Chemistry of Heterocyclic Compounds 2015, 51(3), 259–268
spectrum, δ, ppm: –65.00. Compound 20 was used further
without additional purification.
temperature, the homogenous solution was evaporated to
dryness, the residue was dried under vacuum. Yield 0.16 g
(100%). Orange solid. 1H NMR spectrum, δ, ppm: 8.03–8.10
(2Н, m, H Ar); 8.27–8.35 (2Н, m, H Ar). 19F NMR
spectrum, δ, ppm: –64.5. Compound 27 was used further
without additional purification.
Ethyl 3-(trifluoromethyl)quinoxaline-2-carboxylate
(21) was obtained according to a published procedure.7a
1H NMR spectrum, δ, ppm (J, Hz): 1.46 (3Н, t, J = 7.1,
OCH2CH3); 4.56 (2Н, q, J = 7.1, OCH2CH3); 7.95–8.00
(2Н, m, H Ar); 8.24–8.29 (2Н, m, H Ar). 19F NMR
spectrum, δ, ppm: –65.0.
2-Chloro-1-[3-(trifluoromethyl)quinoxalin-2-yl]etha-
none (28). A solution of acyl chloride 27 (160 mg, 0.6 mmol)
in Et2O (5 ml) was cooled to –10°C and treated by
dropwise addition of diazomethane (126 mg, 3 mmol) in
Et2O (7 ml). The solution was then allowed to warm to
room temperature, stirred for 1 h, conc. HCl (12 ml) was
cautiously added, and the reaction mixture was stirred for 1 h
at 40°C. The obtained solution was neutralized with saturated
NaHCO3 solution, extracted with Et2O (5×5 ml). The
combined organic phases were dried over anhydrous
Na2SO4 and evaporated. The residue was triturated with
heptane (2 ml) and dried under vacuum. Yield 130 mg
The reaction of ethyl 2-chloro-4,4-difluoro-3-oxobuta-
noate (24) with o-phenylenediamine (1). Synthesis of 2-di-
fluoromethyl)benzimidazole (25) and ethyl 3-(difluoro-
methyl)quinoxaline-2-carboxylate (26). A solution of
β-ketoester 24 (2.00 g, 10 mmol) in EtOH (40 ml) was
treated with the diamine 1 (1.10 g, 10 mmol) and refluxed
for 16 h. The reaction mixture was poured into Н2О (200 ml),
extracted with CHCl3 (3×25 ml). The combined extracts
were dried over anhydrous MgSO4, and the solvent was
removed by evaporation. The oily residue crystallized, its
recrystallization from a minimum amount of CHCl3 gave
2-(difluoromethyl)benzimidazole (25). Yield 0.35 g (21%).
Reddish prisms. Mp 150°C (mp 153°C)16. 1H NMR
spectrum, δ, ppm (J, Hz): 6.94 (1Н, t, J = 53.8, CF2H);
7.35–7.39 (2Н, m, H Ar); 7.69–7.73 (2Н, m, H Ar); 10.90
(1Н, br. s, NH). 19F NMR spectrum, δ, ppm (J, Hz): –115.6
(d, J = 52.9). The filtrate was separated by column
chromatography (eluent CH2Cl2), giving ethyl 3-(difluoro-
1
(76%). Orange powder. Mp 88–89°C. H NMR spectrum,
δ, ppm: 5.06 (2Н, s, CH2); 8.00–8.05 (2Н, m, H Ar); 8.22–
8.32 (2Н, m, H Ar). 19F NMR spectrum, δ, ppm: –64.7.
Compound 28 was used further without additional
purification.
2-(2-Aminothiazol-4-yl)-3-(trifluoromethyl)quinoxa-
line (29). A mixture of ketone 28 (130 mg, 0.47 mmol) and
thiourea (37 mg, 0.47 mmol) in acetone (20 ml) was
refluxed for 14 h. The solvent was removed by evaporation;
the residue was treated with saturated NaHCO3 solution
(15 ml) and extracted with Et2O (5×5 ml). The combined
organic extracts were dried over anhydrous Na2SO4, evapo-
rated, and the residue was recrystallized from heptane. Yield
methyl)quinoxaline-2-carboxylate (26). Yield 0.30
g
(12%). Yellowish crystals. Mp 95–97°C. 1H NMR
spectrum, δ, ppm (J, Hz): 1.49 (3Н, t, J = 7.0, OCH2CH3);
4.58 (2Н, q, J = 7.0, OCH2CH3); 7.41 (1Н, t, J = 54.3,
CF2H); 7.92–7.97 (2Н, m, H Ar); 8.24–8.30 (2Н, m, H Ar).
13С NMR spectrum, δ, ppm (J, Hz): 14.1 (OCH2CH3); 63.2
(OCH2CH3); 111.3 (t, J = 243.1, CF2H); 129.8, 130.1, 132.5,
132.9 (С-5,6,7,8); 141.6, 142.6, 145.83 (С-2,4a,8a); 145.81
(t, J = 24.2, C-3); 164.4 (СO). 19F NMR spectrum, δ, ppm
(J, Hz): –118.8 (d, J = 54.9). Compound 26 was used further
without additional purification.
1
100 mg (71%). Yellow crystals. Mp 166–167°C. H NMR
spectrum, δ, ppm: 5.20 (2Н, br. s, NH2); 7.10 (1Н, s, Н-5
thiazole); 7.81–7.95 (2Н, m, H Ar); 8.20–8.24 (2Н, m,
H Ar). 19F NMR spectrum, δ, ppm: –63.2. Found, %:
С 48.54; Н 2.27. C12H7F3N4S. Calculated, %: C 48.65;
H 2.38.
3-(Difluoromethyl)quinoxaline-2-carboxylic acid (23). A
solution of ester 26 (150 mg, 0.6 mmol) in MeOH (50 ml)
was cooled to –20°C and treated with aqueous 0.5 M
solution of NaOH (3 ml). The mixture was stirred at room
temperature for 3 days, then the solvent was removed by
evaporation under vacuum, the solid residue was dissolved
in Н2О (30 ml). The solution was washed with Et2O (5 ml),
acidified with dilute HCl to pH 1, the product was
extracted with Et2O (3×15 ml), the combined extracts were
dried over anhydrous Na2SO4, and the solvent was
removed by evaporation. Yield 120 mg (90%). Creme
[3-(Trifluoromethyl)quinoxalin-2-yl]amine (31).
Method X. A suspension of carboxylic acid 20 (0.35 g,
1.45 mmol) in toluene (20 ml) at room temperature was
treated with Et3N (0.15 g, 1.45 mmol) and diphenyl-
phosphoryl azide (0.40 g, 1.45 mmol). The reaction mix-
ture was stirred for 30 min at room temperature, then heated
at 80°C for 6 h. Toluene was evaporated, the residue was
treated with CHCl3 (30 ml) and H2O (10 ml). The organic
phase was washed with NaHCO3 solution (2×10 ml), dried
over anhydrous Na2SO4. The solvent was evaporated, and
the residue was recrystallized from toluene, giving N,N'-bis-
[3-(trifluoromethyl)quinoxalin-2-yl]urea (30). Yield 0.05 g
1
colored powder. Mp 149–150°C. H NMR spectrum, δ,
1
ppm (J, Hz): 7.89 (1Н, t, J = 53.8, CF2H); 7.99–8.11 (2Н,
m, H); 8.23–8.27 (1Н, m, H Ar); 8.36–8.41 (1Н, m, H Ar);
10.40 (1Н, br. s, CO2H). 19F NMR spectrum, δ, ppm
(J, Hz): –120.1 (d, J = 52.7). Found, %: С 53.72; Н 2.95.
C10H6F2N2O2. Calculated, %: C 53.58; H 2.70.
(15%). Yellow crystals. Mp 221–222°C (subl.). H NMR
spectrum, δ, ppm (J, Hz): 7.80 (2Н, td, J = 8.0, J = 1.0,
H Ar); 7.93 (2Н, td, J = 8.0, J = 0.8, H Ar); 8.10 (2Н, d,
J = 8.0, H Ar); 8.19 (2Н, d, J = 8.0, H Ar); 10.00 (2Н, br. s,
2NH). 19F NMR spectrum, δ, ppm: –66.1. Mass spectrum,
m/z (Irel, %): 452 [М]+ (8), 239. [М–HetNH2]+ (44), 213
[HetNH2]+ (100), 144 [HetNH2–CF3]+ (14), 69 [CF3]+ (4).
The obtained urea 30 (0.05 g) was combined with filtrate,
treated with 20% HCl solution (15 ml), and the obtained
mixture was stirred at 90°C for 3 days (control by 19F NMR
3-(Trifluoromethyl)quinoxaline-2-carbonyl
chloride
(27). A suspension of carboxylic acid 20 (0.15 g,
0.6 mmol) in CH2Cl2 (20 ml) was stirred and treated by
dropwise addition of (COCl)2 (2.00 g, 15.7 mmol) and 1 drop
of DMF. The mixture was stirred overnight at room
266