteriochloroform): d 2.13 (s, 6H, CH3), 2.91
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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N. Rojas, Y. Grillasca, A. Acosta, I. Audelo, and G. G. de la Mora
Vol 50
REFERENCES AND NOTES
(t, 4H, CH2, J= 6.0 Hz), 3.08 (t, 4H, CH2, J= 6.0 Hz), 8.42 (s, 2H,
pyrazine); 13C NMR (deuteriochloroform): 15.7 (CH3), 33.6
(CH2), 34.9 (CH2), 144.0 (CH, pyrazine), 153.3 (C, pyrazine).
HRMS (esi: m/z) Calcd for C10H16N2S2 228.0749. Found:
228.0735.
2,5-Bis((1H-indol-3-yl)methyl)pyrazine (5). This compound
was obtained from tryptophan methyl ester as a reddish solid;
0.038g (50%), mp 160–162ꢀC; 1H NMR (DMSO-d6) 4.16 (s,
4H, CH2), 7.46–6.89 (m, 10H, indole), 8.45 (s, 2H, pyrazine),
10.90 (s, 4H, NH-indole); 13C NMR (DMSO-d6) 30.9 (CH2),
136.3–111.5 (indole), 143.0 (CH, pyrazine), 153.8 (C, pyrazine);
HRMS (esi: m/z) Calcd for C22H18N4 338.1526. Found:
338.1512.
[1] Shu, C. K. J Agric Food Chem 1998, 46, 1515.
[2] Musada, H.; Yoshida, M.; Shibamoto, T. J Agric Food Chem
1981, 29, 944.
[3] Amrani-Hemaimi, M.; Cerny, C.; Fay, L. B. J Agric Food
Chem 1995, 43, 2818.
[4] Elmaaty, T. A.; Castle, L. W. Org Lett 2005, 7, 5529.
[5] (a) Aparicio, D.; Attanas, O. A.; Filippone, P.; Ignacio, R.; Lil-
lini, S.; Mantellini, F.; Palacios, F.; De los Santos, J.M. J Org Chem 2006,
71, 5897.; (b) Mosrin, M.; Bresser, T.; Knochel, P. Org Lett 2009, 11, 3406.
[6] Betancor, C.; Freire, R.; Perez-Martín, I.; Prange, T.; Suárez,
E. Tetrahedron 2005, 61, 2803.
[7] Li, W.; Fuchs, P. L. Org Lett 2003, 5, 2849.; (b) Morsin, M.;
Bresser, T.; Knochel, P. Org Lett 2009, 11, 3406.
2,5-Bis(4-hydroxybenzyl)pyrazine (6). This compound was
obtained from tyrosine methyl ester as a white solid; 0.036 g
(49%), mp 210–210ꢀC; 1H NMR (CD3OD): d 4.03 (s, 4H,
CH2), 7.06 (d, 4H, phenyl, J = 8.7 Hz), 6.71 (d, 4H, phenyl,
J = 8.7), 8.36 (s, 2H, pyrazine); 13C NMR (DMSO-d6) 39.6
(CH2), 129.9, 115.4 (CH, phenyl), 129.2 (C, phenyl), 143.3
(CH, pyrazine), 154.0 (C, pyrazine), 155.9 (C, phenyl); ms: m/z
292 (100), 294 (2), 293 (20), 291 (95), 131 (12), 107 (29), 77
(2); HRMS (esi: m/z) Calcd for C18H16O2N2 292.1206. Found:
292.1198.
[8] LaCour, T. G.; Guo, C.; Boyd, M. R.; Fuchs, P. L. Org Lett
2000, 2, 33.
[9] (a) European Pharmacopoeia, 7ꢀ Ed. Vol. II 2011, 2764.;
(b) Brethaver, S.; Held, M.; Panke, S. J Pharm Sci 2008, 97, 3451.
[10] Ohta, A.; Masano, S.; Iwakura, S.; Tamura, A.; Watahiki, H.;
Tsutsui, M.; Akita, Y.; Watanabe, T. J Heterocycl Chem 1982, 19, 465.
[11] a) Hou, J.-T.; Liu, Y.-H.; Zhang, Z.-H. J Heterocycl Chem
2010, 47, 703.; b) Parasa, H.; Gogoi, P.; Konwar, D. Synth Commun
2007, 37, 3447.
[12] Iida, H.; Hayashida, K.; Yamada, M. Synth Commun 1973, 3, 225.
[13] Newbold, G. T.; Spring, F. S. J Chem Soc 1947, 373.
[14] Katritzky, A.; Rees, C. W. Comprehensive Heterocyclic
Chemistry Ed.; Pergamon Press; Oxford, 1984; Vol. 3, pp 157–197.
[15] (a) Szantay, C.; Toke, L.; Kolonits, P. J Org Chem 1996, 31,
1447.; (b) Kennedy, R. J.; Stock, A. M. J Org Chem 1960, 25, 1901.
[16] Bodanszky M.; Bodanszky A. The Practice of Peptide
Synthesis; Springer Verlag; New York, 1994; pp. 29.
Acknowledgments. The authors thank Dr. Joaquín Tamariz for his
helpful insights. We are grateful to Gutierrez M., Duarte G., and
Guzmán M. for excellent technical assistance in NMR, IR, and
MS analysis.
[17] Still, W. C.; Kahn, M.; Mitra, A. J. J Org Chem 1978, 43, 2923.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet