Trifluoromethoxypyrazines: Preparation and Properties

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.


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 CF 3 O 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(OCF 3 ) = +1.04 compared to π(OCH 3 ) = −0.02) [6]. Additionally, the unique conformation of trifluoromethoxyarenes, in which the OCF 3 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 fluorinecontaining substituents, such as SCF 3 , CF 3 , CHF 2 , OCHF 2 , SHCF 2 , and OCH 2 F [9][10][11][12]. The synthetic utility of pyridine with the OCF 3 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][14][15], as well as a number of pharmaceuticals (antitubarcular pyrazinamide, anti-HIV oltipraz, proteasome inhibitor bortezomib, narcotic addiction varenceline, fungal antibiotic

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 4 was prepared in 20-25 g scale) in common laboratory glass equipment. 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 3methylthiophenol 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-5fluoropyrazine 5 was the main product when pyrazine 4 reacted with 10 mol% 3-methylthiophenol 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-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 8 was the single product when this reaction was performed with an excess of 3-methylthiophenol.
Molecules 2020, 25, x FOR PEER REVIEW  3 of 14 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 8 was the single product when this reaction was performed with an excess of 3-methylthiophenol.
Taking into account the destruction of OCF3 moiety in the presence of catalytic amounts of thiophenolate anions, we proposed the following scheme for trifluorometoxy group degradation (Scheme 3): 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 5 and 7 or the chlorine atom of pyrazines 5 and 6 is the route of removing thiophenol from the catalytic cycle (only pyrazine 5 was shown in Scheme 3 as an example). A high yield of fluoropyrazine 5 is evidence of the high catalytic activity of thiophenol for this reaction. 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][36][37]. Palladium dibenzoylacetonate (Pd2dba3)/DPEphos catalysis took place and the Boc-protected amine 9 was prepared in high yield (Scheme 4).
Taking into account the destruction of OCF 3 moiety in the presence of catalytic amounts of thiophenolate anions, we proposed the following scheme for trifluorometoxy group degradation (Scheme 3): 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 5 and 7 or the chlorine atom of pyrazines 5 and 6 is the route of removing thiophenol from the catalytic cycle (only pyrazine 5 was shown in Scheme 3 as an example). A high yield of fluoropyrazine 5 is evidence of the high catalytic activity of thiophenol for this reaction. 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 8 was the single product when this reaction was performed with an excess of 3-methylthiophenol.
Taking into account the destruction of OCF3 moiety in the presence of catalytic amounts of thiophenolate anions, we proposed the following scheme for trifluorometoxy group degradation (Scheme 3): 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 5 and 7 or the chlorine atom of pyrazines 5 and 6 is the route of removing thiophenol from the catalytic cycle (only pyrazine 5 was shown in Scheme 3 as an example). A high yield of fluoropyrazine 5 is evidence of the high catalytic activity of thiophenol for this reaction. 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][36][37]. Palladium dibenzoylacetonate (Pd2dba3)/DPEphos catalysis took place and the Boc-protected amine 9 was prepared in high yield (Scheme 4). The nucleophilic substitution of chlorine atoms in pyrazine 4 by diethylamine as an example of Nnucleophiles 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][36][37]. Palladium dibenzoylacetonate (Pd 2 dba 3 )/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 Pd 2 dba 3 /diphenylphos phinoferrocene (dppf ) catalysis (Scheme 5). 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/diphenylphosphinoferrocene (dppf) catalysis (Scheme 5). Alkylpyrazines, especially bearing methoxy group ones, are compounds of great interest due to their odor properties [38][39][40]. For instance, the odor threshold of 2-methoxy-3-sec-buthyl-pyrazine in water solution is 1 part per 10 12 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][42][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. 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 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/diphenylphosphinoferrocene (dppf) catalysis (Scheme 5). Alkylpyrazines, especially bearing methoxy group ones, are compounds of great interest due to their odor properties [38][39][40]. For instance, the odor threshold of 2-methoxy-3-sec-buthyl-pyrazine in water solution is 1 part per 10 12 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][42][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. 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 Alkylpyrazines, especially bearing methoxy group ones, are compounds of great interest due to their odor properties [38][39][40]. For instance, the odor threshold of 2-methoxy-3-sec-buthyl-pyrazine in water solution is 1 part per 10 12 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][42][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. 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/diphenylphosphinoferrocene (dppf) catalysis (Scheme 5). Alkylpyrazines, especially bearing methoxy group ones, are compounds of great interest due to their odor properties [38][39][40]. For instance, the odor threshold of 2-methoxy-3-sec-buthyl-pyrazine in water solution is 1 part per 10 12 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][42][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. 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 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. 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. 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 [47,48] resulted in 2acethyl-5-trifluoromethoxy-pyrazine 19 formation in a high yield (Scheme 8). 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. 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 [47,48] resulted in 2acethyl-5-trifluoromethoxy-pyrazine 19 formation in a high yield (Scheme 8). 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 [47,48] resulted in 2-acethyl-5-trifluoromethoxy-pyrazine 19 formation in a high yield (Scheme 8).

Materials and Methods
1 H-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). 13 C-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). 19 F-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 Me 4 Si and CCl 3 F, respectively, as internal or external standards. The 1 H-, 13 C-, and 19 F-NMR spectra of the compounds can be found 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-5chloropyrazine 1 was prepared starting from 2-amino-5-chloropyrazine according to method [50] in a 37 g scale.
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).

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 × 100 mL). The combined organic layers were washed with water and dried with MgSO 4 . 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 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.

2-Chloro-5-trifluoromethoxypyrazine 4
Method A. The mixture of freshly sublimated SbF 3 (103.7 g, 0.58 mol) and SbCl 5 (17.4 g, 0.06 mol) was heated at 125-130 • C for 15 min and 2-chloro-5-(trichloromethoxy)pyrazine 2 (47.9 g, 0.19 mol) 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 CH 2 Cl 2 (700 mL), and solutions of K 2 CO 3 (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 CH 2 Cl 2 (3 × 100 mL). The combined extracts were washed with water and dried with MgSO 4 . The solvent was distilled off at atmospheric pressure and the product was distilled in a vacuum.
Method B. Silver tetrafluoroborate (24.3 g, 0.125 mol) was added in portions to the solution of 2-(bromodifluoromethoxy)-5-chloropyrazine 3 (29.4 g, 0.11 mol) in CH 2 Cl 2 (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 CH 2 Cl 2 (3 × 100 mL). The combined extracts were washed with water and dried with MgSO 4 . 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 MgSO 4 . 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.
Method C. The mixture of 2-chloro-5-trifluoromethoxypyrazine 4 (0.5 g 2.5 mmol), 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 MgSO 4 . 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. 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 HBF 4 (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 MgSO 4 . The solvent was distilled off at atmospheric pressure and the product was distilled in a vacuum.

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 MgSO 4 . The solvent was distilled off at atmospheric pressure and the product was distilled in a vacuum.

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 × 10 mL). The combined organic solutions were washed with brine and dried with MgSO 4 . After the removal of the solvent at atmospheric pressure, the residue was distilled in a vacuum.
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 × 10 mL). The combined organic solutions were washed with brine and dried with MgSO 4 . After the removal of the solvent at atmospheric pressure, the residue was distilled in a vacuum.
Supplementary Materials: 1 H-, 13 C-, and 19 F-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.