Trifluoromethoxypyrazines: Preparation and properties

Article abstract of DOI:10.3390/molecules25092226

The incorporation of the trifluoromethoxy group into organic molecules has become very popular due to the unique properties of the named substituent that has a “pseudohalogen” character, while the chemical properties of the synthesized compound, especially heterocycles with such a group, are less studied. As trifluoromethoxy-substituted pyrazines are still unknown, we have developed efficient and scalable methods for 2-chloro-5-trifluoromethoxypyrazine synthesis, showing the synthetic utility of this molecule for Buchwald-Hartwig amination and the Kumada-Corriu and Suzuki and Sonogashira coupling reactions. Some comparisons of chlorine atom and trifluoromethoxy group stability in these transformations have been carried out.

Full text of DOI:10.3390/molecules25092226

molecules
Article
Trifluoromethoxypyrazines: Preparation
and Properties
Taras M. Sokolenko and Yurii L. Yagupolskii *
Institute of Organic Chemistry, NAS of Ukraine, Murmans’ka St. 5, Kyiv 02660, Ukraine; taras_sk@ukr.net
* Correspondence: Yagupolskii@ioch.kiev.ua; Tel.: +380-44-559-03-49
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editor: Valentine G. Nenajdenko
Received: 30 March 2020; Accepted: 7 May 2020; Published: 9 May 2020
Abstract: The incorporation of the trifluoromethoxy group into organic molecules has become very
popular due to the unique properties of the named substituent that has a “pseudohalogen” character,
while the chemical properties of the synthesized compound, especially heterocycles with such a group,
are less studied. As trifluoromethoxy-substituted pyrazines are still unknown, we have developed
efficient and scalable methods for 2-chloro-5-trifluoromethoxypyrazine synthesis, showing the
synthetic utility of this molecule for Buchwald-Hartwig amination and the Kumada-Corriu and
Suzuki and Sonogashira coupling reactions. Some comparisons of chlorine atom and trifluoromethoxy
group stability in these transformations have been carried out.
Keywords: pyrazine; trifluoromethoxy group; chlorination; fluorination; antimony trifluoride;
coupling reactions
1. Introduction
Among fluorine-containing substituents, the trifluoromethoxy group have gained considerable
interest from the modern synthetic audience due to its high influence on molecules for biological
and material sciences [
1,
2]. This moiety is often viewed as a privileged substituent in the field of
medicinal chemistry and is routinely considered during drug design [3]. This growing interest in
trifluoromethyl ethers is caused by the very peculiar characteristics of the CF3O group. This substituent
possesses electron-withdrawing properties by the induction effect and an electron-donating one
by the mesomeric for chlorine atoms. For this reason, it has been named “super-halogen” or
“pseudo-halogen” [2,4,5]. Moreover, it is one of the most hydrophobic substituents (π(OCF3) = +1.04
compared to π(OCH3) = −0.02) [6]. Additionally, the unique conformation of trifluoromethoxyarenes,
in which the OCF3 moiety is orthogonal to the ring plane, must be noted [7,8].
The trifluoromethoxy group attached to aromatics and heteroaromatics is relatively inert and
demonstrates the highest stability towards heating, acidic or basic conditions among other fluorine-
containing substituents, such as SCF3, CF3, CHF2, OCHF2, SHCF2, and OCH2F [
9–12]. The synthetic
utility of pyridine with the OCF3 group was well documented by Leroux and coworkers [
8]. It was
shown that the trifluoromethoxy group in the 3-rd and even 2-nd position of the ring is tolerant
to various reaction conditions, including metallation and catalytic reduction. The authors showed
that the trifluoromethoxy group in the 4-th position is less stable and undergoes replacement by
bromine atoms under the action of TMSBr. The trifluoromethoxy group easily undergoes nucleophilic
displacement when attached to a electron-deficient benzene ring, which was demonstrated by Langlois
and coworkers for the example of dinitro-trifluoromethoxybenzene [5].
Taking into account that pyrazine derivatives play an important biological role as food components
and scent markers [13–15], as well as a number of pharmaceuticals (antitubarcular pyrazinamide,
anti-HIV oltipraz, proteasome inhibitor bortezomib, narcotic addiction varenceline, fungal antibiotic
Molecules 2020, 25, 2226; doi:10.3390/molecules25092226
www.mdpi.com/journal/molecules

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aspergillic acid, pulmonary heart disease drug ligustrazine, hypnotic eszopiclone, and eye drops for
glaucoma or ocular hypertension brimonidine [13
provide perspective molecules for investigation.
,16]), the trifluoromethoxylated pyrazines family
Since the first publication in 1955 [17], the main classical methods of trifluoromethoxy ether
syntheses are based on chlorination/fluorination techniques or the oxidative desulfofluorination of
xanthates [
oxygen atoms [
8
,
18
–
3
22]. The range of novel approaches, including the electrophilic trifluoromethylation of
23 28] or the incorporation of the trifluoromethoxy group [ 29 34], were developed
,
–
5,
–
during recent years and successfully applied for aliphatic, aromatic, and heteroaromatic substrates.
Nevertheless, pyrazines with such a group are still unknown.
A pyrazine ring is more electron-deficient than a pyridine one due to the influence of the second
nitrogen atom [13]. The highly electron-deficient nature of the pyrazine system allows the successful
use of the aromatic nucleophilic substitution and cross-coupling reactions for the functionalization
of halogenated pyrazines [13,16,35]. 2-Chloro-5-trifluoromethoxypyrazine is a unique compound
because both substituents—chlorine atoms and the trifluoromethoxy group—are in equivalent positions.
This specific feature opens the possibility to compare the mentioned moieties in various types of
reactions and raises the question: are the pyrazines bearing trifluoromethoxy group stable and suitable
for synthetic transformations?
2. Results and Discussion
We have prepared 2-chloro-5-trifluoromethoxypyrazine
4 by the action of thiophosgene on
hydroxypyrazine, with further chlorination and a chlorine/fluorine exchange using antimony trifluoride
(Scheme 1). We used an alternative route based on the halophilic alkylation of pyrazine by
dibromodifluoromethane, followed by a bromine/fluorine exchange with silver tetrafluoroborate
(Scheme 1). The last method is less favorable due to the low yield in the first stage and the expensive
reagents used. Nonetheless, both methods are suitable for a large scale experiment (pyrazine
prepared in 20–25 g scale) in common laboratory glass equipment.
4 was
Scheme 1. Preparation of the 2-chloro-5-trifluoromethoxypyrazine.
It must be noted that the presence of chlorine atoms in the pyrazine ring is critical for the success
of both methods. We have found that trichloromethoxy and bromodifluoromethoxypyrazine cannot
be prepared by these methods starting from 2-hydroxypyrazine. The same peculiarity was shown by
Leroux and coworkers for a trifluoromethoxypyridine preparation [8].
We have studied the 2-chloro-5-trifluoromethoxypyrazine behavior with nucleophiles using
3-methylthiophenol as an example of S-nucleophile. If one equivalent of 3-methylthiophenol was used
in this reaction, 2-chloro-5-fluoropyrazine
5 was the main fluorinated product (Scheme 2), but a range
of products with thiophenol moiety were also formed in these conditions. Surprisingly, 2-chloro-5-

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fluoropyrazine
5
was the main product when pyrazine
4
reacted with 10 mol% 3-methylthiophenol
and an excess of cesium carbonate at room temperature. In the absence of thiophenol, this reaction did
not occur even after 1 week of stirring at r.t. Pyrazine
performed with an excess of 3-methylthiophenol.
8 was the single product when this reaction was
Scheme 2. Reaction of 2-chloro-5-trifluoromethoxypyrazine with 3-methylthiophenol.
Taking into account the destruction of OCF3 moiety in the presence of catalytic amounts of
thiophenolateanions, weproposedthefollowingschemefortrifluorometoxygroupdegradation(Scheme3):
the thiophenolate anion reacts with trifluorometoxy pyrazine 4, with an S-aryl fluorocarbamate formation
that can be recovered to thiophenolate by the action of cesium carbonate. The nucleophilic substitution
of the fluorine atom of pyrazins
removing thiophenol from the catalytic cycle (only pyrazine
A high yield of fluoropyrazine is evidence of the high catalytic activity of thiophenol for this reaction.
5
and
7
or the chlorine atom of pyrazines
5 and 6 is the route of
5
was shown in Scheme 3 as an example).
5
Scheme 3. Probable mechanism of OCF3 group destruction with the S-nucleophiles.
The nucleophilic substitution of chlorine atoms in pyrazine
4 by diethylamine as an example
of N- nucleophiles did not occur at room temperature. The prolonged heating (24 h) of the reaction
◦
mixture in various solvents at 100 C led to the complete destruction of the starting material.
Nevertheless, the chlorine atom of this molecule was successfully replaced by nitrogen nucleophile
under Buchwald-Hartwig amination reaction conditions [35–37]. Palladium dibenzoylacetonate
(Pd2dba3)/DPEphos catalysis took place and the Boc-protected amine
9 was prepared in high yield
(Scheme 4).
The replacement of chlorine atom in compound
4 with the nitrile group using potassium cyanide
failed, however pirazinenitrile 10 was prepared with zinc cyanide under Pd2dba3/diphenylphos
phinoferrocene (dppf) catalysis (Scheme 5).

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Scheme 4. 2-Chloro-5-trifluoromethoxypyrazine 4 in the Buchwald-Hartwig amination reaction.
Scheme 5. 2-Chloro-5-trifluoromethoxypyrazine 4 in the palladium-catalyzed cyanation reaction.
Alkylpyrazines, especially bearing methoxy group ones, are compounds of great interest due to
their odor properties [38–40]. For instance, the odor threshold of 2-methoxy-3-sec-buthyl-pyrazine in
water solution is 1 part per 1012 parts of water [39].
We have shown that the alkyl pirazines-bearing trifluoromethoxy group can be prepared in high
yield by Kumada–Corriu coupling [41–43] with iron acetylacetonate (Fe(acac)2) as a catalyst (Scheme 6).
It must be noted that both alkylmagnesium halides (bromide or chloride) are suitable for this reaction.
Scheme 6. 2-Chloro-5-trifluoromethoxypyrazine 4 in the iron-catalyzed Kumada–Corriu coupling.
Suzuki coupling [44] is a powerful method for pyrazine derivatization [35]. We have found
that 2-chloro-5-trifluoromethoxypyrazine 4 is a suitable substrate for coupling with boronic acids as
well as with trifluoroborates. The reaction with phenylboronic acid resulted in phenylpyrazine 13
formation in a high yield (Scheme 7). In the case of potassium ethenyl trifluoroborate, the result of the
reaction is dependent on the solvents used (Scheme 7). We tested various solvents for this reaction
(DMF, MeOH, EtOH, i-PrOH). In DMF, unidentified products were formed. Meanwhile, in the cases of
MeOH and EtOH, the reaction resulted in the substitution of the chlorine atom to give product 14
as well as both the chlorine atom and trifluoromethoxy group removal with the pyrazine 15 formation.
Bis-ethenyl pyrazine 15 was formed selectively if a large excess of potassium ethenyl trifluoroborate
was used. Monoethenyl pyrazine 14 was produced selectively when i-PrOH was used as the solvent.
Unfortunately, it is difficult to isolate the product in a pure state in this case, and pyrazine 14 was
obtained only with a 62% yield.
,

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Scheme 7. 2-Chloro-5-trifluoromethoxypyrazine 4 in Suzuki coupling.
The reaction of 2-chloro-5-trifluoromethoxypyrazine
4 with ethynyltrimethylsilane under
Sonogashira [45] reaction conditions led to 2-ethynyl-5-trifluoromethoxypyrazine 16 formation in a
high yield (Scheme 8).
Scheme 8. 2-Chloro-5-trifluoromethoxypyrazine Sonogashira coupling and Kucherov hydration.
Ethynylpyrazine 16 can be successfully desililated by the action of potassium carbonate under
heterogeneous reaction conditions in the THF/water mixture. When the desililation of pyrazine
16 was performed with KOH in a methanol/water solution, as was described in the literature [46],
a mixture of trifluoromethoxypirazine 17 and methoxypyrazine 18 was obtained. Methoxypyrazine
18 was prepared starting from trifluoromethoxypyrazine 17 or sililated pyrazine 16 by the action
of KOH in methanol. The hydration of acetylene 17 via the Kucherov reaction [47
2-acethyl-5-trifluoromethoxy-pyrazine 19 formation in a high yield (Scheme 8).
,48] resulted in
3. Materials and Methods
1H-NMR spectra were recorded at 300 MHz with a Varian VXR-300 spectrometer (Varian Inc.,
Palo Alto, CA, USA), at 500 MHz with a Bruker AVANCE DRX 500 instrument (Bruker, Billerica,
MA, USA), or at 400 MHz with a Varian UNITY-Plus 400 spectrometer (Varian Inc., Palo Alto, CA,
USA).13C-NMR-spectra (proton decoupled) were recorded on a Bruker AVANCE DRX 500 instrument at
125 MHz, or at 100 MHz with a Varian UNITY-Plus 400 spectrometer (Varian Inc., Palo Alto, CA, USA).
19F-NMR spectra were recorded at 376 MHz with a Varian UNITY-Plus 400 spectrometer (Varian Inc.,
Palo Alto, CA, USA). The chemical shifts are given in ppm relative to Me4Si and CCl3F, respectively,
as internal or external standards. The 1H-, 13C-, and 19F-NMR spectra of the compounds can be found

Molecules 2020, 25, 2226
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in the Supplementary Materials. The LC-MS spectra were registered on an “Agilent 1100 Series”
instrument with a diode-matrix and mass-selective detector “Agilent 1100 LS/MSD SL” (ionization
method: chemical ionization at atmospheric pressure; ionization chamber operation conditions:
simultaneous scanning of positive and negative ions in the range 80–1000 m/z, Agilent Technologies,
Santa Clara, CA, USA). The GC-MS spectra were registered on a Hewlett-Packard HP GC/MS 5890/5972
instrument (EI 70 eV) (Philips, Bothell, WA, USA). The melting points were determined in open
capillaries using an SMP3 instrument (Stuart Scientific Bibby Sterlin Ltd., Stone, Staffordshire, UK).
An elemental analysis was performed in the Analytical Laboratory of the Institute of Organic Chemistry,
NAS, Ukraine, Kyiv.
Unless otherwise stated, commercially-available reagents were purchased from Enamine Ltd. (Kyiv,
Ukraine) and were used without purification. The solvents were purified according to the standard
procedures [49]. Antimony trifluoride was sublimated immediately prior to use. The 2-Hydroxy-5-
chloropyrazine
37 g scale.
1 was prepared starting from 2-amino-5-chloropyrazine according to method [50] in a
All the reactions were performed in an argon atmosphere. For the column chromatography, Merck
Kieselgel 60 silica gel (Merck, Darmstadt, Germany) was used. Thin-layer chromatography (TLC)
was carried out on aluminum-backed plates coated with silica gel (Merck Kieselgel 60 F254, Merck,
Darmstadt, Germany).
3.1. 2-Chloro-5-(trichloromethoxy)pyrazine 2
5-Chloropyrazin-2-ol 1 (40 g, 0.31 mol) was added in portions to the solution of NaOH (14.1 g,
0.35 mol) in water (250 mL) at 5–10 ◦C. The mixture was cooled to 0 ◦C and the solution of thiophosgene
(35.3 g, 0.31 mol) in chloroform (250 mL) was added dropwise over 1 h under vigorous stirring.
After the addition was complete, the mixture was vigorously stirred for a further 3 h at 0 ◦C before
being extracted with chloroform (5
and dried with MgSO4. After the dehydration agent had been filtered off, the mixture was saturated
with chlorine and stirred for 3 days at 25 C. The excess of chlorine was removed with nitrogen
×
100 mL). The combined organic layers were washed with water
◦
gas stream, the solvent was distilled off in a vacuum (300 mbar), and the residue was distilled in a
vacuum, yielding trichloromethoxypyrazine
2
as a colorless oil or solid. The yield was 47.9 g (63%);
8.32 (s, 1H, HPy), 8.37 (s, 1H,
b.p. 100–101 ◦C (1 mbar); m.p. 26–28 ◦C. 1H-NMR (400 MHz, CDCl3)
δ
HPy). 13C-NMR (126 MHz, CDCl3)
δ 108.9 (s, OCCl3), 136.0, 140.8, 145.6, 154.0. GC-MS, 70 eV, m/z (rel.
int.): 248 (100) [M(335Cl + 37Cl)]+, 246 (80) [M(435Cl)]+, 250 (50) [M(235Cl + 237Cl)]+. Anal. Calcd. for
C4H2ClFN2: Cl, 57.20; Found: Cl, 57.26.
3.2. 2-(Bromodifluoromethoxy)-5-chloropyrazine 3
To the solution of 5-chloropyrazin-2-ol (40 g, 0.31 mol) and tetrabutylammonium bromide (4.9 g,
15 mmol) in anhydrous DMF (300 mL), NaH (60% in mineral oil) (14.7 g, 0.37 mol) was added in
◦
◦
portions at 0 C and the mixture was stirred for 2 h at r.t. The mixture was cooled to 30 C and
−
dibromodifluoromethane (257 g, 1.23 mol) was added dropwise. The mixture was carefully warmed
and stirred at 30–35 ◦C for 6 h. Water (900 mL) was added dropwise to the mixture and the excess of
CBr2F2 was distilled in a dry ice trap. The residue was extracted with MTBE (tert-butyl-methyl ether)
(7
atmospheric pressure and the product was distilled in a vacuum. The yield was 29.4 g (37%); colorless
liquid or solid; b.p. 80–81 ◦C (10 mbar); m.p. 14–17 ◦C. 1H-NMR (400 MHz, CDCl3)
8.27 (s, 1H,
HPy), 8.35 (s, 1H, HPy). 13C-NMR (126 MHz, CDCl3) 111.5 (t, 1JCF = 315.5 Hz, CBrF2), 135.2, 141.0,
×
100 mL), extract was washed with brine and dried with MgSO4. The solvent was distilled off at
δ
δ
145.9, 152.6. 19F-NMR (376.5 MHz, CDCl3) δ −18.4 (s, CBrF2). GC-MS, 70 eV, m/z (rel. int.): 258 (75)
[M(79Br + 35Cl)]+, 260 (100) [M(79Br + 37Cl) or (81Br + 35Cl)]+, 262 (25) [M(81Br + 37Cl)]+. Anal. Calcd.
for C5H2BrClF2N2O: C, 23.15; H, 0.78; N, 10.80; Found: C, 23.12; H, 0.68; N, 10.72.

Molecules 2020, 25, 2226
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3.3. 2-Chloro-5-trifluoromethoxypyrazine 4
Method A. The mixture of freshly sublimated SbF3 (103.7 g, 0.58 mol) and SbCl5 (17.4 g, 0.06 mol)
was heated at 125–130 ◦C for 15 min and 2-chloro-5-(trichloromethoxy)pyrazine
(47.9 g, 0.19 mol)
2
was added in portions at 100 ◦C to this mixture. The reaction mixture was stirred at 145–150 ◦C for
5 h and then 1 h at 155–160 ◦C. After cooling to r.t., the mixture was suspended in CH2Cl2 (700 mL),
and solutions of K2CO3 (138 g, 1 mol) in 700 mL of water and KF (174 g, 3 mol) in 500 mL of water
were carefully added to the mixture. The mixture was filtered through celite, the organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3
were washed with water and dried with MgSO4. The solvent was distilled off at atmospheric pressure
and the product was distilled in a vacuum.
×
100 mL). The combined extracts
Method B. Silver tetrafluoroborate (24.3 g, 0.125 mol) was added in portions to the soluti◦on
of 2-(bromodifluoromethoxy)-5-chloropyrazine
3
(29.4 g, 0.11 mol) in CH2Cl2 (250 mL) at 78 C.
−
The mixture was warmed to r.t. and stirred for 24 h in darkness. The solution of sodium bicarbonate
(11.4 g, 0.136 mol) in 150 mL of water was added to the reaction mixture and the mixture was filtered
through celite. The organic layer was separated and the aqueous layer was extracted with CH2Cl2
(
3 × 100 mL). The combined extracts were washed with water and dried with MgSO4. The solvent
was distilled off at atmospheric pressure and the product was distilled in a vacuum.
◦
The yield (Method A) was 26.0 g (68%); (Method B) 20.7 g (92%); colorless liquid; b.p. 80–81 C
1
(100 mbar). H-NMR (400 MHz, CDCl3)
δ
8.23 (s, 1H, HPy), 8.29 (s, 1H, HPy). 13C-NMR (126 MHz,
1
CDCl3)
δ
119.5 (q, JCF = 262.5 Hz, CF3), 134.6, 140.9, 145.8, 151.8. 19F-NMR (376.5 MHz, CDCl3)
57.6 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 198 (100) [M(35Cl)]+, 20 (30) [37Cl)]+. Anal. Calcd. for
δ
−
C5H2ClF3N2O: C, 30.25; H, 1.02; Cl, 17.86; N, 14.11; Found: C, 30.22; H, 0.98; Cl, 17.93; N, 14.09.
3.4. Reaction of 2-Chloro-5-trifluoromethoxypyrazine 4 with 3-Methylthiophenol and Alternative Route to
2-Chloro-5-fluoropyrazine 5
Method A. The mixture of 2-chloro-5-trifluoromethoxypyrazine 4 (1.0 g 5 mmol), 3-methylthiophenol
(0.06 g, 0.5 mmol), and cesium carbonate (2.46 g, 7.5 mmol) in anhydrous DMF (5 mL) was stirred
at r.t. under Argon for 24 h. The mixture was poured into water (20 mL) and extracted with ether
(5
×
10 mL). The etheral solution was washed with 5% sodium bicarbonate solution and then with
brine and dried with MgSO4. The solvent was distilled off at atmospheric pressure and the product
was distilled in a vacuum.
Method B. The mixture of 2-chloro-5-trifluoromethoxypyrazine 4 (1.0 g 5 mmol), 3-methylthiophenol
(0.62 g, 5 mmol), and cesium carbonate (2.46 g, 7.5 mmol) in anhydrous DMF (5 mL) was stirred
at r.t. under Argon for 24 h. The mixture was poured into water (20 mL) and extracted with ether
(
5 × 10 mL). The etheral solution was washed with 5% sodium bicarbonate solution and then with
brine and dried with MgSO4. The solvent was distilled off at atmospheric pressure and the volatile
products were distilled into a liquid nitrogen trap in a high vacuum (0.2 mbar) at 35–40 C (bath
◦
temperature). After redistillation at 100 mbar, 2-chloro-5-fluoropyrazine was obtained. The residue
after the high vacuum distillation was separated by TLS chromatography using pentane/ethylacetate
(5:1 by vol.) as an eluent, yielding a mixture of pirazines
6
and
7 (with ratio 1:2 by weight) and
disubstituted pyrazine 8.
MethodC. Themixtureof2-chloro-5-trifluoromethoxypyrazine
4
(0.5g2.5mmol), 3-methylthiophenol
(0.93 g, 7.5 mmol), and cesium carbonate (2.46 g, 7.5 mmol) in anhydrous DMF (5 mL) was stirred
at r.t. under Argon for 24 h. The mixture was poured into water (20 mL) and extracted with ether
(
5 × 10 mL). The etheral solution was washed with 5% sodium bicarbonate solution and then with
brine and dried with MgSO4. The solvent was distilled off in a vacuum and the residue was purified
by column chromatography using a mixture of hexane/ethylacetate (5:1 by vol.) as an eluent, yielding
disubstituted pyrazine 8.

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An alternative route to 2-chloro-5-fluoropyrazine 5. To the solution of 2-amino-5-chloropyrazine
(5 g, 38.6 mmol) in 50% aqueous HBF4 (20 mL), sodium nitrite (5.3 g, 77.2 mmol) was added in portions
at 0–5 ◦C. The reaction mixture was gently heated to 18–20 ◦C and stirred for 4 h. The mixture was
extracted with ether (5
×
20 mL), and the etheral solution was washed with brine and dried with MgSO4.
The solvent was distilled off at atmospheric pressure and the product was distilled in a vacuum.
2-Chloro-5-fluoropyrazine
5
. The yield was (Method A) 0.49 (74%), (method B) 0.12 g (18%), (alternative
1
method) 4.77 g (93%); colorless liquid, b.p. 80–81 ◦C (100 mbar). H-NMR (500 MHz, CDCl3)
δ
8.22 (s,
1H, H30), 8.24 (d, 1H, 3JHF = 8.5 Hz, H60). 13C-NMR (126 MHz, CDCl3)
δ
132.4 (d, 2JCF = 40.2 Hz, C60),
141.2 (d, 3JCF = 10.0 Hz, C30), 145.3 (CCl), 159.3 (d, 1JCF = 252.7 Hz, CF). 19F-NMR (376.5 MHz, CDCl3)
δ −85 (s, CF). GC-MS, 70 eV, m/z (rel. int.): 132 (100) [M(35Cl)]+, 134 (32) [M(37Cl)]+. Anal. Calcd. for
C4H2ClFN2: C, 36.25; H, 1.52; Cl, 26.75; N, 21.14; Found: C, 36.22; H, 1.53; Cl, 26.73; N, 21.09.
The mixture of 2-chloro-5-(m-tolylthio)pyrazine
6 and 2-fluoro-5(m-tolylthio)pyrazine 7. The yield of the
mixture was 0.33 g: chloropyrazine 6–11%, fluoropyrazine 7–22% (the yield was determined by NMR
and LC analyses of the mixture of pyrazines
6
and
7
). Rf = 0.8 pentane/ethylacetate (5:1). Chloropyrazine
1
6
: H-NMR (500 MHz, CDCl3)
δ
2.36 (s, 3H, CH3), 7.25–7.27 (m, 1H, CHAr), 7.34–7.37 (m, 1H, CHAr),
7.40–7.42 (m, 2H, 2CHAr), 7.96 (s, 1H, H60Py), 8.37 (s, 1H, H60Py); LC/MS (CI): m/z = 237 [M(35Cl) + H]+,
239 [M(37Cl) + H]+. Fluoropyrazine 7 1H-NMR (500 MHz, CDCl3)
CHAr), 7.34–7.37 (m, 1H, CHAr), 7.40–7.42 (m, 2H, 2CHAr), 7.84 (s, 1H, H60Py), 7.26 (d, 1H, 3JHF = 8.5 Hz
δ 2.36 (s, 3H, CH3), 7.25–7.27 (m, 1H,
,
H30Py). 19F-NMR (376.5 MHz, CDCl3) δ −87.9 (s, CF). LC/MS (CI): m/z = 221 [M + H]+.
2,5-Bis(m-tolylthio)pyrazine
m.p. 102–103 ◦C. Rf = 0.6 pentane/ethylacetate (5:1). H-NMR (400 MHz, CDCl3)
7.18–7.21 (m, 2H, 2CHAr), 7.27 (t, 2H, 3JHH = 7.6 Hz, 2m-CHAr), 7.33–7.37 (m, 4H, 4CHAr), 8.03 (s, 2H,
8. Yield (method B) 0.4 g (25%), (method C) 0.75 g (93%); yellowish powder,
1
δ
2.34 (s, 6H, 2CH3),
CHPy). 13C-NMR (126 MHz, CDCl3)
δ 21.3, 129.4, 129.6, 130.3, 131.7, 135.2, 139.7, 142.5, 153.6. LC/MS
(CI): m/z = 325 [M + H]+. Calcd. for C18H16N2S2: C, 66.63; H, 4.97; N, 8.63; S, 19.76; Found: C, 66.68; H,
5.02; N, 8.59; S, 19.70.
3.5. tert-Butyl Methyl(5-(trifluoromethoxy)pyrazin-2-yl)carbamate 9
To the carefully degassed mixture of 2-chloro-5-trifluoromethoxypyrazine
4 (2 g, 10 mmol),
N-Boc-methylamine (2 g, 15 mmol) and Cs2CO3 (6.5 g, 20 mmol) in anhydrous dioxane (30 mL)
Pd2dba3 (0.09 g, 0.1 mmol) and bis[(2-diphenylphosphino)phenyl] ether (DPEphos) (0.05 g, 0.1 mmol)
were added and the mixture was stirred at 100 ◦C for 12 h. After cooling to r.t., the mixture was diluted
with water (20 mL), filtered through celite, and extracted with ethylacetate (5
extract was washed with brine, dried with MgSO4, and concentrated in a vacuum. After column
chromatography with the mixture of hexane/ethylacetate (5:1 by vol.) as the eluent, pyrazine was
×
10 mL). The organic
9
obtained. The yield was 2.4 g (82%); colorless powder, m.p. 78–79 ◦C. 1H-NMR (400 MHz, CDCl3)
δ
1.54 (s, 9H, C(CH3)3), 3.39 (s, 3H, CH3), 8.18 (s, 1H, HPy), 8.82 (s, 1H, HPy). 13C-NMR (100 MHz,
1
CDCl3)
δ
28.2 (C(CH3)3), 33.8 (NCH3), 82.5 (
C(CH3)3), 120.2 (q, JCF = 262.5 Hz, CF3), 132.1, 137.6,
148.5, 150.1, 153.6. 19F-NMR (376.5 MHz, CDCl3) δ −57.5 (s, CF3). LC/MS (CI): m/z = 294 [M + H]+.
Calcd. for C11H14F3N3O3: C, 45.05; H, 4.81; N, 14.33; Found: C, 45.08; H, 4.88; N, 14.29.
3.6. 5-(Trifluoromethoxy)pyrazine-2-carbonitrile 10
To the carefully degassed mixture of 2-chloro-5-trifluoromethoxypyrazine
4 (1.00 g, 5 mmol),
Zn(CN)2 (0.39 g, 3.3 mmol) and Zn dust (0.6 g, 0.9 mmol) in anhydrous dimethylacetamide (10 mL)
Pd2dba3 (0.14 g, 0.15 mmol) and dppf (0.17 g, 0.3 mmol) were added, and the mixture was stirred at
100 ◦C for 8 h. After cooling to r.t., the mixture was diluted with water (30 mL), filtered through celite,
and extracted with ether (7
with MgSO4, and the solvent was distilled off under atmospheric pressure. The residue was purified
×
10 mL). The etheral solution was washed with brine (3
×
10 mL), dried
by TLC chromatography, yielding 0.34 g (36%) cyanopyrazine 10 as a colorless liquid with an intense
◦
almond scent, b.p. 95–96 C (100 mbar). Rf = 0.8 pentane/ethylacetate (10:1). 1H-NMR (400 MHz,

Molecules 2020, 25, 2226
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CDCl3)
δ
8.51 (s, 1H, HPy), 8.62 (s, 1H, HPy). 13C-NMR (125.6 MHz, CDCl3)
δ
114.5 (CN), 119.8 (q,
1JCF = 266.5 Hz, CF3), 127.5, 136.9, 145.7, 154.3. 19F-NMR (376.5 MHz, CDCl3) δ −57.5 (s, CF3). GC-MS,
70 eV, m/z (rel. int.): 189 (100) [M]+. Calcd. for C6H2F3N3O: C, 38.11; H, 1.07; N, 22.22; Found: C, 38.18;
H, 1.16; N, 22.19.
3.7. Synthesis of Alkylpyrazines-Bearing Trifluoromethoxy Group by Kumada-Corriu Coupling
The solution of ethylmagnesium bromide (18 mL, 18 mmol, 1 mol/L solution in THF) or
butylmagnesium chloride (9 mL, 18 mmol, 2 mol/L solution in THF) was added dropwise at 0 ◦C
in an Argon atmosphere to the mixture of 2-chloro-5-trifluoromethoxypyrazine
4 (3.0 g, 15 mmol)
and Fe(acac)2 (0.19 g, 0.75 mmol) in 30 mL of anhydrous THF. The mixture was warmed to r.t. and
stirred for 3 h (in the case of ethylmagnesium bromide) or 4 h (in the case of butylmagnesium chloride).
The reaction mixture was cooled to 0 ◦C and neutralized with 3% aqueous HCl. The product was
extracted with ether (5
×
10 mL) and the etheral solution was washed with brine (5
×
10 mL) and dried
with MgSO4. The solvent was distilled off at atmospheric pressure and the product was distilled in
a vacuum.
2-Ethyl-5-(trifluoromethoxy)pyrazine 11. Yield 2.77 g (96%); colorless liquid with intense fruit scent, b.p.
◦
3
83–85 C (100 mbar). 1H-NMR (400 MHz, CDCl3)
δ
1.31 (t, 3H, JHH = 7.6 Hz, CH3), 2.84 (q, 2H,
3JHH = 7.6 Hz, CH2) 8.13 (s, 1H, HPy), 8.35 (s, 1H, HPy). 13C-NMR (126 MHz, CDCl3)
13.3 (s, CH3),
22.8 (s, CH2), 120.1 (q, 1JCF = 262.7 Hz, CF3), 135.0, 140.1, 151.8, 156.7. 19F-NMR (376.5 MHz, CDCl3)
57.3 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 192 (100) [M]+. Anal. Calcd. for C7H7F3N2O: C, 43.76; H,
3.67; N, 14.58; Found: C, 43.62; H, 3.53; N, 14.49.
δ
δ
−
2-Butyl-5-(trifluoromethoxy)pyrazine 12. 3.03 g (92%); colorless liquid with intense fruit scent, b.p.
1
83–85 ◦C (20 mbar). H-NMR (400 MHz, CDCl3)
δ
0.92 (t, 3H, 3JHH = 7.6 Hz, CH3), 1.37 (sext, 2H,
3JHH = 7.6 Hz, CH2CH3), 1.67 (quint, 2H, 3JHH = 7.6 Hz, CH2CH2CH2), 2.82 (t, 2H, 3JHH = 7.6 Hz,
CH2) 8.11 (s, 1H, HPy), 8.34 (s, 1H, HPy). 13C-NMR (126 MHz, CDCl3)
δ 13.8 (s, CH3), 22.2 (s, CH2), 31.5
(s, CH2), 34.2 (s, CH2), 120.1 (q, 1JCF = 262.3 Hz, CF3), 135.0, 140.5, 151.8, 155.8. 19F-NMR (376.5 MHz,
CDCl3) δ −57.3 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 220 (100) [M]+. Anal. Calcd. for C9H11F3N2O: C,
49.09; H, 5.04; N, 12.72; Found: C, 49.02; H, 5.03; N, 12.79.
3.8. 2-Phenyl-5-(trifluoromethoxy)pyrazine 13
Palladium acetate (34 mg, 0.15 mmol) and triphenylphosphine (158 mg, 0.6 mmol) were mixed
together in carefully degassed dimethoxiethane (25 mL) and stirred for 15 min at r.t. under an Ar
atmosphere. Chloropyrazine
4 (1.0 g, 5 mmol), phenylboronic acid (0.7 g, 6 mmol), and K2CO3 (1.4 g,
10 mmol) were added to the reaction mixture and the mixture was stirred at 75 ◦C for 20 h. After cooling
to r.t., the mixture was diluted with water, filtered through celite, and extracted with tret-buthylmethyl
ether (3
×
25 mL). The organic solution was washed with brine, dried with MgSO4, and evaporated
in a vacuum. The residue was purified by column chromatography with hexane/ethylacetate (10:1
by vol.) as the eluent (Rf = 0.6). The yield was 0.95 g (80%); colorless powder, m.p. 80 ◦C. 1H-NMR
(400 MHz, CDCl3)
δ 7.48–7.55 (m, 3H, 3CHPh), 7.92–8.00 (m, 2H, 2CHPh), 8.50 (s, 1H, HPy), 8.70 (s, 1H,
HPy). 13C-NMR (126 MHz, CDCl3)
δ
120.2 (q, 1JCF = 262.7 Hz, CF3), 126.8, 129.1, 130.0, 135.1, 135.2,
138.4, 150.9, 152.4. 19F-NMR (376.5 MHz, CDCl3) δ −57.2 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 240
(100) [M]+. Anal. Calcd. for C11H7F3N2O: C, 55.01; H, 2.94; N, 11.66; Found: C, 49.9; H, 3.00; N, 11.69.
3.9. Reaction of 2-Chloro-5-trifluoromethoxypyrazine 4 with Potassium Ethenyl Trifluoroborate
3.9.1. 2-(Trifluoromethoxy)-5-vinylpyrazine 14
To the carefully degassed mixture of 2-chloro-5-trifluoromethoxypyrazine
potassium ethenyl trifluoroborate (2.0 g, 15 mmol) and NEt3 (2 g, 20 mmol) in anhydrous iso-propanole
(10 mL) PdCl2dppf
CH2Cl2 (0.4 g, 0.5 mmol) were added and the mixture was stirred for 20 h at 75 ◦C.
4 (2.0 g, 10 mmol),
·

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After cooling to r.t., the mixture was diluted with water (20 mL), filtered through celite, and extracted
with CH2Cl2 (5 10 mL). The organic extract was washed with 1% aqueous HCl, then with water,
×
and dried with CaCl2. After the removal of the solvent at atmospheric pressure, the residue was
distilled with deflegmator in a vacuum. The yield was 1.17 g (62%); colorless liquid with a pungent
1
odor, b.p. 90–91 ◦C (100 mbar). H-NMR (500 MHz, CDCl3)
δ
5.63 (d, 1H, 3JHH = 11.0 Hz, =CH2), 6.33
(d, 1H, 3JHH = 17.5 Hz, =CH2), 6.83 (dd, 1H, 3JHH-trans = 17.5 Hz, 3JHH-cis = 11.0 Hz, =CH2), 8.27 (s, 1H,
HPy), 8.41 (s, 1H, HPy). 13C-NMR (100 MHz, CDCl3) 119.9 (q, 1JCF = 262.7 Hz, CF3), 120.6, 131.7, 135.1,
δ
139.1, 148.9, 152.1. 19F-NMR (376.5 MHz, CDCl3) δ −57.3 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 190
(100) [M]+. Anal. Calcd. for C7H5F3N2O: C, 44.22; H, 2.65; N, 14.73; Found: C, 44.29; H, 2.60; N, 14.69.
3.9.2. 5-Divinylpyrazine 15
The reaction was performed in the glass high pressure tube 50 mL vol. To the carefully degassed
mixture of 2-chloro-5-trifluoromethoxypyrazine
(5.4 g, 40 mmol) and NEt3 (4.1 g, 40 mmol) in anhydrous methanol (10 mL) PdCl2dppf
4
(2.0 g, 10 mmol), potassium ethenyl trifluoroborate
CH2Cl2 (0.8 g,
·
15 mmol) were added and the mixture was stirred for 20 h at 75 ◦C. After cooling to r.t., the mixture was
diluted with water (20 mL), filtered through celite, and extracted with CH2Cl2 (5 × 10 mL). The organic
extract was washed with 1% aqueous HCl, then with water, and dried with CaCl2. After the removal
of the solvent at atmospheric pressure, the residue was purified by flash column chromatography with
pentane/ethylacetate (5:1 by vol.) as the eluent (Rf = 0.8). The yield was 0.75 g (57%); colorless liquid,
b.p. 45–47 ◦C (10 mbar). Compound 15 was partly polymerized under distillation and completely
polymerized after 1-month storage in a refrigerator. 1H-NMR (500 MHz, CDCl3)
δ
5.60 (d, 2H,
3
3
3JHH = 11.0 Hz, 2 =CH2), 6.34 (d, 2H, JHH = 17.5 Hz, =CH2), 6.83 (dd, 2H, JHH-trans = 17.5 Hz,
3JHH-cis =11.0 Hz, =CH2), 8.54 (s, 2H, HPy). 13C-NMR (100 MHz, CDCl3)
δ 120.3, 133.3, 142.4, 149.5.
GC-MS, 70 eV, m/z (rel. int.): 132 (100) [M]+. Anal. Calcd. for C8H8N2: C, 72.70; H, 6.10; N, 21.21;
Found: C, 72.72; H, 6.10; N, 21.19.
3.10. 2-(Trifluoromethoxy)-5-((trimethylsilyl)ethynyl)pyrazine 16
To the carefully degassed mixture of 2-chloro-5-trifluoromethoxypyrazine
ethynyltrimethylsilane (4.4 g, 45 mmol) and NEt3 (9.2 g, 90 mmol) in anhydrous DMF (25 mL)
PdCl2dppf CH2Cl2 (0.62 g, 0.75 mmol) and CuI (0.14 g, 0.75 mmol) were added and the mixture was
stirred for 20 h at r.t. The mixture was diluted with water (75 mL), filtered through celite, and extracted
with MTBE (5 50 mL). The organic extract was washed with 1% aqueous HCl, then with brine, and
4 (3.0 g, 15 mmol),
·
×
dried with MgSO4. After the removal of the solvent, the residue was distilled in a vacuum. An effective
deflegmator was necessary, due to difficulties in the separation of 1,4-bis(trimethylsilyl)buta-1,3-diyne
that was formed as by-product. The yield was 3.0 g (77%); colorless oil, b.p. 118–120 ◦C (100 mbar).
1H-NMR (400 MHz, CDCl3)
δ
0.26 (s, 9H, SiMe3), 8.35 (s, 2H, 2 HPy). 13C-NMR (100 MHz, CDCl3)
C), 120.0 (q, 1JCF = 263.6 Hz, CF3), 135.4 (s, CPy), 137.2 (s,
δ
-0.48 (s, SiMe3), 99.4 (s, C C), 100.2 (s, C
≡
≡
CPy), 144.5 (s, CPy), 151.8 (s, CPy). 19F-NMR (376.5 MHz, CDCl3) δ −57.3 (s, CF3). GC-MS, 70 eV, m/z
(rel. int.): 260 (100) [M]+. Anal. Calcd. for C10H11F3N2OSi: C, 46.14; H, 4.26; N, 10.76; Found: C, 46.19;
H, 4.20; N, 10.69.
3.11. 2-Ethynyl-5-(trifluoromethoxy)pyrazine 17
The solution of 2-(trifluoromethoxy)-5-((trimethylsilyl)ethynyl)pyrazine 16 (2 g, 7.7 mmol) and
18-crown-6 (0.05 g, 0.2 mmol) in THF (20 mL) was added dropwise at 5–10 ◦C to the solution of K2CO3
(1.1 g, 7.7 mmol) in 3 mL of water. The mixture was stirred for 2 h at 10–15 ◦C, neutralized with 5%
aqueous HCl, and extracted with MTBE (5 × 25 mL). The organic extract was washed with brine and
dried with MgSO4. After the removal of the solvent at atmospheric pressure, the residue was distilled
in a vacuum. The yield was 1.2 g (85%); colorless oil or solid with a grass scent, b.p. 76–77 ◦C (10 mbar),
m.p. 45–46 ◦C. 1H-NMR (400 MHz, CDCl3)
δ
3.33 (s, 1H,
CH), 8.39 (s, 2H, 2 HPy). 13C-NMR (100 MHz,
≡
CDCl3) 78.8 (s, -C ), 81.4 (s,
δ
≡
≡
CH), 119.9 (q, 1JCF = 263.6 Hz, CF3), 135.6 (s, CPy), 136.4 (s, CPy), 144.8

Molecules 2020, 25, 2226
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(s, CPy), 152.2 (s, CPy). 19F-NMR (376.5 MHz, CDCl3) δ −57.3 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 188
(100) [M]+. Anal. Calcd. for C7H3F3N2O: C, 44.70; H, 1.61; N, 14.89; Found: C, 44.79; H, 1.60; N, 14.88.
3.12. 2-Ethynyl-5-methoxypyrazine 18
Method A. The solution of 2-(trifluoromethoxy)-5-((trimethylsilyl)ethynyl)pyrazine 16 (1 g,
3.8 mmol) in anhydrous methanol (3 mL) was added to 5 mL of the methanolic solution of KOH
(0.43 g, 7.7 mmol) at 0 ◦C. The mixture was stirred for 2 h at 15 ◦C and the solvent was removed in a
vacuum (without heating). The residue was suspended in ether and neutralized with 3% aqueous
HCl. The organic solution was separated and the aqueous layer was extracted with ether (3
The combined organic solutions were washed with brine and dried with MgSO4. After the removal of
the solvent at atmospheric pressure, the residue was distilled in a vacuum.
×
10 mL).
Method B. The solution of 2-Ethynyl-5-(trifluoromethoxy)pyrazine 17 (1 g, 5.3 mmol) in anhydrous
methanol (3 mL) was added to 5 mL of the methanolic solution of KOH (0.43 g, 7.7 mmol) at
10 ◦C.
−
The mixture was stirred for 2 h at 15 ◦C and the solvent was removed in a vacuum (without heating).
The residue was suspended in ether and neutralized with 3% aqueous HCl. The organic solution was
separated and the aqueous layer was extracted with ether (3
were washed with brine and dried with MgSO4. After the removal of the solvent at atmospheric
pressure, the residue was distilled in a vacuum.
×
10 mL). The combined organic solutions
The yield (Method A) was 0.34 g (65%), (Method B) 0.63 g (88%); colorless solid, m.p. 40–41 ◦C, b.p.
88–90 ◦C (10 mbar); 1H-NMR (400 MHz, CDCl3)
δ
3.22 (s, 1H,
≡
CH), 3.98 (s, 3H, CH3), 8.18 (s, 2H,
2 HPy), 8.25 (s, 2H, 2 HPy). 13C-NMR (100 MHz, CDCl3)
δ
53.9 (s, CH3), 78.9 (s,
≡
CH), 80.0 (s, -C ),
≡
130.4 (s, CPy), 135.6 (s, CPy), 144.4 (s, CPy), 159.4 (s, CPy). GC-MS, 70 eV, m/z (rel. int.): 134 (100) [M]+.
Anal. Calcd. for C7H6N2O: C, 62.68; H, 4.51; N, 20.88; Found: C, 62.62; H, 4.44; N, 20.80.
3.13. 1-(5-(Trifluoromethoxy)pyrazin-2-yl)ethan-1-one 19
Mercury oxide (0.38 g, 1.8 mmol) was added to the mixture of trifluoroacetic acid (60 mL, 800 mmol)
and water (6 mL, 332 mmol) and stirred until dissolving (apr 10 min). The mixture was cooled to 10 ◦C
and 2-ethynyl-5-(trifluoromethoxy)pyrazine 17 (1.0 g, 5.3 mmol) was added. The mixture was stirred at
40 ◦C for 1 h and trifluoroacetic acid was removed in a vacuum (300 mbar). Water (20 mL) was added
to the residue and the mixture was neutralized with NaHCO3 to pH 6. The product was extracted with
CHCl3 (3
of the solvent at atmospheric pressure, the residue was distilled in a vacuum. The yield was 0.92 g
(84%); colorless solid, m.p. 44–45 ◦C, b.p. 94–95 ◦C (10 mbar); 1H-NMR (400 MHz, CDCl3)
2.69 (s,
3H, CH3), 8.42 (s, 2H, 2 HPy), 8.92 (s, 2H, 2 HPy). 13C-NMR (100 MHz, CDCl3)
25.9 (s, CH3), 119.9 (q,
×
10 mL) and the extract was washed with water and dried with MgSO4. After the removal
δ
δ
1JCF = 264.6 Hz, CF3), 134.1 (s, CPy), 141.3 (s, CPy), 145.6 (s, CPy), 155.1 (s, CPy), 197.5 (s, CO). 19F-NMR
(376.5 MHz, CDCl3) δ −57.3 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 206 (100) [M]+. Anal. Calcd. for
C7H5F3N2O: C, 40.79; H, 2.45; N, 13.59; Found: C, 40.70; H, 2.44; N, 13.60.
4. Conclusions
It was shown that 2-chloro-5-trifluoromethoxypyrazine is suitable for further transformations
via chlorine atom substitution in Buchwald-Hartwig amination, Kumada-Corriu, and Suzuki and
Sonogashira coupling reactions. At the same time, the trifluoromethoxy group attached to the electron-
deficient pyrazine ring was easily destructed and displaced under the action of O- or S- nucleophiles.
This property must be taken into account, especially in the processes of bioactive molecules modeling.
On the other hand, this fact opens up the possibility to explore trifluoromethoxy moiety as a leaving
group for nucleophilic substitution.
Efficient and scalable methods for 2-chloro-5-trifluoromethoxypyrazine synthesis, developed
in this work, and its synthetic profile allow us to consider this molecule as perspective for wide
synthetic utility.

Molecules 2020, 25, 2226
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Supplementary Materials: 1H-, 13C-, and 19F-NMR spectra of products associated with this article are
available online.
Author Contributions: T.M.S. and Y.L.Y. conceived the idea of the article, conceived and performed the experiments,
and wrote the paper. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1–19 are available from the authors.
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