A simple synthesis of salicylamide and 2,5-diphenylpyrazine

Article abstract of DOI:10.1007/s11164-013-1466-8

The compound I (C₇H₇NO₂, salicylamide) and the compound II (C₁₆H₁₂N₂, 2,5-diphenylpyrazine) were both obtained as the by-product of the onepot synthesis of oxazolinyl zinc complexes from the reaction of 2-hydroxybenzonitrile and 3-(N-ethyl-N-phenyl)-propanenitrile with D-phenylalaninol, which was catalyzed by 235 and 83.1 mol% zinc dichloride. Their structures were determined by X-ray diffraction, IR ,and elemental analysis.

Full text of DOI:10.1007/s11164-013-1466-8

Res Chem Intermed
DOI 10.1007/s11164-013-1466-8
A simple synthesis of salicylamide
and 2,5-diphenylpyrazine
•
Luo Mei Yan Bing
Received: 28 March 2013 / Accepted: 20 October 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract The compound I (C7H7NO2, salicylamide) and the compound II
(C16H12N2, 2,5-diphenylpyrazine) were both obtained as the by-product of the one-
pot synthesis of oxazolinyl zinc complexes from the reaction of 2-hydroxybenzo-
nitrile and 3-(N-ethyl-N-phenyl)-propanenitrile with D-phenylalaninol, which was
catalyzed by 235 and 83.1 mol% zinc dichloride. Their structures were determined
by X-ray diffraction, IR ,and elemental analysis.
Keywords Salicylamide Á 2,5-Diphenylpyrazine Á 3-(N-ethyl-N-phenyl)-
propanenitrile Á D-phenylalaninol Á Oxazoliny zinc complexes Á One-pot Á
Zinc chloride
Introduction
Salicylamide is an antipyretic analgesic for fever, headache, neuralgia, joint pain,
and activity rheumatism. It is also a common intermediate in the production of
pharmaceuticals, pesticides, and fine chemicals. The synthetic methods for
salicylamide have been reported in recent years [1–6], and usually it was obtained
by organometallic catalysts after heating and hydrolysis on o-hydroxybenzonitrile.
Pyrazine and its derivatives are also important medical products [7–9], as they
can be used for treating atherosclerosis, and neurological, cardiovascular, and other
diseases, and also used as intermediates for agrochemicals, pharmaceuticals, and
perfumes. Many publications have reported the methodology for 2,5-diphenylpyr-
azine [10–14]. This is the second time that our research group has reported its
L. Mei (&)
Department of Chemical Engineering, Hefei University of Technology, Hefei 230009, China
e-mail: luomei@pku.edu.cn; lmhh5523385@yahoo.cn
Y. Bing
Department of chemical engineering, Shandong University, Jinan 250100, China
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L. Mei, Y. Bing
synthetic method [15]. Our original target was to synthesize the oxazolinyl zinc
complex, but, instead, we got the by-product, 2,5-diphenylpyrazine.
Experimental
General
2-Hydroxybenzonitrile, 3-(N-ethyl-N-phenyl)-propanenitrile, D-phenylalaninol, and
CuCl2 were purchased from Acros. Infrared spectra were recorded on a Mattson
Galaxy Series FTIR 3000 spectrometer. Elemental analysis was carried out with a
Perkin–Elmer 2400-CHN instrument.
Preparation of salicylamide [compound I]
Amounts of 4.3915 g of dry ZnCl2, 1.1755 g (9.88 mmol) of 2-hydroxybenzonitrile,
and 4.1210 g of D-phenyl alaninol were added under anhydrous and oxygen-free
conditions in a dry 100-mL Schlenk flask. They were dissolved in 30 mL of dry
chlorobenzene, and the reaction mixture was refluxed for 72 h. The solvent was
removed under reduced pressure and the residue was dissolved in 15 mL H2O,
extracted with 10 9 3 mL of dichloromethane. Then, the solvent was removed
under vacuum to give a crude red oil. Further purification was performed by silica
gel (petroleum ether/dichlormethane 1/4), and the yellow crystals of compound
I were obtained in the final component of the collection points. Yield: 20 %; m.p.:
1
139–142 °C; HNMR (500 MHz, CDCl3, 27 °C), d (ppm) = 6.84–7.71 (m, 4H),
5.96( s, 2H) IR (KBr, cm-1): 3,397(s), 1,675(s), 1,590(m), 1,492(m), 1,447(m),
1,304(w), 1,082(w), 951(w), 751(w); HRMS(EI): m/z(%): calcd for C7H7NO2:
137.0477; found: 137.0481.
Preparation of 2,5-diphenylpyrazine [compound II]
Amounts of 0.6728 g (4.947 mmol) of dry ZnCl2, 1.0367 g (5.95 mmol) of 3-(N-
ethyl-N-phenyl)-propanenitrile, and 4.20 g of D-phenylalaninol were added under
anhydrous and oxygen-free conditions in a dry 100-mL Schlenk flask. They were
dissolved in 40 mL of dry chlorobenzene, and the reaction mixture was refluxed for
72 h. The solvent was removed under reduced pressure and the residue was
dissolved in 15 mL H2O, extracted with 10 9 3 mL of dichloromethane. Then, the
solvent was removed under vacuum to give a crude red oil. Further purification was
performed by silica gel (petroleum ether/dichlormethane 1/4), and the colorless
crystals of compound II were obtained in the first component of the collection
points. Yield: 15 %, Elemental analysis: Anal. Calcd. for C16H12N2: C%: 82.73; H:
5.21; N: 12.06; Found: C%: 82.54; H%: 5.04; N%: 15.50; HRMS(EI): m/z(%): calcd
for C8H12N2: 232.1000; found: 232.1008.
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Synthesis of salicylamide and 2,5-diphenylpyrazine
O
CH2OH
325mol% ZnCl2
NH2
H2O
H
NH2
+
CN
Ph
OH
OH
Scheme 1 The synthetic route to compound I
CH2OH
N
83.1mol%ZnCl2
H
NH2
+
N
N
N
Ph
Scheme 2 The synthetic route to compound II
Fig. 1 The crystal structure of
compound I
Results and discussion
The synthetic route can be summarized as follows (Schemes 1, 2). We adopted an
efficient, one-pot method to synthesize salicylamide and 2,5-diphenylpyrazine.
They were both prepared from the reaction of 2-hydroxybenzonitrile and 3-(N-
ethyl-N-phenyl)-propanenitrile with D-phenylalaninol in chlorobenzene under dry,
anaerobic conditions. ZnCl2 (235 and 83.1 mol%) and D-phenylalaninol both acted
as the Lewis acid and Lewis base catalysts separately in this reaction. After the
reaction mixture was refluxed for 72 h, the solvent was removed under reduced
pressure and the residue was dissolved in 15 mL H2O, which is the source of water
in the hydrogenation of 2-hydroxybenzonitrile. But, interestingly, in the process of
silical gel column chromatography, the colorless crystals of compound I were
obtained in the first component of the collection points, which was eluted with
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L. Mei, Y. Bing
Fig. 2 Packing of the molecule
in a unit cell
N
N
CH2OH
HN
N
-3H2
2
H
NH2
NH
N
83.1mol%ZnCl2
Ph
Scheme 3 The proposed mechanism for the synthesis of 2,5-diphenylpyrazine
Fig. 3 The crystal structure of compound II
petroleum/CH2Cl2(1/8) (Figs. 1, 2). And the yellow crystals of compound II were
obtained in the final component of the collection points, which was eluted with
petroleum/CH2Cl2(1/9) (Figs. 3, 4).
The mechanism for compound I can be proposed as follows: the water molecules
as the nucleophile attack 2-hydroxybenzonitrile, which is catalyzed by 325 mol%
the zinc dichloride, as a result providing the product salicylamide, but when the
amount of the catalyst is decreased to 50–200 mol%, we did not get compound I.
The mechanism for compound II can be proposed as follows: in the presence of
83.1 mol% zinc dichloride and 3-(N-ethyl-N-phenyl)-propanenitrile, which acted as
the Lewis acid and Lewis base catalyst in the D-phenylglycinol intermolecular
condensation reaction, first two molecules of water were removed, and then, at high
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Synthesis of salicylamide and 2,5-diphenylpyrazine
Fig. 4 Packing of the molecule
in a unit cell
temperatures, there was the further removal of three moles of hydrogen to form 2,5-
diphenylpyrazine (Scheme 3; Figs. 3, 4).
Conclusions
In summary, we report a novel, simple method of synthesizing salicylamide and 2,5-
diphenylpyrazine by a one-step reaction. Further studies are in progress in
synthesizing our target products, namely the oxazolinyl zinc complexes.
Acknowledgments This work was supported by the Hefei University of Technology, and the authors
acknowledge the University of Science and Technology of China for providing the spectral measurements
conditions.
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