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DOI: 10.1055/s-0037-1610792
Synthesis of 5-Trifluoromethyl-Substituted (Z)-N,N-Dimethyl-N′-(pyrazin-2-yl)formimidamides from 2-Aminopyrazines, LiI/Selectfluor, FSO2CF2CO2Me and DMF under Cu Catalysis
We gratefully acknowledge the National Natural Science Foundation of China (NSFC) (Grant no. 21971193) and the Fundamental Research Funds for the Central Universities for generous financial support.
Abstract
The synthesis of 5-trifluoromethyl-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides via the iodination of 2-aminopyrazines with Selectfluor/LiI followed by a domino trifluoromethylation with FSO2CF2CO2Me and a condensation with DMF in the presence of CuI is realized under mild conditions. This three-step method offers CF3-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides in yields of 55–70% and with high regioselectivities. LiI serves as an iodine source, whilst DMF functions as both a solvent and a condensation reagent. The regioselectivity of these trifluoromethylation reactions is strongly dependent upon the substituent pattern on the 2-aminopyrazines. A possible mechanism for this method is also discussed.
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Aryl and heteroaryl compounds possessing a trifluoromethyl (CF3) group are of significant importance to the pharmaceutical industry.[1] There are several representative drugs, including antimalarials,[2] pexidartinib,[3] and siponimod,[4] that contain a CF3 group. Introducing a CF3 group into organic molecules may produce novel and unique properties such as changing the electron distribution, increasing the acidity of adjacent functional groups, and enhancing the antioxidant ability of the target molecules.[5] Therefore, the CF3 group plays an important role in the design and development of drugs,[6] pesticides[7] and functional materials.[8] New methods for the introduction of a CF3 group into heteroaryl rings have attracted attention over the past several decades.[9] Strategies for introducing a CF3 group into organic compounds include nucleophilic trifluoromethylation,[10] electrophilic trifluoromethylation,[11] and radical trifluoromethylation.[12] Copper-catalyzed trifluoromethylation of aryl and heteroaryl iodides with a trifluoromethylating agent has become a practical tool for the synthesis of CF3-substituted aryl and heteroaryl compounds (Scheme [1], eq 1 and eq 2).[13] The presence of a CF3 group at different positions (e.g., o-, m- or p-) of a heteroaryl ring such as pyridine has a significant influence on the chemical, physical, and biological properties.[14] Consequently, regioselective trifluoromethylation of a heteroaryl ring under Cu catalysis remains a big challenge. N,N-Dimethylformamide (DMF) is a common solvent and is utilized as a reagent for the synthesis of aldehydes[15] and amides.[16] However, the Cu-catalyzed condensation between a CF3-substituted heteroaryl amine and DMF has not been described as yet. In our previous work, we found that 2-aminopyrazines are oxidized by Selectfluor to give a 2-aminopyrazine radical.[17] We envisioned that this 2-aminopyrazine radical might react with an iodine source to give an iodinated product, which can then be subjected to Cu-catalyzed trifluoromethylation (Scheme [1], eq 3). In this paper, we report the synthesis of 5-CF3-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides derived from 2-aminopyrazines, Selectfluor/LiI, FSO2CF2CO2Me and DMF under Cu catalysis.
To test our hypothesis, we examined the reaction of 2-aminopyrazine derivatives 1 with various iodine sources 2 in the presence of Selectfluor, followed by the use of a range of copper salts and ligands. After screening the reaction conditions, we found that the reaction of 3-chloro-2-aminopyrazine (1a) with lithium iodide (LiI) (2a)/Selectfluor (3) followed by coupling with FSO2CF2CO2Me (4a) in the presence of CuI (15 mol%) in DMF occurred at 100 °C to give (Z)-N′-[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]-N,N-dimethylformimidamide (5a) in 62% yield, whilst the alternative product 2-amino-3-chloro-5-(trifluoromethyl)-pyrazine (5a′) was not observed (Table [1], entry 1). Interestingly, a condensation between 2-aminopyrazine and DMF was observed. Furthermore, the reaction did not occur in the absence of Selectfluor (Table [1], entry 2). The use of Selectfluor without LiI led to complex results (Table [1], entry 3). Significantly, the alkali metal iodides potassium iodide (KI) and sodium iodide (NaI) were tested and were found to give 5a in 21% and 30% yields, respectively (Table [1], entry 4). Different solvents such as toluene, acetonitrile, DMSO and 1,4-dioxane gave rise to product 5a′ in yields of 0–15%, and 5a was not observed in these cases (Table [1], entry 5). These outcomes revealed that DMF indeed was involved in the condensation reaction. Copper salts are essential for the trifluoromethylation of aryl and heteroaryliodines with a trifluoromethylating agent.[13] Therefore, CuBr, CuI, and Cu(OAc)2 were utilized; among these, CuI was more suitable than CuBr, whilst Cu(OAc)2 was ineffective for this reaction (Table [1], entries 1 and 6). Taking into consideration the influence of ligands on such reactions, 1,10-phenanthroline (Phen) was employed and was found to give complex results (Table [1], entry 7). Various trifluoromethylating agents such as FSO2CF3CO2Me (4a), Togni’s reagent (4b), TMSCF3 (4c) and CF3SO2Cl (4d) were examined, with FSO2CF3CO2Me (4a) proving to be the most active (Table [1], entries 1 and 8).
a Reaction conditions: 3-chloro-2-aminopyrazine (1a) (0.10 mmol), Selectfluor (3) (0.10 mmol), LiI (2a) (0.1 mmol), DMF (2 mL), 15 °C, 3 h; then CuI (15 mol%), FSO2CF2CO2Me (4a) (0.3 mmol).
b Yield of isolated product.
The reaction was carried out at different temperatures ranging from 25 °C to 110 °C; the results indicated that increasing the temperature was beneficial to these reactions, with that at 100 °C giving the highest yield (Table [1], entry 9). Also, changing the amount of FSO2CF3CO2Me (4a) had a large impact on the results (Table [1], entry 10). The reaction was carried out under the standard conditions in one pot and the complex results were observed.
With optimized conditions in hand, we examined the scope of a diverse range of 2-aminopyrazines 1 (Scheme [2]). Reactions of 3-substituted 2-aminopyrazine derivatives 1a–h, with either electron-rich (e.g., 3-Me, 3-Ph, 3-o-MeC6H4,) or electron-poor (e.g., 3-m-MeOC6H4, 3-m-ClC6H4, 3-Cl, 3-Br and 3-CF3) substituents on the pyrazine ring, gave the corresponding products 5a–h in moderate to good yields and high regioselectivities, whilst no other products were observed. The molecular structure of 5g was established by X-ray crystal structure analysis (Figure [1]).[18] Significantly, with the 3,6-disubstituted substrate 3-bromo-6-chloro-2-aminopyrazine (1i), the desired product 5i was obtained in 63% yield, which can undergo various transformations.[13] With 6-substituted 2-aminopyrazine derivatives 1j–n, possessing either electron-rich (e.g., 6-Me, 6-Ph, and 6-m-MeC6H4) or electron-poor (e.g., 6-m-ClC6H4, 6-Cl) substituents on the pyrazine ring, the corresponding products 5j–n were obtained in fair to moderate yields and high regioselectivities; again, no other products were observed. Notably, reaction of unsubstituted 2-aminopyrazine (1o) did not give the corresponding product 5o, probably because 1o has no substituent at the 3- or 6-position The presence of a substituent at the 3- or 6-position of the 2-aminopyrazine may stabilize the radical formed at C3 or N1 on the pyrazine ring.[17] Instead, 5-iodo-2-aminopyrazine (5o′) along with trace 3-iodo-2-aminopyrazine (5o′′) were obtained the reasons for this outcome remain unclear, however, we are currently pursuing further investigations in this area.
The large-scale synthesis of trifluoromethylated pyrazine 5a is shown in Scheme [3]. The reaction of 3-chloro-2-aminopyrazine (1a) (903 mg, 7.0 mmol) with LiI (2a) (938 mg, 7.0 mmol) in DMF in the presence of Selectfluor (3) (2.48 g, 7.0 mmol) was conducted at 15 °C. After completion of this iodination step, CuI (200 mg, 15 mol%) and FSO2CF2CO2Me (4a) (4.03 g, 21 mmol) were added at 100 °C and the reaction mixture was stirred for ca.12 h. The expected trifluoromethylated product 5a was obtained in 55% yield (Scheme [3], eq 1). Removal of the formamidine moiety was investigated using product 5b (Scheme [2], eq 2). The deprotection[19] of 5b (0.10 mmol) in the presence of ZnCl2 (0.43 mmol) in refluxing ethanol (2 mL) proceeded to give 3-bromo-5-(trifluoromethyl)pyrazin-2-amine (5b′)[20] in 92% yield.
Preliminary mechanistic investigations were conducted via four control experiments (Scheme [4]). Treatment of 1a (0.10 mmol) with LiI (2a) (0.10 mmol)/Selectfluor (3) (0.10 mmol) in DMF at 15 °C gave 6a [21] in 90% yield (Scheme [4], eq 1). The trifluoromethylation of 6a (0.10 mmol) with FSO2CF2CO2Me (4) (0.30 mmol) in DMF with the assistance of CuI (15 mmol%) at 100 °C produced 5a in 80% yield (Scheme [4], eq 2). The condensation between 1a and DMF did not occur in the presence of CuI (15 mol%) at 100 °C (Scheme [4], eq 3); these results indicate that Selectfluor, LiI, and FSO2CF2CO2Me are all required for this reaction. The condensation of 8a [22] with DMF under similar conditions occurred to give 5a in an 80% yield; however, the reaction did not occur without CuI (Scheme [4], eq 4). These results revealed that a CF3 group at the 5-position of the 2-aminopyrazine was beneficial in their condensation reactions.
Based on our previous work[17] [23] and the control experiments (see Scheme [4]), a possible mechanism is outlined in Scheme [5]. The reaction between pyrazine 1 and Selectfluor (3) via single-electron transfer (SET) in DMF at 15 °C gives intermediate A together with intermediate B. Subsequent isomerization of intermediate A then forms the pyrazine radical C.[17] [23] Treatment of B with LiI (2a) provides the iodine radical D.[17] [23] Next, iodination of C with D occurs to form E. Cu-catalyzed trifluoromethylation of E with FSO2CF2CO2Me (4)[24] at 100 °C then occurs to form F. The reaction of F with DMF under Cu catalysis gives G, which undergoes dehydration to produce 5 and regenerates CuI.[13] [25] Interestingly, CuI functions as a catalyst for the domino trifluoromethylation and the condensation.
In conclusion, we have developed a new method for the synthesis of 5-CF3-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides by regioselective iodination of 2-aminodiazines with Selectfluor/LiI followed by a domino reaction involving trifluoromethylation and condensation under Cu catalysis. This method utilizes LiI as the iodine source and DMF as a condensation agent, and tolerates various 2-aminopyrazines and functional groups.
All manipulations were carried out under an air atmosphere using standard Schlenk techniques. All glassware was oven- or flame-dried immediately prior to use. Solvents were purified and dried according to standard methods prior to use, unless stated otherwise. All reagents were obtained from commercial sources and were used without further purification. Products were purified by column chromatography on silica gel. Infrared (IR) spectra were recorded as KBr discs or as films on a KBr plate. 1H NMR spectra were obtained at 600 MHz, and the chemical shifts are recorded relative to the tetramethylsilane signal (0 ppm) or residual protonated solvent. Data for 1H NMR are recorded as follows: chemical shift (δ, ppm), [multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, br s = broad singlet), coupling constant(s) (Hz), integration]. 13C NMR spectra were obtained at 151 MHz, and chemical shifts are recorded relative to the solvent resonance (CDCl3, 77.50 ppm). 19F NMR spectra were obtained at 565 MHz, and CF3CO2H was used as an internal standard. High-resolution mass spectrometry (HRMS) was performed on a microTOF II mass spectrometer using electrospray ionization (ESI).
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(Z)-N,N-Dimethyl-N′-(pyrazin-2-yl)formimidamides 5; General Procedure
2-Aminopyrazine 1 (0.10 mmol), LiI (2a) (0.10 mmol) and Selectfluor (3) (0.10 mmol) were dissolved in DMF (2 mL) in a sealed tube, and the resulting mixture was stirred at 15 °C for 3 h. The mixture was diluted with aqueous NaCl solution, extracted with EtOAc (3 × 10 mL), and the combined organic layer was dried over Na2SO4. After concentration of the filtrate, the residue was dissolved in DMF (2 mL) in a sealed tube. CuI (15 mol%) and FSO2CF2CO2Me (4) (0.3 mmol) were added and the resulting mixture was stirred at 100 °C for 12 h. The mixture was diluted with aqueous NaCl solution and extracted with EtOAc (3 × 10 mL). The combined organic layer was then dried over Na2SO4 and filtered. After concentration of the filtrate, purification of the residue by column chromatography on silica gel (petroleum ether/EtOAc, 10:1 to 5:1) gave the desired product 5.
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(Z)-N,N-Dimethyl-N′-[3-chloro-5-(trifluoromethyl)-2-pyrazinyl]methanimidamide (5a)
Yield: 15.6 mg (62%); pale yellow oil.
IR (KBr): 2918, 2848, 1644, 1576, 1380, 1158, 732 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.55 (s, 1 H), 8.34 (s, 1 H), 3.24 (s, 3 H), 3.22 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.0, 157.9, 143.8, 138.2 (q, 3 J = 3.4 Hz), 134.9 (q, 2 J = 36.0 Hz), 121.8 (q, 1 J = 272.7 Hz), 41.8, 35.8.
19F NMR (565 MHz, CDCl3): δ = –66.49.
HRMS (ESI): m/z [M + Na]+ calcd for C8H8ClF3N4Na: 275.0287; found: 275.0284.
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(Z)-N,N-Dimethyl-N′-[3-bromo-5-(trifluoromethyl)-2-pyrazinyl]methanimidamide (5b)
Yield: 18.1 mg (61%); pale yellow solid; mp 78.2 °C.
IR (KBr): 2985, 2896, 1674, 1595, 1365, 1108, 685 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.54 (s, 1 H), 8.35 (s, 1 H), 3.16 (s, 6 H).
13C NMR (151 MHz, CDCl3): δ = 157.9, 157.8, 143.6, 138.2 (q, 3 J = 3.4 Hz), 134.8 (q, 2 J = 36.2 Hz), 121.6 (q, 1 J = 272.9 Hz), 41.6, 35.7.
19F NMR (565 MHz, CDCl3): δ = –66.74.
HRMS (ESI): m/z [M + H]+ calcd for C8H9BrF3N4: 296.9963; found: 296.9961.
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(Z)-N,N-Dimethyl-N′-[3,5-(ditrifluoromethyl)-2-pyrazinyl]methanimidamide (5c)
Yield: 17.2 mg (60%); pale yellow oil.
IR (KBr): 2931, 2898, 1686, 1625, 1480, 1348, 842 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.65 (s, 1 H), 8.57 (s, 1 H), 3.22 (s, 6 H).
13C NMR (151 MHz, CDCl3): δ = 157.7, 156.6, 147.3 (q, 3 J = 2.8 Hz), 132.2 (q, 2 J = 35.2 Hz), 130.5 (q, 2 J = 37.3 Hz), 122.1 (q, 1 J = 271.6 Hz), 121.9 (q, 1 J = 273.9 Hz), 41.7, 35.7.
19F NMR (565 MHz, CDCl3): δ = –66.45, –67.40.
HRMS (ESI): m/z [M + H]+ calcd for C9H9F6N4: 287.0731; found:287.0732.
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(Z)-N,N-Dimethyl-N′-[3-methyl-5-(trifluoromethyl)-2-pyrazinyl]methanimidamide (5d)
Yield: 12.8 mg (55%); pale yellow solid; mp 45.5 °C.
IR (KBr): 2958, 2862, 1658, 1605, 1468, 1342, 782 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.47 (s, 1 H), 8.29 (s, 1 H), 3.17 (s, 3 H), 3.16 (s, 3 H), 2.58 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 159.1, 156.9, 150.5, 137.5 (q, 3 J = 3.4 Hz), 135.6 (q, 2 J = 34.5 Hz), 122.8 (q, 1 J = 272.7 Hz), 41.5, 35.4, 21.3.
19F NMR (565 MHz, CDCl3): δ = –66.71.
HRMS (ESI): m/z [M + H]+ calcd for C9H12F3N4: 233.1014; found: 233.1015.
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(Z)-N,N-Dimethyl-N′-[3-(3-methoxyphenyl)-5-(trifluoromethyl)-2-pyrazinyl]methanimidamide (5e)
Yield: 21.1 mg (65%); pale yellow oil.
IR (KBr): 2974, 2865, 1676, 1607, 1521, 1463, 1106, 795 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.54 (s, 1 H), 8.40 (s, 1 H), 7.82 (d, J = 7.6 Hz, 2 H), 7.35 (t, J = 8.1 Hz, 1 H), 7.03–6.92 (m, 1 H), 3.86 (s, 3 H), 3.18 (s, 3 H), 3.14 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.1, 157.5, 145.8, 139.4, 139.2 (d, 3 J = 3.3 Hz), 136.7 (q, 2 J = 35.2 Hz), 134.3, 131.3, 129.8, 129.7, 129.2, 122.9 (q, 1 J = 272.8 Hz), 54.3, 41.9, 36.1.
19F NMR (565 MHz, CDCl3): δ = –66.68.
HRMS (ESI): m/z [M + H]+ calcd for C15H16F3N4O: 325.1276; found: 325.1277.
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(Z)-N,N-Dimethyl-N′-[3-(3-chlorophenyl)-5-(trifluoromethyl)-2-pyrazinyl]methanimidamide (5f)
Yield: 23.1 mg (70%); pale yellow oil.
IR (KBr): 3074, 2849, 1663, 1630, 1436, 1265, 1178, 737 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.57 (s, 1 H), 8.42 (s, 1 H), 8.37 (s, 1 H), 8.14–8.09 (m, 1 H), 7.36 (d, J = 5.3 Hz, 2 H), 3.19 (s, 3 H), 3.15 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 157.7, 157.1, 145.4, 139.1, 138.8 (q, 3 J = 3.0 Hz), 136.3 (q, 2 J = 35.1 Hz), 133.9, 130.9, 129.4, 129.3, 128.8, 122.6 (q, 1 J = 272.9 Hz), 41.6, 35.8.
19F NMR (565 MHz, CDCl3): δ = –66.67.
HRMS (ESI): m/z [M + H]+ calcd for C14H13ClF3N4: 329.0781; found: 329.0779.
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(Z)-N,N-Dimethyl-N′-[3-phenyl-5-(trifluoromethyl)-2-pyrazinyl]methanimidamide (5g)
Yield: 18.6 mg (63%); pale yellow oil.
IR (KBr): 3096, 2958, 1641, 1597, 1468, 1351, 1106, 782 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.54 (s, 1 H), 8.40 (s, 1 H), 8.24–8.16 (m, 2 H), 7.42 (m, 3 H), 3.17 (s, 3 H), 3.12 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 157.6, 157.1, 145.3, 138.6 (q, 3 J = 3.1 Hz), 137.4, 136.5 (q, 2 J = 35.5 Hz), 130.7, 129.8, 129.4, 128.7, 128.1, 122.7 (q, 1 J = 272.6 Hz), 41.5, 35.7.
19F NMR (565 MHz, CDCl3): δ = –66.68.
HRMS (ESI): m/z [M + H]+ calcd for C14H14F3N4: 295.1171; found: 295.1173.
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(Z)-N,N-Dimethyl-N′-[3-(2-methylphenyl)-5-(trifluoromethyl)-2-pyrazinyl]methanimidamide (5h)
Yield: 20.3 mg (66%); pale yellow solid; mp 65.8 °C.
IR (KBr): 2919, 2845, 1644, 1558, 1477, 1351, 1106, 575 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.50 (s, 1 H), 8.45 (s, 1 H), 7.41–7.34 (m, 1 H), 7.30–7.26 (m, 1 H), 7.25–7.20 (m, 2 H), 3.11 (s, 3 H), 2.92 (s, 3 H), 2.23 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.5, 156.8, 150.4, 138.7 (q, 3 J = 3.2 Hz), 137.7, 137.4, 136.3 (q, 2 J = 35.3 Hz), 130.5, 130.4, 128.8, 125.6, 122.7 (q, 1 J = 272.7 Hz), 41.4, 35.4, 20.6.
19F NMR (565 MHz, CDCl3): δ = –66.46.
HRMS (ESI): m/z [M + Na]+ calcd for C15H15F3N4Na: 331.1147; found: 331.1145.
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(Z)-N,N-Dimethyl-N′-[3-bromo-5-(trifluoromethyl)-6-chloro-2-pyrazinyl]methanimidamide (5i)
Yield: 20.8 mg (63%); pale yellow oil.
IR (KBr): 2967, 2884, 1682, 1656, 1396, 1176, 732, 655 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.65 (s, 1 H), 3.25 (s, 3 H), 3.23 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.3, 158.2, 144.0, 138.5 (q, 3 J = 3.5 Hz), 135.1 (q, 2 J = 36.1 Hz), 122.0 (q, 1 J = 272.9 Hz), 42.3, 36.0.
19F NMR (565 MHz, CDCl3): δ = –66.41.
HRMS (ESI): m/z [M + H]+ calcd for C8H8BrClF3N4: 330.9573; found: 330.9576.
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(Z)-N,N-Dimethyl-N′-[5-(trifluoromethyl)-6-chloro-2-pyrazinyl]methanimidamide (5j)
Yield: 15.4 mg (61%); pale yellow oil.
IR (KBr): 2926, 2871, 1659, 1582, 1368, 1176, 756 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.59 (s, 1 H), 8.15 (s, 1 H), 3.21 (s, 3 H), 3.18 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 157.9, 157.8, 143.7, 138.1 (q, 3 J = 3.4 Hz), 134.8 (q, 2 J = 36.1 Hz), 121.7 (q, 1 J = 272.7 Hz), 41.7, 35.7.
19F NMR (565 MHz, CDCl3): δ = –66.90.
HRMS (ESI): m/z [M + H]+ calcd for C8H9ClF3N4: 253.0468; found: 253.0469.
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(Z)-N,N-Dimethyl-N′-[5-(trifluoromethyl)-6-methyl-2-pyrazinyl]methanimidamide (5k)
Yield: 12.8 mg (55%); pale yellow solid; mp 42.2 °C.
IR (KBr): 2998, 2849, 1639, 1598, 1449, 1369, 793 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.48 (s, 1 H), 8.17 (s, 1 H), 3.14 (s, 3 H), 3.13 (s, 3 H), 2.51 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.9, 156.5, 150.1, 145.1 (q, 3 J = 3.2 Hz), 135.1 (q, 2 J = 32.8 Hz), 122.6 (q, 1 J = 274.6 Hz), 41.1, 34.8, 20.9.
19F NMR (376 MHz, CDCl3): δ = –66.30.
HRMS (ESI): m/z [M + H]+ calcd for C9H12F3N4: 233.1014; found: 233.1016.
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(Z)-N,N-Dimethyl-N′-[5-(trifluoromethyl)-6-(3-chlorophenyl)-2-pyrazinyl]methanimidamide (5l)
Yield: 22.3 mg (68%); pale yellow oil.
IR (KBr): 3198, 2976, 1683, 1614, 1485, 1216, 1180, 792 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.55 (s, 1 H), 8.40 (s, 1 H), 8.34 (s, 1 H), 8.13–8.03 (m, 1 H), 7.35 (d, J = 5.0 Hz, 2 H), 3.17 (s, 3 H), 3.13 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 157.6, 157.1, 145.3, 139.0, 138.7 (q, 3 J = 3.0 Hz), 136.2 (q, 2 J = 35.2 Hz), 133.9, 130.8, 129.3, 129.2, 128.7, 122.4 (d, 1 J = 273 Hz), 41.5, 35.6.
19F NMR (565 MHz, CDCl3): δ = –66.64.
HRMS (ESI): m/z [M + H]+ calcd for C14H12ClF3N4: 329.0781; found: 329.0784.
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(Z)-N,N-Dimethyl-N′-[5-(trifluoromethyl)-6-phenyl-2-pyrazinyl]methanimidamide (5m)
Yield: 17.7 mg (60%); pale yellow solid; mp 65.3 °C.
IR (KBr): 3058, 2964, 1685, 1608, 1452, 1349, 1127, 709 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.72 (s, 1 H), 8.55 (s, 1 H), 8.02 (d, J = 8.1 Hz, 2 H), 7.57–7.47 (m, 3 H), 3.20 (s, 6 H).
13C NMR (151 MHz, CDCl3): δ = 157.5, 156.8, 147.1, 136.7 (q, 3 J = 3.1 Hz), 137.1, 136.1 (q, 2 J = 33.1 Hz), 130.4, 129.5, 129.2, 128.4, 127.8, 122.4 (q, 1 J = 274.0 Hz), 41.2, 35.4.
19F NMR (565 MHz, CDCl3): δ = –66.06.
HRMS (ESI): m/z [M + H]+ calcd for C14H14F3N4: 295.1171; found: 295.1172.
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(Z)-N,N-Dimethyl-N′-[5-(trifluoromethyl)-6-(3-methylphenyl)-2-pyrazinyl]methanimidamide (5n)
Yield: 20.1 mg (65%); pale yellow oil.
IR (KBr): 3026, 2939, 1643, 1586, 1415, 1389, 1153, 609 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.70 (s, 1 H), 8.53 (s, 1 H), 7.81 (s, 1 H), 7.39 (t, J = 7.7 Hz, 2 H), 7.30 (d, J = 7.2 Hz, 1 H), 3.20 (s, 6 H), 2.46 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 157.9, 156.3, 149.9, 138.2 (q, 3 J = 3.5 Hz), 137.2, 136.8, 135.5 (q, 2 J = 34.9 Hz), 129.9, 128.3, 125.1, 123.1, 122.2 (q, 1 J = 271.8 Hz), 40.8, 34.8, 20.0.
19F NMR (565 MHz, CDCl3): δ = –66.01.
HRMS (ESI): m/z [M + H]+ calcd for C15H16F3N4: 309.1327; found: 309.1329.
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3-Bromo-5-(trifluoromethyl)pyrazin-2-amine (5b′)[20]
Compound 5b (30.0 mg, 0.1 mmol), zinc chloride (54.0 mg, 0.4 mmol) and absolute ethanol (2 mL) were refluxed for 20 h. After the reaction completed (monitored by TLC), the mixture was diluted with CH2Cl2 and washed with water. It gave 21.8 mg (92% yield) of the deprotected aniline 5b' without further purification.
Yield: 21.8 mg (92%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.30 (s, 1 H), 5.09 (br s, 2 H).
19F NMR (376 MHz, CDCl3): δ = –67.18.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0037-1610792.
- Supporting Information
-
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For selected examples, see:
For selected examples, see:
For selected examples, see:
Corresponding Authors
Publication History
Received: 17 September 2021
Accepted after revision: 15 December 2021
Article published online:
09 February 2022
© 2022. Thieme. All rights reserved
Georg Thieme Verlag KG
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-
References
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- 23b Zhou G, Tian Y, Zhao X, Dan W. Org. Lett. 2018; 20: 4858
- 23c Tian Y, Zhou G, Zhao X, Dan W. Acta Chim. Sinica 2018; 76: 962
- 23d Zhao M, Cai J, Zhao X. Org. Chem. Front. 2019; 6: 426
- 24 Konovalov AI, Lishchynskyi A, Grushin VV. J. Am. Chem. Soc. 2014; 136: 13410
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For selected examples, see:
For selected examples, see:
For selected examples, see:
