Synthesis of fluorinated 3-aminobenzofurans via a tandem S_NAr-cyclocondensation strategy

Abstract

A small library of twenty-seven novel 3-amino-2,6-disubstituted-4,5,7-trifluorobenzofurans was successfully synthesized with the compounds formed in low to good yield using a tandem S_NAr-cyclocondensation reaction of 4-substituted perfluorobenzonitriles with α-hydroxycarbonyl compounds employing DBU as base. The compounds were prepared as part of a medicinal chemistry project to develop novel fluorinated heterocyclic leads and were characterised by ¹H and ¹⁹F NMR spectroscopy, IR spectroscopy, high resolution mass spectrometry and elemental analysis. The X-ray crystal structure of the 2-(4-methoxybenzoyl)-6-morpholino derivative was determined, which showed the benzoyl substituent to be coplanar with the benzofuran ring, and to form a hydrogen bond to the 3-amino group. Attempts to synthesise the corresponding 3-unsubstituted or 3-methyl analogues using 4-substituted perfluoro-benzaldehydes or acetophenones were unsuccessful, with cleavage of the carbonyl group occurring. A mechanistic study indicated that alkoxide ions attacked the carbonyl group, rather than effecting S_NAr reaction at C-2, leading to loss of a perfluoroaryl anion which was trapped with D₂O.

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Introduction

Benzofurans are an important class of heterocyclic compound and have found diverse application in medicinal chemistry as antibacterial, antimicrobial, anti-ulcer and antimalarial agents,¹ and as ischemic cell death inhibitors.² Methods to prepare both synthetic^3,4 and naturally occurring⁵ benzofurans have been reviewed recently. As part of a programme to develop new leads based on polyfluorinated scaffolds, we have applied our general approach to the rapid construction of fluorinated heterocycles through the use of reliable S_NAr reactions of perfluorinated arene building blocks to effect easy annelation of a new heteroatom ring. Having demonstrated this strategy in the synthesis of benzothiophene⁶ derivatives, in this paper we report the preparation of polyfluorinated benzofuran derivatives. The presence of fluorine imparts desirable properties for drug development, and also allows additional functionalisation through further S_NAr reaction.

Results and discussion

The synthesis of the benzofuran targets first required the preparation of 4-substituted tetrafluorobenzonitrile derivatives 2 (Scheme 1). Sandford and co-workers have shown⁷ that nucleophilic substitution in pentafluorobenzonitrile 1 occurred regioselectively, at first the 4-, and then the 2-position, and reported the synthesis of the 4-morpholino derivative 2e by heating 1 with morpholine in THF or MeCN in the presence of diisopropylethylamine. We found substitution of the 4-fluorine atom by amines, imidazoles and phenols occurred more rapidly in DMF as solvent, and the benzonitriles 2a–h were formed in good yield (typically >80%) after 15 h at room temperature.

Scheme 1 Synthesis of 4-substituted tetrafluorobenzonitriles and their conversion to 3-amino-2,6-disubstituted-4,5,7-trifluorobenzofurans.

After successfully obtaining the benzonitrile precursors 2, conversion to substituted fluorinated benzofurans was explored. Reaction with α-hydroxy carbonyl compounds 3 (Scheme 1) as bis-nucleophilic reagents was investigated. Suh and co-workers have synthesised non-fluorinated benzofurans, active as ischemic cell death inhibitors, utilising a related strategy.² Methyl glycolate, hydroxyacetone and two hydroxyacetophenones were employed as nucleophiles to react with benzonitriles 2. The latter were prepared by reaction of the corresponding bromoacetophenones with sodium formate in ethanol (Scheme 2). The intermediate formate esters were not observed, presumably undergoing transesterification in situ. The use of DBU as base was then found to be effective in promoting attack of the alcohol at the 2-position of the tetrafluorobenzontriles 2, and subsequent enolisation and cyclo-condensation with the nitrile group to close the five-membered furan ring forming compounds 4 in low to high yield (Fig. 1).

Scheme 2 Preparation of α-hydroxyacetophenone bis-nucleophiles.

Fig. 1 Structures and isolated yields of the novel fluorinated benzofurans synthesised.

Reaction was found to proceed well in DMF at 80 °C in 2–3 h although boiling THF was also suitable as a solvent. None of the intermediate 5 was observed indicating the enolisation and cyclisation was rapid in either solvent. On completion of the reaction, the crude products, in most cases, precipitated as solids on dilution of the reaction mixture with water. Products were chromatographed to analytical purity or recrystallized from ethanol as they were to be screened for biological activity. The structures of compounds isolated were confirmed by ¹H, ¹⁹F and ¹³C NMR and IR spectroscopy. Composition and purity were confirmed by HRMS and combustion analysis. The ¹⁹F NMR spectra in most cases showed three distinct signals in the range 5–20 ppm (relative to C₆F₆) for the trifluorinated products. For example the 2-acetyl-6-morpholino compound 4eb showed doublet signals at 11.5 (J 17 Hz) and 9.3 (J 20 Hz) and a matching double doublet at 10.3 for the F-5 atom. The amino group protons of 4eb exhibited a singlet peak at 5.88 in the ¹H NMR spectrum with the other derivatives having signals in the range 5.6–6.2 ppm. The structure of the 2-(4-methoxybenzoyl)-6-morpholino substituted benzofuran 4ed was confirmed by single crystal X-ray diffraction analysis (Fig. 2). This showed the 4-methoxybenzoyl group to be coplanar with the benzofuran ring (plane twist angle = 1.21(3)°, plane fold angle = 7.43(3)°) and to form an intramolecular hydrogen bond to the neighbouring 3-amino substituent (N1⋯O1 = 2.7709(11) Å).

Fig. 2 Molecular structure of benzofuran 4ed determined by single crystal X-ray diffraction. ADP ellipsoids shown at 50% probability.

The synthesized compounds are currently undergoing evaluation as cytotoxic agents against a range of pathogens.

We then investigated the possibility of synthesising the analogous 3-unsubstituted, or 3-methyl benzofurans using 4-substituted tetrafluorobenzaldehydes 6a or acetophenones 6b (Scheme 3) as substrates. However, despite precedent from our earlier work using methyl thioglycolate which afforded benzothiophenes,⁶ attempted reactions with methyl glycolate in the presence of base (DBU or NaH) failed to give the desired benzofurans 7, and deacylation of the substrates 6 was observed. The tetrafluorobenzene derivatives 8 were identified by the characteristic triplet of triplets signal around 6.9 ppm (tt, J = 9, 7 Hz) in the ¹H NMR spectra of the products. It appears that the alkoxide ion generated (Scheme 4) attacks the carbonyl group forming a hemi-acetal anion 9a which then collapses expelling the fluoroaryl anion 11. This was confirmed by conducting a reaction of the 4-morpholinotetrafluorobenzaldehyde 6ea in deuterated methanol which led to the benzene derivative 8e with up to 95% deuterium incorporation (Scheme 5). This finding is in line with early reports that pentafluorobenzaldehyde fails to undergo the Cannizzaro reaction. Isolation of S-benzylthiouronium formate indicated the aldehyde group was lost as formate.⁸ The reaction appears to be a particularly facile version of the Haller–Bauer reaction.⁹ Base catalysed ring opening of cyclic perfluorobenzocycloalkenones has recently been reported, which also involves cleavage of the aryl carbonyl bond, generating tetrafluoroarylperfluoroalkanoic acids.¹⁰ A related study on the rate of protodeboronation of arylboronic acids, also invoking an aryl anion intermediate, showed the perfluoroaryl derivative had a half-life of only 2.6 ms in aqueous dioxane at pH 13.¹¹

Scheme 3 Attempted synthesis of 4,5,7-trifluorobenzofurans from perfluorobenzaldehydes or perfluoroacetophenones.

Scheme 4 Alkoxide induced cleavage mechanism leading to protio-deacylation.

Scheme 5 Deuterium incorporation confirmed tetrafluoroaryl anion formation.

When either pentafluorobenzaldehyde 12a or pentafluoroacetophenone 12b was treated with methoxide (Scheme 6) and the reaction followed by NMR spectroscopy we were able to identify the mono- and di-substitution products, 13 and 14, and the deacylated 1,3-dimethoxybenzene 15 which indicated that substitution occurs before deacylation. In the reaction with methyl glycolate it is thought that the more bulky nucleophile will attack the carbonyl group preferentially rather than adding to the more hindered 2-position of the benzene ring.

Scheme 6 Methoxide induced substitution and deacylation in pentafluorobenzaldehyde and pentafluoroacetophenone.

In conclusion twenty-seven fluorinated 3-aminobenzofurans have been accessed via a tandem S_NAr cyclo-condensation reaction of perfluorobenzonitriles with α-hydroxycarbonyl compounds, and were characterized by IR spectroscopy, NMR spectroscopy, HRMS, and elemental analysis. Single crystal X-ray diffraction analysis of the 2-methoxybenzoyl-6-morpholino-derivative confirmed the formation of the core 3-aminobenzofuran ring. The compounds are undergoing screening for biological activity against a number of pathogens and the biological results will be reported in due course.

Experimental

Starting materials for the synthesis of new compounds were obtained from Sigma Aldrich, Alfa Aesar or Fluorochem and used as received. 40–60 Micron silica was used for column chromatography and thin layer chromatography (TLC) was performed using Supleco pre-cut aluminium backed silica gel plates. Compounds on TLC plates were visualised under UV radiation at 254 nm wavelength. Melting points were carried out on a Stuart SMP10 melting point apparatus. IR spectroscopy was carried out on a PerkinElmer Spectrum 65 FT-IR, and NMR spectra were recorded on JEOL ECS400 or JEOL ESZ500 spectrometers with ¹H spectra recorded at 400 or 500 MHz, ¹³C spectra at 100 or 125 MHz and ¹⁹F spectra at 376 or 470 MHz respectively. High resolution mass spectrometry (HRMS) was carried out on a ThermoFisher Exactive (Orbitrap) instrument with an ESI probe and a max ion source. X-ray crystallography was carried out at the UK National Crystallography Service, Southampton.

General procedure for the synthesis of 4-substituted perfluorobenzonitriles

Nucleophile R-H (15 mmol, 1 eq.) was dissolved in DMF (5 mL) and triethylamine (3.04 g, 30 mmol, 2 eq.) was added. Pentafluorobenzonitrile (2.90 g, 15 mmol, 1 eq.) was added and the reaction mixture was stirred at room temperature for 15 h. Water (10 mL) was added to the reaction mixture which was filtered under suction if a solid precipitated, and the solid product dried under vacuum, or, if no solid formed on addition of water, the mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over MgSO₄, filtered and evaporated to dryness on a rotary evaporator to give the following compounds.

4-(1H-Benzo[d]imidazol-1-yl)-2,3,5,6-tetrafluorobenzonitrile (2a). Yellow solid (3.97 g, 91%), mp 160–167 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.01 (t, J = 1.5 Hz, 1H), 7.88 (m, 1H), 7.41 (m, 2H), 7.25 (m, 1H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 32.3 (m, 2F), 20.2 (m, 2F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 148.0, 143.2, 142.1, 141.7, 132.7, 125.2, 124.3, 121.5, 121.2, 110.6, 106.7, 94.3. IR, ν_max/cm⁻¹ 3022, 2244, 1726, 1652, 1609, 1496, 1476, 1455, 1385, 1345, 1304, 1265, 1208, 1128, 1114, 1013, 990, 887 and 867. HRMS expected for C₁₄H₆F₄N₃ 292.0492 observed m/z 292.0492 [M + H⁺].¹²

2,3,5,6-Tetrafluoro-4-(1H-imidazol-1-yl)benzonitrile (2b). Colourless solid (3.56 g, 99%), mp 52–56 °C. ¹H-NMR (400 MHz, CDCl₃) δ_H 7.78 (d, J = 0.8 Hz, 1H), 7.22 (d, J = 18.0, 1.6 Hz, 2H). ¹⁹F-NMR (376 MHz, CDCl₃) δ_F 31.7 (m, 2F), 16.9 (m, 2F). IR, ν_max/cm⁻¹ 3584, 3344, 3137, 2919, 2233, 1696, 1667, 1655, 1520, 1504, 1437, 1362, 1314, 1287, 1226, 1169, 1107, 1085, 1040, 993, 809 and 738. HRMS expected for C₁₀H₄F₄N₃ 274.0962 observed m/z 274.0961 [M + H⁺].¹³

4-(Cyclopropylamino)-2,3,5,6-tetrafluorobenzonitrile (2c). White solid (3.16 g, 92%), mp 115–122 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 4.82 (s, 1H), 2.96 (m, 1H), 0.86 (m, 2H), 0.66 (m, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 26.2 (m, 2F), 2.9 (d, J = 14.1 Hz, 2F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 148.0, 135.8, 134.0, 109.1, 79.3, 27.2, 8.8. IR, ν_max/cm⁻¹ 3420, 3336, 3095, 3019, 2989, 2919, 2849, 2236, 1657, 1537, 1513, 1458, 1361, 1266, 1019, 836 and 737. HRMS expected for C₁₀H₇F₄N₂ 231.0540 observed m/z 231.0547 [M + H⁺].

4-(Cyclopentylamino)-2,3,5,6-tetrafluorobenzonitrile (2d). White solid (3.55 g, 92%), mp 99–107 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 4.40 (s, 2H), 4.25 (m, 1H), 2.03 (m, 2H), 1.70 (m, 4H), 1.52 (m, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 26.4 (m, 2F), 1.9 (d, J = 14.3 Hz, 2F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 148.1, 135.7, 133.1, 109.2, 78.5, 56.6, 34.7, 23.7. IR, ν_max/cm⁻¹ 3467, 3336, 2959, 2924, 2854, 2239, 1655, 1535, 1513, 1480, 1438, 1365, 1314, 1288, 1189, 1126, 1072, 988, 960 and 721. HRMS expected for C₁₂H₁₀F₄N₂Na 281.0672 observed m/z 281.0673 [M + Na⁺].

2,3,5,6-Tetrafluoro-4-morpholinobenzonitrile (2e)⁷. White solid (3.11 g, 80%), mp 76–82 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 3.82 (t, J = 4.5 Hz, 4H), 3.42 (m, 4H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 27.8 (m, 2F), 12.2 (m, 2F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 148.2, 140.6, 135.4, 108.4, 84.5, 67.1, 51.0. IR, ν_max/cm⁻¹ 2968, 2920, 2860, 2235, 1647, 1491, 1444, 1372, 1339, 1263, 1172, 1110, 1067, 1031, 981, 963, 916,858 and 725. HRMS expected for C₁₁H₈F₄N₂ONa 283.0465 observed m/z 283.0465 [M + Na⁺]. In agreement with literature values.⁷

2,3,5,6-Tetrafluoro-4-(4-methylpiperazin-1-yl)benzonitrile (2f). White solid (4.04 g, 99%), mp 72–80 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 3.40 (t, J = 4.5 Hz, 4H), 2.49 (t, J = 4.5 Hz, 4H), 2.31 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 27.2 (m, 2F), 12.1 (m, 2F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 148.2, 140.5, 135.8, 108.5, 83.6, 55.2, 50.6, 46.2. IR, ν_max/cm⁻¹ 3436, 3031, 2984, 2947, 2922, 2849, 2804, 2777, 2755, 2709, 2589, 2236, 1860, 1790, 1723, 1647, 1498, 1455, 1390, 1377, 1336, 1292, 1233, 1184, 1153, 1137, 1076, 988, 935, 816 and 782. HRMS expected for C₁₂H₁₂F₄N₃ 274.0962 observed m/z 274.0961 [M + H⁺].

4-(4-Bromophenoxy)-2,3,5,6-tetrafluorobenzonitrile (2g). White solid (3.41 g, 66%), mp 58–65 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 7.44 (dt, J = 9.0, 3.5 Hz, 2H), 6.89 (dt, J = 9.5, 3.0 Hz, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 29.9 (m, 2F), 11.4 (m, 2F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 155.5, 148.1, 141.4, 139.1, 133.1, 118.0, 117.6, 107.1, 90.3. IR, ν_max/cm⁻¹ 3681, 3448, 3095, 3063, 2936, 2856, 2774, 2648, 2559, 2436, 2323, 2274, 2243, 2042, 1889, 1869, 1787, 1651, 1581, 1497, 1482, 1437, 1404, 1317, 1297, 1277, 1209, 1168, 1102, 1010, 996, 936, 812, 699 and 581. HRMS expected for C₁₃H₄⁷⁹BrF₄NO·Na 367.9305 observed m/z 367.9306 [M + Na⁺].

2,3,5,6-Tetrafluoro-4-(4-nitrophenoxy)benzonitrile (2h). White solid (4.10 g, 87%), mp 124–131 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.27 (dt, J = 9.6, 3.2 Hz, 2H), 7.12 (dt, J = 9.5, 2.4 Hz, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 31.3 (m, 2F), 12.4 (m, 2F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 160.3, 148.2, 144.6, 141.4, 137.7, 126.4, 116.4, 106.9, 91.6. IR, ν_max/cm⁻¹ 3114, 3082, 2249, 1706, 1646, 1615, 1589, 1487, 1438, 1340, 1331, 1317, 1298, 1217, 1166, 1117, 994, 958, 855, 751 and 686.

2-Hydroxy-1-(4-methoxyphenyl)ethanone (3d). 2-Bromo-4-methoxyacetophenone (5.66 g, 24.7 mmol) was dissolved in ethanol (90 mL) and sodium formate (10.8 g, 159 mmol) was added and the mixture was refluxed for 12 h. The reaction was cooled to room temperature and concentrated under vacuum. Water (10 mL) was then added to the residue and the mixture extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried with MgSO₄, filtered and evaporated to dryness to give an orange solid (3.41 g, 83%), mp 105–111 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 7.88 (dt, J = 9.0, 2.0 Hz, 2H), 6.95 (dt, J = 9.0, 2.0 Hz, 2H), 4.81 (s, 2H), 3.87 (s, 3H), 3.58 (s, 1H). ¹³C-NMR (126 MHz, CDCl₃) δ_C 196.8, 164.5, 130.1, 126.4, 114.3, 65.0, 55.4. IR, ν_max/cm⁻¹ 3388, 3080, 3058, 3018, 2975, 2927, 2844, 2054, 1914, 1733, 1681, 1674, 1603, 1577, 1512, 1474, 1464, 1444, 1425, 1406, 1315, 1250, 1185, 1108, 1030, 1008, 992, 979, 836, 822, 635, 609, 569, 497 and 473. GC-MS 166.10.

General procedure for the synthesis of 2,6-disubstututed 3-amino-4,5,7-trifluoro-1-benzofurans 4

The appropriate benzonitrile derivative 2a–h (2 mmol) and hydroxy carbonyl compound 3a–d (2 mmol) were dissolved in the minimum convenient volume of either anhydrous THF (3 mL) or DMF (4 mL) and DBU (0.75 mL, 5 mmol) added. The resulting solution was heated under reflux if THF was employed, or at 80 °C for reactions in DMF, for 1–3 h until consumption of starting material was complete by TLC analysis. The cooled mixture was diluted with water (20 mL) and product collected by suction filtration if solid precipitated, or by extraction with ethyl acetate (3 × 50 mL) if no solid formed. The product was then purified by column chromatography over silica, using gradient elution with dichloromethane : methanol (99 : 1 to 95 : 5), or by recrystallisation from ethanol.

Methyl 3-amino-6-(1H-1,3-benzodiazol-1-yl)-4,5,7-trifluoro-1-benzofuran-2-carboxylate 4aa. Methyl glycolate (0.16 mL, 2.0 mmol) and 4-benzimidazol-1-yltetrafluorobenzonitrile (0.603 g, 2.07 mmol) in DMF afforded 4aa as an off-white solid (0.337 g; 47%), after recrystallization from ethanol, mp 195–206 °C. ¹H-NMR (400 MHz, CDCl₃) δ_H 8.05 (s, 1H), 7.90 (td, J = 10.0, 4.0 Hz, 1H), 7.37 (m, 2H), 7.24 (m, 1H), 5.25 (s, 2H), 3.97 (s, 3H). ¹⁹F-NMR (376 MHz, CDCl₃) δ_F 19.0 (d, J = 16.9 Hz, 1F), 12.4 (d, J = 20.7 Hz, 1F), 12.2 (dt, J = 21.1, 1.9 Hz, 1F). ¹³C-NMR (101 MHz, CDCl₃) δ_C 160.9, 143.3, 142.7, 141.0 (d, J 248 Hz), 140.7 (dd, J 251, 16 Hz), 139.8 (d, J 257 Hz), 137.5–137.3 (m), 137.0, 133.8, 127.7, 124.5, 123.5, 120.9, 114.7–114.6 (m), 113.5–113.4 (m), 110.3, 51.9. IR, ν_max/cm⁻¹ 3400, 1632, 1582, 1531, 1501, 1467, 1427, 1398, 1343, 1300, 1283, 1257, 1212, 1133, 1048, 1000, 960, 892, 873, 847, 762, 743 and 457. HRMS expected for C₁₇H₁₁F₃N₃O₃ 362.0747 observed m/z 362.0746 [M + H⁺]. Elemental Analysis C₁₇H₁₀F₃N₃O₃.0.5H₂O requires C 55.15%, H 2.99% and N 11.35%. Found C 55.26%, H 2.81% and N 11.16%.

1-[3-Amino-6-(1H-1,3-benzodiazol-1-yl)-4,5,7-trifluoro-1-benzofuran-2-yl]ethan-1-one 4ab. Hydroxyacetone (0.14 mL, 2.0 mmol) and 4-benzimidazol-1-yltetrafluorobenzonitrile (0.554 g, 1.87 mmol) in DMF gave 4ab as a yellow solid (0.169 g; 24%), purified by column chromatography, mp 138–144 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.03 (s, 1H), 7.87 (m, 1H), 7.33 (m, 2H), 7.23 (m, 1H), 5.88 (s, 2H), 2.48 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 18.3 (dd, J = 18.4, 4.5 Hz, 1F), 13.3 (dd, J = 21.1, 18.8 Hz, 1F), 11.9 (dd, J = 21.1, 4.5 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 189.7, 143.2, 142.8, 141.3, 140.4, 139.7, 137.1, 137.1, 136.6, 133.7, 124.5, 123.5, 120.8, 113.3, 110.4, 110.4, 26.2 and (101 MHz, CDCl₃) δ_C 189.7, 143.2, 142.8, 141.3 (ddd, J 250, 14, 4 Hz), 140.5 (dd, J 249, 13 Hz), 139.7 (d, J 256 Hz), 137.2 (dd, J 11, 8 Hz), 136.64, 136.58, 133.7, 124.5, 123.5, 120.8, 114.8 (t, J 11 Hz), 113.3 (d, J 16 Hz), 110.4, 26.2. IR, ν_max/cm⁻¹ 3584, 3424, 3312, 3203, 3105, 2918, 2849, 1647, 1614, 1554, 1518, 1501, 1464, 1422, 1390, 1361, 1339, 1297, 1279, 1256, 1210, 1175, 1154, 1124, 1096, 1004, 953, 890, 832, 814, 779, 764, 743, 700, 666 and 470. HRMS expected for C₁₇H₁₁F₃N₃O₃ 346.0798 observed m/z 346.0797 [M + H⁺]. Elemental analysis requires C₁₇H₁₀F₃N₃O₂ C 59.14%, H 2.92% and N 12.17%. Found C 59.12%, H 3.07% and N 11.83%.

2-Benzoyl-6-(1H-1,3-benzodiazol-1-yl)-4,5,7-trifluoro-1-benzofuran-3-amine 4ac. Hydroxyacetophenone (0.282 g, 2.07 mmol) and 4-benzimidazol-1-yltetrafluorobenzonitrile (0.524 g, 2.01 mmol) in THF gave 4ac as a red brown solid (0.310 g; 59%) purified by chromatography, mp 165–171 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.22 (dt, J = 7.0, 1.5 Hz, 2H), 8.11 (m, 1H), 7.92 (m, 1H), 7.60 (tt, J = 7.0, 1.5 Hz, 1H), 7.53 (tt, J = 7.0, 1.5 Hz, 2H), 7.40 (m, 2H), 7.28 (d, J = 6.5 Hz, 1H), 6.28 (s, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 18.8 (dd, J = 18.4, 3.3 Hz, 1F), 13.5 (dd, J = 21.2, 18.8 Hz, 1F), 12.3 (dd, J = 20.7, 3.8 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 183.3, 143.2, 141.3, 140.5 139.7, 137.4, 132.9, 129.3, 128.7, 123.7, 120.9, 115.3, 113.0, 110.5. IR, ν_max/cm⁻¹ 3584, 3350, 3306, 3091, 3059, 2919, 2850, 2218, 1630, 1615, 1600, 1578, 1544, 1501, 1460, 1343, 1322, 1301, 1281, 1259, 1211, 1183, 1154, 1126, 1101, 1042, 1006, 932, 889, 846, 824, 813, 793, 779, 763, 742, 718, 695, 678 and 462. HRMS expected for C₂₂H₁₃N₃O₂F₃ 408.0954 observed m/z 408.0947 [M + H⁺].

(3-Amino-6-(1H-benzo[d]imidazole-1-yl)-4,5,7-trifluorobenzofuran-2-yl)(4-methoxyphenyl)methanone 4ad. Hydroxyketone 3d (0.345 g, 2.08 mmol) and 4-benzimidazolyltetrafluorobenzonitrile 2a (0.382 g, 1.31 mmol) in DMF gave 4ad as a yellow solid (0.118 g, 21%) purified via column chromatography, ¹H-NMR (500 MHz, CDCl₃) δ_H 8.28 (dt, J = 9.0, 2.5 Hz, 2H), 8.06 (m, 1H), 7.91 (m, 1H), 7.39 (m, 2H), 7.28 (m, 1H), 7.03 (dt, J = 9.0, 2.0 Hz, 2H), 6.15 (s, 2H), 3.89 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 18.5 (dd, J = 18.4, 3.8 Hz, 1F), 13.1 (dd, J = 20.7, 18.4 Hz, 1F), 12.1 (dd, 21.2, 4.2 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₆) δ_C {¹H, ¹⁹F} 181.9, 163.5, 143.2, 142.8, 141.3, 140.6, 139.8, 139.3, 137.2, 136.7, 133.8, 131.7, 129.4, 124.6, 123.6, 120.9, 114.9, 114.0, 113.1, 110.5 55.6. IR ν_max/cm⁻¹ 3584, 3339, 2921, 2853, 1629, 1600, 1543, 1504, 1457, 1342, 1304, 1255, 1211, 1171, 1105, 1027, 1005, 963, 933, 843, 763 and 745. HRMS expected for C₂₃H₁₅F₃N₃O₃ 438.1060 observed m/z 438.1060 [M + H⁺].

Methyl 3-amino-4,5,7-trifluoro-6-(1H-imidazol-1-yl)-1-benzofuran-2-carboxylate 4ba. Methyl glycolate (0.21 mL, 2.8 mmol) and 4-imidazol-1-yltetrafluorobenzonitrile 2b (0.664 g, 2.8 mmol) in THF (3 mL) gave 4ba as a red brown solid (0.547 g; 64%), mp 175–181 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 7.79 (s, 1H), 7.28 (t, J = 1.5 Hz, 1H), 7.22 (t, J = 1.5 Hz, 1H), 5.22 (s, 2H), 3.97 (m, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 15.8 (d, J = 17.9 Hz, 1F), 12.1 (t, J = 19.8 Hz, 1F), 9.9 (dt, J = 21.2, 2.4 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 160.9, 140.9, 139.8, 138.6, 138.0, 137.3, 137.0, 130.1, 127.6, 120.5, 116.2, 112.6, 52.0. IR, ν_max/cm⁻¹ 3584, 3437, 3359, 2956, 2862, 2218, 1690, 1633, 1581, 1535, 1519, 1502, 1459, 1426, 1395, 1346, 1316, 1285, 1258, 1207, 1135, 1083, 1040, 1006, 996, 958, 908, 846, 813, 794, 761, 736 and 655. HRMS expected for C₁₃H₉F₃N₃O₃ 312.0591 observed m/z 312.0590 [M + H⁺].

1-[3-Amino-4,5,7-trifluoro-6-(1H-imidazol-1-yl)-1-benzofuran-2-yl]ethan-1-one 4bb. Hydroxyacetone (0.18 mL, 2.6 mmol) and 4-imidazol-1-yltetrafluorobenzonitrile 2b (0.634 g, 2.6 mmol) in THF gave 4bb as a red solid (0.491 g; 63%), mp 108–112 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 7.77 (m, 1H), 7.28 (t, J = 1.0 Hz, 2H), 7.22 (t, J = 1.5 Hz, 1H) 5.74 (s, 2H), 2.51 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 15.3 (dt, J = 18.4, 2.83 Hz, 1F), 12.9 (dd, J = 21.2, 18.4 Hz, 1F), 10.0–9.9 (m, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 189.8, 141.3 (ddd, J 250, 14, 4), 139.6 (dd, J 247, 14), 138.7 (dd, J 253, 3), 138.0, 137.1 (dd, J 13, 8), 136.7, 136.4 (d, J 3), 130.2, 120.4, 116.6 (t, J 14), 112.5 (dd, J 17, 2), 26.2. IR, ν_max/cm⁻¹ 3584, 3401, 3306, 3207, 3120, 2918, 2850, 2218, 1647, 1621, 1555, 1519, 1501, 1465, 1361, 1343, 1314, 1271, 1205, 1136, 1108, 1083, 1040, 1005, 952, 906, 876, 829, 812, 734 and 653. HRMS expected for C₁₃H₉F₃N₃O₂ 296.0641 observed m/z 296.0641 [M + H⁺].

2-Benzoyl-4,5,7-trifluoro-6-(1H-imidazol-1-yl)-1-benzofuran-3-amine 4bc. 2-Hydroxyacetophenone (0.076 g, 0.56 mmol) and 4-imidazol-1-yltetrafluorobenzonitrile 2b (0.134 g, 0.56 mmol) in THF gave 4bc as an orange solid (0.091 g; 50%), purified by column chromatography, mp 196–204 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.21 (dt, J = 7.0, 1.5 Hz, 2H), 7.86 (s, 1H), 7.60 (tt, J = 7.0, 1.5 Hz, 1H), 7.53 (m, 2H) 7.34 (s, 1H), 7.26 (s, 1H), 6.18 (s, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 15.7 (dd, J = 18.4, 3.8 Hz, 1F), 13.3 (dd, J = 20.7, 18.4 Hz, 1F), 10.1 (dt, J = 21.2, 2.4 Hz, 1F). IR, ν_max/cm⁻¹ 3584, 3369, 2917, 2849, 1630, 1599, 1577, 1547, 1507, 1462, 1441, 1346, 1317, 1284, 1208, 1183, 1153, 1104, 1079, 1040, 1008, 928, 909, 822, 812 and 714. HRMS expected for C₁₈H₁₁F₃N₃O₂ 358.0798 observed m/z 358.0792 [M + H⁺].

Methyl 3-amino-6-(cyclopropylamino)-4,5,7-trifluoro-1-benzofuran-2-carboxylate 4ca. Methyl glycolate (0.16 mL, 2.0 mmol) and 4-cyclopropylaminotetrafluorobenzonitrile 2c (0.345 g, 1.5 mmol) in DMF gave 4ca as a light brown solid (0.103 g; 22%) purified by column chromatography, ¹H-NMR (500 MHz, CDCl₃) δ_H 5.10 (s, 2H), 4.20 (s, 1H), 3.90 (s, 3H), 2.89 (m, 1H), 0.76 (m, 2H), 0.60 (m, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 8.5 (m, 1F), 2.6 (m, 1F), 1.0 (dd, J = 20.3, 3.3 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹⁹F} 161.3, 140.7, 138.9, 138.5, 137.1, 133.5, 128.6, 125.2, 125.0, 102.1, 51.5 (q, ¹J_CH 183 Hz), 27.8 (d, ¹J_CH 226 Hz), 8.74 (t, ¹J_CH 202 Hz). IR, ν_max/cm⁻¹ 3585, 3494–3372, 3091, 3010, 2956, 2919, 2851, 1675, 1624, 1575, 1534, 1509, 1453, 1423, 1384, 1363, 1348, 1300, 1269, 1229, 1183, 1128, 1022, 1049, 965, 953, 927, 847, 832, 819, 797, 759, 734 and 457. HRMS expected for C₁₃H₁₂F₃N₂O₃ 301.0795 observed m/z 301.0794 [M + H⁺]. Elemental analysis expected for C₁₉H₁₈F₃N₅ C 50.49% H 3.88% N 9.05%, found C 50.79% H 3.51% N 9.01%.

1-[3-Amino-6-(cyclopropylamino)-4,5,7-trifluoro-1-benzofuran-2-yl]ethan-1-one 4cb. Hydroxyacetone (0.14 mL, 2.00 mmol) and 4-cyclopropylaminotetrafluorobenzonitrile 2c (0.516 g, 2.24 mmol) in DMF gave 4cb as an off-white solid (0.086 g; 15%) purified by chromatography, mp 123–129 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 5.71 (s, 2H), 4.34 (s, 1H), 2.93 (m, 1H), 2.44 (s, 3H), 0.80 (m, 2H), 0.62 (m, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 9.3 (dd, J = 20.3, 16.0 Hz, 1F), 2.0 (dt, J = 16.0, 3.3 Hz, 1F), 0.9 (dd, J = 20.3, 3.3 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹⁹F} 188.3, 141.1, 139.0, 138.4, 136.8, 135.4133.4, 129.1, 101.8, 27.8 (d, ¹J_CH 180 Hz), 25.7 (q, ¹J_CH 127 Hz), 8.79 (t, ¹J_CH 164 Hz). IR, ν_max/cm⁻¹ 3584, 3497, 3313, 3016, 1775, 1732, 1661, 1640, 1596, 1555, 1503, 1452, 1392, 1361, 1300, 1269, 1232, 1172, 1130, 1105, 1046, 1017, 946, 931, 848, 833, 799, 765, 739, 693, 675, 656 and 459. HRMS expected for C₁₃H₁₂F₃N₂O₂ 285.0845 observed m/z 285.0845 [M + H⁺]. Elemental analysis expected for C₁₃H₁₁F₃N₂O₂ C 53.61% H 4.12% N 9.62%, found C 53.19% H 3.74% N 9.57%.

2-Benzoyl-N⁶-cyclopropyl-4,5,7-trifluoro-1-benzofuran-3,6-diamine 4cc. 2-Hydroxyacetophenone (0.273 g, 2.01 mmol) and 4-cyclopropylaminotetrafluorobenzonitrile 2c (0.516 g, 2.24 mmol) in DMF gave 4cc as a brown solid (0.617 g; 89%) purified by chromatography, ¹H-NMR (400 MHz, CDCl₃) δ_H 8.18 (m, 2H), 7.52 (m, 3H), 6.15 (m, 2H), 4.38 (m, 1H), 2.94 (m, 1H), 0.84 (m, 2H), 0.65 (m, 2H). ¹⁹F-NMR (376 MHz, CDCl₃) δ_F 9.6 (dd, J = 20.3, 16.0 Hz, 1F), 2.2 (d, J = 16.0 Hz, 1F), 0.9 (dd, J = 20.3, 4.2 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 181.7, 142.1, 141.1, 137.4, 137.1, 135.2, 133.4, 132.0, 132.0, 129.2, 128.4, 124.7, 101.4, 27.8 (d, ¹J_CH 181 Hz), 8.84 (t, ¹J_CH 164 Hz). IR, ν_max/cm⁻¹ 3584, 3492, 3346, 3060, 2957, 2850, 2230, 1665, 1618, 1600, 1576, 1554, 1494, 1453, 1438, 1382, 1361, 1350, 1306, 1272, 1230, 1182, 1123, 1074, 1048, 1022, 961, 947, 912, 847, 743, 712, 694, 677 and 458. HRMS expected for C₁₈H₁₄F₃N₂O₂ 347.1002 observed m/z 347.1001 [M + H⁺].

Methyl 3-amino-6-(cyclopentylamino)-4,5,7-trifluoro-1-benzofuran-2-carboxylate 4da. Methyl glycolate (0.16 mL, 2.0 mmol) and 4-cyclopentylaminotetrafluorobenzonitile 2d (0.516 g, 2.0 mmol) in DMF gave 4da as an orange solid (0.145 g, 22%) purified by chromatography, ¹H-NMR (500 MHz, CDCl₃) δ_H 5.07 (s, 2H), 4.18 (m, 1H), 3.89 (s, 3H), 3.66 (s, 1H), 1.96 (m, 2H), 1.66 (m, 4H), 1.46 (m, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 8.7 (m, 1F), 2.3 (m, 1F), 0.8 (dq, J = 20.3, 2.4 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 161.3, 140.8, 138.9, 137.4, 134.8, 133.6, 132.5, 124.9, 101.9 57.0, 51.5, 34.4, 23.7. IR, ν_max/cm⁻¹ 3584, 3379, 2956, 2871, 2225, 1826, 1678, 1624, 1575, 1532, 1454, 1422, 1384, 1344, 1314, 1294, 1263, 1191, 1149, 1130, 995, 974, 950, 896, 878, 819, 760, 733 and 455. HRMS expected for C₁₅H₁₆F₃N₂O₃ 329.1108 observed m/z 329.1107 [M + H⁺].

1-[3-Amino-6-(cyclopentylamino)-4,5,7-trifluoro-1-benzofuran-2-yl]ethan-1-one 4db. Hydroxyacetone (0.14 mL, 2.00 mmol) and 4-cyclopentylaminotetrafluorobenzonitrile 2d (0.501 g, 1.94 mmol) in DMF gave 4db as a brown solid (0.464 g; 76%) purified by chromatography, mp 98–105 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 5.74 (s, 2H), 4.23 (s, 1H, NH), 3.89 (s, 1H), 2.44 (s, 3H), 2.01 (m, 2H), 1.64 (m, 4H), 1.53 (m, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 9.4 (dd, J = 20.7, 16.0 Hz, 1F), 1.6 (d, J = 16.0 Hz, 1F), 0.8 (d, J = 20.3 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 188.3, 145.0, 140.4, 140.3, 138.4, 136.2, 135.4, 128.6, 101.8, 57.0, 34.5, 25.9, 23.7. IR, ν_max/cm⁻¹ 3584, 3498, 3429, 3338, 3205, 2959, 2872, 1664, 1638, 1604, 1558, 1510, 1455, 1392, 1380, 1361, 1342, 1311, 1294, 1265, 1173, 1095, 1002, 975, 944, 741 and 460. HRMS expected for C₁₅H₁₆F₃N₂O₂ 313.1158 observed m/z 313.1158 [M + H⁺].

2-Benzoyl-N⁶-cyclopentyl-4,5,7-trifluoro-1-benzofuran-3,6-diamine 4dc. 2-Hydroxyacetophenone (0.272 g, 2.00 mmol) and 4-cyclopentylaminotetrafluorobenzonitrile 2d (0.202 g, 0.78 mmol) in DMF gave 4dc as a brown solid (0.293 g; 39%) purified by chromatography, mp 105–111 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.20 (m, 2H), 7.45 (m, 3H), 6.20 (s, 2H), 4.29 (s, 1H), 3.77 (m, 1H, NH), 2.00 (m, 2H), 1.69 (m, 4H), 1.51 (m, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 9.8 (dd, J = 20.7, 16.5 Hz, 1F), 1.7 (d, J = 16.0 Hz, 1F), 0.7 (dd, J = 20.3, 1.9 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 181.6, 142.1, 141.2, 139.5, 137.5, 137.3, 135.2, 134.4, 133.4, 131.9, 129.2, 128.4, 107.2, 57.0, 34.5, 29.8, 23.7. IR, ν_max/cm⁻¹ 3584, 3427, 3340, 3061, 3026, 2960, 2872, 2247, 2223, 1818, 1664, 1620, 1575, 1554, 1494, 1455, 1438, 1380, 1346, 1323, 1313, 1295, 1266, 1183, 1157, 1101, 1073, 1003, 970, 931, 914, 847, 793, 733, 710, 695, 678, 632 and 647. HRMS expected for C₂₀H₁₈F₃N₂O₂ 375.1315 observed m/z 375.1314 [M + H⁺].

Methyl-3-amino-4,5,7-trifluoro-6-(morpholin-4-yl)-1-benzofuran-2-carboxylate 4ea. Methyl glycolate (0.16 mL, 2.0 mmol) and 4-morpholinotetrafluorobenzonitrile 2e (0.522 g, 2.0 mmol) in DMF gave 4ea as an off-white solid (0.375 g; 57%) purified by chromatography, mp 138–143 °C. ¹H-NMR (400 MHz, CDCl₃) δ_H 5.12 (s, 2H), 3.95 (m, 3H), 3.81 (m, J = 4.4 Hz, 4H), 3.28 (t, J = 4.0 Hz, 4H). ¹⁹F-NMR (376 MHz, CDCl₃) δ_F 12.2 (m, 1F), 9.4 (m, 2F). ¹³C-NMR (101 MHz, CDCl₃) δ_C 161.2, 141.8, 140.9, 139.5, 138.3, 137.8, 130.0, 125.9, 107.3, 67.5, 51.7, 51.5. IR, ν_max/cm⁻¹ 3583, 3449, 3380, 2958, 2850, 1682, 1658, 1627, 1573, 1520, 1449, 1424, 1388, 1375, 1340, 1305, 1290, 1264, 1194, 1153, 1115, 1069, 1033, 1000, 990, 958, 923, 864, 833, 808, 797, 760 and 733. HRMS expected for C₁₄H₁₄F₃N₂O₄ 331.0900 observed m/z 331.0899 [M + H⁺]. Elemental analysis C₁₄H₁₃F₃N₃O₄ requires C 50.92%, H 3.97% and N 8.48%, found C 50.84%, H 3.99% and N 8.67%.

1-[3-Amino-4,5,7-trifluoro-6-(morpholin-4-yl)-1-benzofuran-2-yl]ethan-1-one 4eb. Hydroxyacetone (0.14 mL, 2.0 mmol) and 4-morpholinotetrafluorobenzonitrile 2e (0.535 g, 2.00 mmol) in DMF (3 mL) gave 4eb as a brown oil (0.537 g; 85%) purified by chromatography which then solidified, mp 198–204 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 5.69 (s, 2H), 3.83 (m, J = 5.0 Hz, 4H), 3.31 (m, 4H), 2.46 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 11.5 (d, J = 17.0 Hz, 1F), 10.3 (dd, J = 20.3, 16.5 Hz, 1F), 9.3 (d, J = 20.3 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 189.2, 141.6, 141.4, 139.5, 138.3, 137.4, 135.9, 130.5 107.0, 67.5, 51.6, 26.0. IR, ν_max/cm⁻¹ 3585, 3429, 3318, 3209, 2965, 2853, 1815, 1731, 1647, 1614, 1545, 1508, 1446, 1385, 1359, 1334, 1304, 1287, 1264, 1215, 1174, 1153, 1116, 1068, 998, 947, 923, 864, 818, 807, 734 and 712. HRMS expected for C₁₄H₁₄F₃N₂O₃ 315.0951 observed m/z 315.0951 [M + H⁺].

2-Benzoyl-4,5,7-trifluoro-6-(morpholin-4-yl)-1-benzofuran-3-amine 4ec. 2-Hydroxyacetophenone (0.273 g, 2.0 mmol) and 4-morpholinetetrafluorobenzonitrile 2e (0.355 g, 1.4 mmol) in DMF gave as a yellow solid 4ec (0.421 g, 56%) purified by chromatography, mp 109–113 °C. ¹H-NMR (400 MHz, CDCl₃) δ_H 8.21 (m, 2H), 7.54 (m, 3H), 6.14 (s, 2H), 3.82 (t, J = 4.8 Hz, 4H), 3.29 (m, 4H). ¹⁹F-NMR (376 MHz, CDCl₃) δ_F 11.8 (d, J = 16.5 Hz, 1F), 10.6 (dd, J = 20.3, 16.9 Hz, 1F), 9.4 (d, J = 20.3 Hz, 1F). ¹³C-NMR (101 MHz, CDCl₃) δ_C 182.5, 141.5, 141.4, 139.4, 138.7, 137.2, 135.2, 132.3, 132.3, 130.8, 129.2, 128.5, 106.6, 67.5, 51.6. IR, ν_max/cm⁻¹ 3434, 3325, 2960–2853, 2758, 2692, 2230, 1823, 1721, 1657, 1626, 1600, 1536, 1493, 1450, 1440, 1386, 1374, 1341, 1307, 1290, 1264, 1181, 1153, 1115, 1069, 1029, 1000, 926, 861, 747, 694, 678 and 463. HRMS expected for C₁₉H₁₆F₃N₂O₃ 377.1108 observed m/z 377.1106 [M + H⁺].

(3-Amino-4,5,7-trifluoro-6-morpholinobenzofuran-2-yl)(4-methoxyphenyl)methanone 4ed. 2-Hydroxy-1-(4-methoxyphenyl)ethan-1-one (0.326 g, 1.96 mmol) and 4-morpholinotetrafluorobenzonitrile 2e (0.570 g, 2.19 mmol) in DMF gave 4ed as a yellow solid (0.316 g, 39%) purified by chromatography eluting with ethyl acetate, mp 159–164 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.24 (dt, J = 9.0, 3.0 Hz, 2H), 6.99 (dt, J = 9.0, 2.5 Hz, 2H), 6.07 (s, 2H), 3.88 (s, 3H), 3.36 (t, J = 3.5 Hz, 4H), 3.32 (t, J = 3.5 Hz, 4H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 11.8 (d, J = 16.5 Hz, 1F), 10.1 (dd, J = 20.7, 17.0 Hz, 1F), 9.4 (d, J = 20.3 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₆) δ_C {¹H, ¹⁹F} 181.2, 163.0, 141.6, 141.3, 140.4, 139.4, 138.4, 135.7, 131.5, 130.5, 129.9, 113.8, 106.8, 55.5, 51.6, 46.3. IR, ν_max/cm⁻¹ 3401, 2929, 2799, 1661, 1623, 1602, 1569, 1540, 1512, 1488, 1456, 1417, 1391, 1372, 1301, 1286, 1255, 1175, 1139, 112, 1029, 1002, 925, 908, 843, 762, 732, 560, 507 and 471. GC-MS for C₂₀H₁₈F₃N₂O₄ found m/z 406.20 (M⁺).

Methyl 3-amino-4,5,7-trifluoro-6-(4-methylpiperazin-1-yl)-1-benzofuran-2-carboxylate 4fa. Methyl glycolate (0.15 mL, 2.0 mmol) and 4-(4-methylpiperazin-1-yl)tetrafluorobenzonitrile 2f (0.545 g, 1.99 mmol) in DMF gave 4fa as a brown solid (0.153 g; 22%) crystallised from ethanol, mp 138–145 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 5.11 (s, 2H), 3.92 (m, 3H), 3.32 (t, J = 4.5 Hz, 4H), 2.55 (m, 4H), 2.30 (m, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 12.5 (d, J = 12.7 Hz, 1F), 9.5 (d, J = 20.3 Hz, 1F), 9.2 (m, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 161.3, 141.8, 140.9, 139.5, 138.4, 137.9, 125.9, 130.4, 107.0, 51.7, 51.0, 46.3, 46.3. IR, ν_max/cm⁻¹ 3584, 3468, 3368, 3189, 2943, 2888, 2849, 2801, 2748, 1682, 1626, 1572, 1520, 1452, 1425, 1391, 1373, 1341, 1301, 1285, 1258, 1230, 1194, 1171, 1132, 1076, 1051, 1035, 1004, 991, 957, 936, 802, 779, 760, 735, 699, 638 and 455. HRMS expected for C₁₅H₁₇F₃N₃O₃ 344.1217 observed m/z 344.1209 [M + H⁺]. Elemental analysis expected for C₁₅H₁₆F₃N₃O₃.0.5H₂O C 51.40% H 4.79% N 11.99%, found C 51.84% H 4.69% N 11.94%.

1-[3-Amino-4,5,7-trifluoro-6-(4-methylpierazin-1-yl)-1-benzofuran-2-yl]ethan-1-one 4fb. Methyl glycolate (0.15 mL, 2.0 mmol) and 4-(4-methylpiperazin-1-yl)tetrafluorobenzonitrile 2f (0.543 g, 1.99 mmol) in DMF gave 4fb as a brown solid (0.477 g; 73%) crystallised from ethanol, mp 128–135 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 5.69 (s, 2H, NH₂), 3.33 (t, J = 4.5 Hz, 4H), 2.55 (t, J = 4.0 Hz, 4H), 2.43 (m, 3H), 2.34 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 11.6 (d, J = 16.5 Hz, 1F), 10.0 (dd, J = 20.7, 17.0 Hz, 1F), 9.4 (d, J = 20.3 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹H, ¹⁹F} 189.1, 141.5, 141.4, 139.5, 138.4, 137.5, 135.8, 130.8, 106.6, 55.5, 51.0, 46.3, 26.0. IR, ν_max/cm⁻¹ 3583, 3414, 2938, 2888, 2850, 2803, 2747, 2694, 2219, 1863, 1841, 1787, 1643, 1545, 1507, 1450, 1391, 1372, 1361, 1333, 1300, 1284, 1259, 1230, 1171, 1154, 1139, 1076, 1052, 999, 950, 833, 810, 781, 732 and 466. HRMS expected for C₁₅H₁₇F₃N₃O₂ 328.1267 observed m/z 328.1258 [M + H⁺]. Elemental analysis C₁₅H₁₆F₃N₃O₂ requires C 55.05%, H 4.93% N 12.84, found C 55.24%, H 5.14% N 12.66%.

2-Benzoyl-4,5,7-trifluoro-6-(4-methylpiperazin-1-yl)-1-benzofuran-3-amine 4fc. 2-Hyroxyacetophenone (0.293 g, 2.15 mmol) and 4-(4-methylpiperazin-1-yl)tetrafluorobenzonitrile 2f (0.566 g, 2.07 mmol) in THF gave 4fc as a yellow-orange solid (0.065 g; 12%) purified by chromatography, mp 138–144 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.20 (dd, J = 8.5, 1.0 Hz, 2H), 7.55 (tt, J = 7.0, 1.5 Hz, 1H), 7.50 (tt, J = 7.5, 1.5 Hz, 2H), 6.13 (s, 2H), 3.43 (m, 4H), 2.70 (m, 4H), 2.44 (m, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 12.1 (d, J = 16.0 Hz, 1F), 10.6 (t, J = 19.3 Hz, 1F), 9.5 (d, J = 20.7 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 182.5, 141.5, 141.4, 140.9, 139.3, 138.7, 137.2, 135.7, 132.3, 130.8, 129.2, 128.5, 106.4, 55.3, 50.6, 45.9. IR, ν_max/cm⁻¹ 3488, 3323, 3193, 3059, 2936, 2888, 2849, 2799, 1658, 1625, 1601, 1577, 1536, 1494, 1452, 1440, 1391, 1373, 1341, 1285, 1261, 1231, 1182, 1168, 1155, 1139, 1075, 1029, 1002, 934, 926, 736, 717, 696, 678, 631, 616, 564 and 458. HRMS expected for C₂₀H₁₉F₃N₃O₂ 390.1424 observed m/z 390.1416 [M + H⁺]. Elemental analysis C₂₀H₁₈F₃N₃O₂.H₂O requires C 58.97%, H 4.91% N 10.32%, found C 58.56%, H 4.43% N 10.17%.

(3-Amino-4,5,7-trifluoro-6-(4-methylpiperazin-1-yl)benzofuran-2-yl)(4-methoxyphenyl)methanone 4fd. 2-Hydroxy-1-(4-methoxyphenyl)ethan-1-one 3d (0.347 g, 2.09 mmol) and 4-(4-methylpiperazin-1-yl)tetrafluorobenzonitrile 2f (0.580 g, 2.12 mmol) in DMF gave 4fd as a yellow solid (0.157 g, 19%) purified by chromatography eluting with ethyl acetate, mp 162–168 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.22 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 6.07 (s, 2H), 3.88 (s, 3H), 3.35 (m, 4H), 2.56 (m, 4H), 2.36 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 11.8 (d, J = 16.5 Hz, 1F), 10.1 (t, J = 19.8 Hz, 1F), 9.3 (d, J = 20.3 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C {¹⁹F, ¹H} 181.0, 162.8, 141.5, 141.3, 140.5, 139.4, 138.5, 135.7, 131.5, 130.9, 130.0, 113.8, 106.4, 55.5 (2xC, OC̲H₃ and MeNC̲H₂), 51.1, 46.3. IR, ν_max/cm⁻¹ 3386, 3288, 2979, 2840, 1659, 1600, 1573, 1536, 1509, 1492, 1447, 1439, 1418, 1385, 1366, 1347, 1302, 1290, 1263, 1250, 1176, 1166, 1033, 1001, 927, 853, 762, 684, 619, 523 and 469. HRMS expected for C₂₁H₂₁F₃N₃O₃ 420.1530 observed m/z 420.1528 [M + H⁺].

Methyl 3-amino-6-(4-bromophenoxy)-4,5,7-trifluoro-1-benzofuran-2-carboxylate 4ga. Methyl glycolate (0.15 mL, 2.00 mmol) and 4-(4-bromophenoxy)tetrafluorobenzonitrile 2g (0.704 g, 2.03 mmol) in THF gave 4ga as a red brown solid (0.580 g; 70%) crystallised from ethanol, mp 74–79 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 7.41 (dt, J = 9.0, 3.5 Hz, 2H), 6.85 (dt, J = 9.5, 3.5 Hz, 2H), 5.19 (s, 2H), 3.96 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 11.1 (t, J = 18.8 Hz, 1F), 9.0 (d, J = 17.0 Hz, 1F), 5.2 (dd, J = 20.7, 1.9 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₆) δ_C {¹H, ¹⁹F} 161.1, 156.6, 140.9, 140.1, 138.6, 137.5, 136.7, 133.0, 132.8, 117.2, 116.2, 109.9, 107.6, 51.9. IR, ν_max/cm⁻¹ 3490, 3370, 2954, 1690, 1627, 1579, 1524, 1483, 1456, 1343, 1309, 1269, 1208, 1168, 1130, 1069, 1008, 950, 825, 761 and 737. HRMS expected for C₁₆H₁₀BrF₃NO₄ 415.9740 observed m/z 415.9740 [M + H⁺].

2-Benzoyl-6-(4-bromophenoxy)-4,5,7-trifluoro-1-benzofuran-3-amine 4gc. 2-Hydroxyacetophenone (0.272 g, 2.00 mmol) and 4-(4-bromophenoxy)tetrafluorobenzonitrile (0.792 g, 2.29 mmol) in DMF gave 4gc as a bright yellow solid (0.705 g; 77%) purified by chromatography and preparative TLC (eluting with light petroleum-ethyl acetate), mp 135–142 °C. ¹H-NMR (400 MHz, CDCl₃) δ_H 8.20 (tt, J = 8.4, 2.0 Hz, 2H), 7.58 (tt, J = 7.2, 1.8 Hz, 1H), 7.51 (tt, J = 6.8, 1.6 Hz, 2H), 7.43 (dt, J = 9.2, 3.2 Hz, 2H), 6.88 (dt, J = 9.2, 3.2 Hz, 2H), 6.17 (s, 2H). ¹⁹F-NMR (376 MHz, CDCl₃) δ_F 12.3 (dd, J = 20.7, 17.3 Hz, 1F), 9.8 (dd, J = 17.3, 1.5 Hz, 1F), 5.3 (m, J = 20.7, 1.5 Hz, 1F). ¹³C-NMR (101 MHz, CDCl₃) δ_C 183.0, 156.6, 141.3, 140.2, 140.0, 138.8, 137.7, 136.8, 136.2, 133.8, 132.8, 132.6, 129.2, 128.6, 117.5, 116.4, 109.3. IR, ν_max/cm⁻¹ 3416, 3308, 2924, 1625, 1574, 1540, 1482, 1461, 1437, 1385, 1345, 1313, 1267, 1211, 1186, 1168, 1153, 1099, 1071, 1008, 916, 824, 735, 704, 683, 608, 549 and 493. HRMS expected for C₂₁H₁₂BrF₃NO₃ 461.9947 observed m/z 461.9942 [M + H⁺].

(3-Amino-6-(4-bromophenoxy)-4,5,7-trifluorobenzofuran-2-yl)(4-methoxyphenyl)methanone 4gd. 2-Hydroxy-1-(4-methoxyphenyl)ethan-1-one 3d (0.377 g, 2.27 mmol) and 4-(4-bromophenoxy)tetrafluorobenzonitrile (0.690 g, 1.99 mmol) in DMF gave 4gd as a yellow solid (0.219 g, 22%) purified by chromatography eluting with light petroleum-ethyl acetate, mp 192–198 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.25 (dt, J = 10.0, 3.0 Hz, 2H), 7.43 (dt, J = 9.0, 2.0 Hz, 2H), 7.00 (dt, J = 9.0, 2.0 Hz, 2H), 6.89 (dt, J = 9.0, 2.0 Hz, 2H), 6.10 (s, 2H), 3.89 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 12.0 (dd, J = 20.7, 17.4 Hz, 1F), 9.5 (dd, J = 17.4, 1.4 Hz, 1F), 5.0 (dd, J = 20.7, 1.4 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₆) δ_C {¹H, ¹⁹F} 181.6, 163.2, 156.7, 141.3, 140.0, 139.7, 138.7, 137.5, 136.3, 133.5, 132.8, 131.6, 129.6, 117.4, 116.3, 113.9, 109.4, 55.5. IR ν_max/cm⁻¹ 3494, 3338, 2931, 2840, 1632, 1603, 1541, 1512, 1483, 1449, 1384, 1348, 1309, 1260, 1216, 1169, 1098, 1072, 1026, 1008, 920, 882, 846, 821, 760, 697, 631, 604, 582, 565 and 551.

Methyl 3-amino-4,5,7-trifluoro-6-(4-nitrophenoxy)-1-benzofuran-2-carboxylate 4ha. Methyl glycolate (0.15 mL, 2.00 mmol) and 4-(4-nitrophenoxy)tetrafluorobenzonitrile (0.656 g, 2.10 mmol) in DMF gave 4ha as a light brown solid (0.222 g; 29%) purified by trituration with ether, mp 91–96 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.24 (dt, J = 9.5, 3.0 Hz, 2H), 7.06 (dt, J = 9.5, 3.0 Hz, 2H), 5.21 (s, 2H), 3.96 (m, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 11.8 (t, J = 20.3 Hz, 1F), 10.5 (d, J = 17.0 Hz, 1F), 5.3 (dd, J = 20.7, 2.8 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 161.7, 161.1, 143.8, 141.0, 139.7, 138.5, 137.5, 137.2, 131.8, 127.2, 126.2, 115.7, 110.6, 52.0. IR, ν_max/cm⁻¹ 3490, 3377, 2929, 2854, 1691, 1615, 1590, 1521, 1490, 1457, 1345, 1308, 1222, 1168, 1113, 1010, 949, 863 and 749. HRMS expected for C₁₆H₁₀F₃N₂O₆ 383.0485 observed m/z 383.0477 [M + H⁺].

2-Benzoyl-4,5,7-trifluoro-6-(4-nitrophenoxy)-1-benzofuran-3-one 4hc. 2-Hydroxyacetophenone (0.269 g, 1.97 mmol) and 4-(4-nitrophenoxy)tetrafluorobenzonitrile (0.666 g, 2.13 mmol) in DMF gave 4hc as a light brown solid (0.235 g; 27%) purified by trituration with ether, mp 121–127 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.25 (tt, J = 9.5, 3.5 Hz, 2H), 8.18 (m, 2H), 7.58 (tt, J = 7.0, 1.5 Hz, 1H), 7.52 (tt, J = 7.5, 1.5 Hz, 2H), 7.09 (tt, J = 9.0, 3.5 Hz, 2H), 6.18 (s, 2H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 12.9 (dd, J = 20.7, 17.4 Hz, 1F), 10.3 (dd, J = 17.4, 2.8 Hz, 1F), 5.4 (dd, J = 20.7, 2.8 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₃) δ_C 183.1, 161.7, 143.9, 141.4, 139.7, 138.6, 137.6, 136.7, 136.4, 132.7, 132.6, 129.2, 128.6, 126.2, 126.1, 115.8, 110.1. IR, ν_max/cm⁻¹ 3056, 2934, 2853, 1617, 1592, 1523, 1490, 1456, 1346, 1265, 1222, 1167, 1113, 1011, 862, 738, 704 and 464. HRMS expected for C₂₁H₁₂F₃N₂O₅ 429.0693 observed m/z 429.0694 [M + H⁺]. Elemental analysis requires C₂₁H₁₁F₃N₂O₅ C 58.89%, H 2.59% and N 6.54%, found C 58.54%, H 2.84% and N 6.42%.

(3-Amino-4,5,7-trifluoro-6-(4-nitrophenoxy)benzofuran-2-yl)(4-methoxyphenyl)methanone 4hd. 2-Hydroxy-1-(4-methoxyphenyl)ethan-1-one 3d (0.335 g, 2.02 mmol) and 4-(4-nitrophenoxy)tetrafluorobenzonitrile (0.683 g, 2.19 mmol) in DMF gave an off-white solid 4hd (0.138 g, 15%) purified by chromatography eluting with light petroleum-ethyl acetate, mp 172–180 °C. ¹H-NMR (500 MHz, CDCl₃) δ_H 8.28–8.23 (m, 4H), 7.12–7.08 (m, 2H), 7.03–7.00 (m, 2H), 6.12 (bs, 2H), 3.89 (s, 3H). ¹⁹F-NMR (471 MHz, CDCl₃) δ_F 12.7 (dd, J = 20.7, 17.4 Hz, 1F), 10.1 (dd, J = 17.0, 2.4 Hz, 1F), 5.2 (dd, J = 20.7, 2.8 Hz, 1F). ¹³C-NMR (126 MHz, CDCl₆) δ_C {¹H, ¹⁹F} 181.7, 163.4, 161.7, 143.9, 141.4, 139.6, 139.5, 138.5, 137.4, 136.5, 132.3, 131.5, 129.5, 126.2, 115.8, 113.9, 110.3, 55.6. IR, ν_max/cm⁻¹ 3485, 3361, 2930, 2850, 1633, 1601, 1574, 1543, 1513, 1489, 1452, 1418, 1346, 1308, 1257, 1217, 1176, 1160, 1112, 1007, 918, 864, 851, 761, 695, 679, 645, 632, 570, 544 and 471. HRMS expected for C₂₂H₁₄F₃N₂O₆ 459.0798 observed m/z 459.0800 [M + H⁺].

Investigations of carbonyl group cleavage

4-Benzimidazol-1-yltetrafluorobenzene 8a was identified from cleavage of 4-benzimidazol-1-yltetrafluorobenzaldehyde in the presence of sodium methoxide.

4-Benzimidazol-1-yltetrafluorobenzene 8a. ¹H-NMR (400 MHz, CDCl₃) δ_H 8.05 (s, 1H), 7.91–7.87 (m, 1H), 7.41–7.37 (m, 2H), 7.29–7.25 (m, 1H), 6.97 (m, 1H).

¹⁹F-NMR (376 MHz, CDCl3) δ_F 25.8–25.6 (m, 2F), 16.5–16.3 (m, 2F).

IR, ν_max/cm⁻¹ 3429, 2926, 2854, 2119, 1646, 1614, 1517, 1452, 1411, 1305, 1289, 1266, 1253, 1207, 1180, 1152, 1136, 1086, 1008, 991, 946, 889, 839, 782, 764, 742, 714 and 702.

LC-MS m/z 266.80.

HRMS calculated for C₁₃H₇F₄N₂ 267.0540, observed m/z 267.0540 [M + H]⁺.

4-(2,3,5,6-Tetrafluorophenyl)morpholine 8e. Attempted reaction of 4-morpholinotetrafluorobenzaldehyde with methyl glycolate and DBU led to formation of an off-white solid 8e in low yield.

¹H-NMR δ_H (400 MHz, CDCl₃) δ_H 6.69 (tt, J = 9.9, 7.1 Hz, 1H, H-1), 3.84–3.75 (m, 4H, H-2′/H-6′), 3.28–3.22 (m, 4H, H-3′/H-5′).

¹⁹F-NMR δ_F (376 MHz, CDCl₃) δ_F 29.0–28.8 (2F, m), 18.2–18.0 (2F, m).

¹³C-NMR δ_C (101 MHz, CDCl₃), 147.6 (dtd, J = 245, 12.5, 3.75 Hz), 145.6 (dtd, J = 245, 12.5, 3.75 Hz), 143.3 (ddt, J = 244, 14, 4 Hz) 141.4 (ddt, J = 244, 14, 4 Hz) 130.6 (t, J = 11 Hz), 99.7–98.6 (m), 67.4 (s, CH₂, C-3’/C-5′), 51.2 (s, CH₂, C-2′/C-6′).

IR, ν_max/cm⁻¹ 3048 (C–H, aromatic), 2966–2863 (C–H, saturated), 1641–1450 (C=C, aromatic), 1378 (C–F), 1184 (C–N), 1137 (C–O).

LC-MS 236.15 [M + H]⁺.

HRMS expected for C₁₀H₁₀F₄NO 236.0676, observed m/z 236.0676 [M + H]⁺.

Reaction of 4-morpholinotetrafluorobenzaldehyde 6ea with sodium methoxide in deuterated methanol – D-8e

Sodium (0.004 g, 0.2 mmol, 1.1 eq.) was dissolved in CD₃OD (1 mL). Then 4-morpholinotetrafluorobenzaldehyde 6ea (0.050 g, 0.18 mmol, 1 eq.) was added and dissolved. The solution was heated under reflux for 2 h. Water (15 mL) was poured into the reaction mixture which was then extracted with ethyl acetate (3 × 15 mL). The organic layer was dried over MgSO₄, filtered and evaporated to dryness. The residue (0.026 g) was taken up in CD₃OCD₃ and shown by NMR to be a mixture containing:

D-8e. NMR δ_H (400 MHz, CD₃OCD₃) 6.69 (tt, J = 9.9, 7.1 Hz, integrates at <0.05 H, 95% deuterium incorporation).

IR ν_max/cm⁻¹ 3584, 2960, 2893, 2855, 2225, 2132, 2073, 1693, 1629, 1472, 1389, 1375, 1342, 1298, 1264, 1148, 1113, 1069, 1047, 1034, 1047, 1008, 927, 895, 859 and 843.

HRMS expected for C₁₀H₉DF₄NO 237.0756, observed m/z 237.0750 [M + H]⁺. Deuterated product D-8e.

HRMS expected for C₁₀H₁₀F₄NO 236.0693, observed m/z 236.0716 [M + H]⁺. Non-deuterated product 8e.

Reaction of pentafluorobenzaldehyde or pentafluoroacetophenone with sodium methoxide

Pentafluorobenzaldehyde or pentafluoroacetophenone (2 mmol) was dissolved in MeOH (3 mL) and NaOMe (10 mmol) was added at −10 °C and the solution was stirred and then heated under reflux for 15 h, during the course of the reaction the solution turned yellow. Water (10 mL) was then poured into the reaction mixture and extracted with CDCl₃ (3 × 5 mL). The combined organic layers were dried over MgSO₄ and filtered and submitted for NMR spectroscopy which showed mixtures from which the following were identified.

From pentafluorobenzaldehyde:

1,2,4,5-Tetrafluoro-3-methoxybenzene (minor). ¹H-NMR (400 MHz, CDCl₃) δ_H 7.57–7.53 (m, 1H, CH), 4.01 (t, J = 1.6 Hz, 3H, OMe).

¹⁹F-NMR (376 MHz, CDCl₃) δF 21.6–21.4 (m, 1F), 4.2–4.0 (m, 1F).

IR, ν_max/cm⁻¹ 3467, 1623, 1509, 1469, 1378, 1285, 1196, 1125, 990, 896, 823, 759 and 562.

2,3,5-Trifluoro-4,6-dimethoxybenzaldehyde 14a. IR, ν_max/cm⁻¹ 3584, 3391, 2951, 2852, 1696, 1649, 1611, 1493, 1479, 1430, 1400, 1361, 1292, 1268, 1203, 1141, 1039, 1003, 903, 811, 739, 703 and 622.

HRMS calculated for C₉H₈F₃O₃ 221.0420, observed m/z 221.0422 [M + H]⁺.

From reaction with pentafluoroacetophenone:

2,3,5-Trifluoro-4,6-dimethoxyacetophenone 14b. HRMS calculated for C₁₀H₁₀F₃O₃ 235.0577, observed m/z 235.0576 [M + H]⁺.

From both reactions:

1,2,4-Trifluoro-3,5-dimethoxybenzene 15. ¹H-NMR (500 MHz, CDCl₃) δ_H 6.74–6.63 (m, 1H), 3.98 (t, J = 2.0 Hz, 3H), 3.93 (t, J = 1.0 Hz, 3H).

¹⁹F-NMR (471 MHz, CDCl₃) δ_F 21.6–21.4 (m, 1F), 10.9 (s, 1F), 3.8–3.6 (m, 1F).

IR, ν_max/cm⁻¹ 3584, 3400, 3003, 2950, 2844, 2586, 2420, 2345, 2308, 2043, 1986, 1943, 1893, 1711, 1616, 1515, 1476, 1424, 1380, 1352, 1295, 1263, 1206, 1179, 1130, 1099, 1045, 1003, 942, 896, 853, 774, 743, 700 and 600.

Conclusions

Twenty-seven aminobenzofurans, as potential drug leads were accessed via tandem S_NAr-cyclocondensation reaction of substituted perfluorobenzonitriles and α-hydroxycarbonyl compounds using DBU as base. The new compounds were characterized by IR spectroscopy, NMR spectroscopy, HRMS, and elemental analysis. The structure of (3-amino-4,5,7-trifluoro-6-morpholinobenzofuran-2-yl)(4-methoxyphenyl)methanone was determined by single crystal X-ray diffraction analysis.

Data availability

The data supporting this article have been included as part of the ESI.† Crystallographic data for compound 4ed has been deposited at the CCDC under 231984 at https://www.ccdc.cam.ac.uk/.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

We thank the British Society of Antimicrobial Chemotherapy for funding (PhD studentship to HT) and the EPSRC X-ray Crystallography Centre at Southampton University.¹⁴ We are grateful to Mr J. Alastair Daley, Dr Emily Gale and Mrs Pauline King for technical support and Loughborough University for facilities. We thanks Mr Wilson Kou and Miss Christy Lee for experimental assistance.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2312984. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5ra02024g

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