α-d-Galacturonic Acid as Natural Ligand for Selective Copper-Catalyzed N-Arylation of N-Containing Heterocycles

Abstract

The first application of α-d-galacturonic acid hydrate (GalA) is reported here, as a potential O-donor ligand. The C–N couplings of N-heterocycles with aryl halides or arylboronic acids could be readily conducted and exhibited good functional group tolerance with characters of selectivity. These N-arylazoles allow rapid access to several pharmaceutical intermediates and can be easily transformed into a variety of other interesting scaffolds as well.

Key words

α-d-galacturonic acid hydrate - C–N couplings - N-arylation - Cu catalyst - ligand

• References and Notes

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• 59 General Procedure All of the starting materials, reagents, and solvents are commercially available and used without further purification. Melting points were determined with a X-4 apparatus and were uncorrected. The nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 400 MHz spectrometer in CDCl₃ or DMSO-d ₆ using tetramethylsilane (TMS) as an internal standard. Electrospray ionization mass spectrometry (MS (ESI)) analyses were recorded in an Agilent 1100 Series MSD Trap SL (Santa Clara, CA, USA). The reactions were monitored by thin-layer chromatography (TLC: HG/T2354-92, GF254), and compounds were visualized on TLC with UV light.
• 60 General Procedure for Catalytic Experiments To a 10 mL vial was charged with aryl halide (0.8 mmol), N-containing heterocycle (1.0 mmol), CuBr (0.04 mmol), GalA (0.08 mmol), K₂CO₃ (2.4 mmol), and 50% aq DMSO. The flask was evacuated and backfilled with argon three times, and the reaction mixture was stirred at appropriate temperature under oil bath for the indicated time. After the complete consumption of aryl halide monitored by TLC, the mixture was then cooled to ambient temperature (if the product was acidic, the mixture was acidified), diluted with ethyl acetate (5 mL), filtered via a Celite pad, and washed with ethyl acetate (10–20 mL). The organic layer was separated by the separating funnel, which was washed successively with water (2 × 10 mL) and brine (2 × 10 mL). The organic layer was dried over anhydrous MgSO₄ and concentrated by reduced pressure in a rotary evaporator, which was then purified by column chromatography on silica gel to provide the desired products. 1-Phenyl-1H-pyrazole (3a)³⁶ Yield: 0.109 g (95%), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.93–7.92 (d, J = 2.4 Hz, 1 H), 7.73–7.68 (m, 3 H), 7.47–7.43 (m, 2 H), 7.30–7.25 (m, 1 H), 6.46 (t, J = 2.3 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 141.0, 129.3, 126.7, 126.4, 119.1, 107.5 ppm. MS (ESI⁺): m/z = 145.04 [M + H]⁺. 1-Phenyl-1H-imidazole (3b)³⁷ Yield: 0.113 g (98%), colorless oil. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.28 (s, 1 H), 7.77 (s, 1 H), 7.67–7.64 (m, 2 H), 7.54–7.50 (m, 2 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.14 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 137.3, 135.5, 130.3, 129.8, 127.4, 121.4, 118.2 ppm. MS (ESI⁺): m/z = 145.04 [M + H]⁺. 2-Methyl-1-(4-nitrophenyl)-1H-imidazole (3c)³⁸ Yield: 0.136 g (84%), light yellow solid; mp 128–130 °C (lit. mp 140–142 °C). ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.38 (d, J = 9.0 Hz, 2 H), 7.78 (d, J = 9.0 Hz, 2 H), 7.45 (d, J = 1.3 Hz, 2 H), 7.0 (d, J = 1.2 Hz, 1 H), 2.38 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 146.8, 144.4, 143.1, 128.7, 125.7, 125.1, 120.1, 14.1 ppm. MS (ESI⁺): m/z = 204.05 [M + H]⁺. 4-Methyl-1-phenyl-1H-imidazole (3d)³⁹ and 5-Methyl-1-phenyl-1H-imidazole (3e)⁴⁰ Yield: 0.123 g (97%), yellow oil. ¹H NMR (400 MHz, CDCl₃, 3d/3e = 7.6:1): δ = 7.76 (d, J = 1.3 Hz, 1 H), 7.57 (br, 0.13 H), 7.50–7.49 (m, 0.2 H), 7.48–7.43 (m, 2 H), 7.37–7.33 (m, 3 H), 7.32–7.28 (m, 0.5 H), 7.01 (t, J = 1.0 Hz, 1 H), 6.91 (br, 0.13 H), 2.31 (d, J = 1.0 Hz, 3 H), 2.18 (d, J = 1.0 Hz, 0.42 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 139.5, 137.5, 134.6, 129.8, 129.5, 128.3, 127.1, 125.6, 121.1, 114.6, 13.7 ppm. MS (ESI⁺): m/z = 159.09 [M + H]⁺. 3-(1H-Pyrazol-1-yl)benzaldehyde (3f)⁴¹ Yield: 0.096 g (70%), off-white solid; mp 28–30 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.08 (s, 1 H), 8.19 (t, J = 1.8 Hz, 1 H), 8.05–8.02 (m, 2 H), 7.81–7.76 (m, 2 H), 7.64 (t, J = 7.9 Hz, 1 H), 6.52 (t, J = 2.1 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 191.4, 141.6, 136.5, 135.8, 130.2, 127.6, 125.9, 124.6, 119.0, 108.3 ppm. MS (ESI⁺): m/z = 173.08 [M + H]⁺. 1-(4-(1H-Pyrazol-1-yl)phenyl)ethan-1-one (3g)⁴² Yield: 0.119 g (80%), white solid; mp 101–104 °C (lit. mp 108 °C). ¹H NMR (400 MHz, CDCl₃): δ = 8.08–8.05 (m, 2 H), 8.02 (d, J = 2.5 Hz, 1 H), 7.83–7.81 (m, 2 H), 7.78 (d, J = 1.5 Hz, 1 H), 6.52 (t, J = 2.0 Hz, 1 H), 2.63 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 196.7, 143.2, 142.0, 134.7, 129.9, 126.8, 118.3, 108.5, 26.5 ppm. MS (ESI⁺): m/z = 187.09 [M + H]⁺. 1-(4-Nitrophenyl)-1H-pyrazole-4-carbaldehyde (3h)⁴³ Yield: 0.162 g (93%), yellow solid; mp 158–160 °C (lit. mp 84 °C). ¹H NMR (400 MHz, CDCl₃): δ = 10.02 (s, 1 H), 8.55 (s, 1 H), 8.41–8.38 (m, 2 H), 8.23 (s, 1 H), 7.97–7.94 (m, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 183.7, 146.6, 143.3, 142.6, 130.3, 126.6, 125.5, 119.7 ppm. MS (ESI⁺): m/z = 218.34 [M + H]⁺. 3-(1H-Pyrazol-1-yl)pyridin-2-amine (3i)⁴⁴ Yield: 0.112 g (88%), brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 10.68 (br, 1 H), 8.08–8.06 (dd, J = 5.0 Hz, 1.6 Hz, 1 H), 7.77–7.75 (m, 2 H), 7.48–7.46 (dd, J = 7.7 Hz, 1.6 Hz, 1 H), 6.74–6.71 (q, J = 7.7 Hz, 5.0 Hz, 1 H), 6.48 (t, J = 2.1 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 152.7, 146.6, 140.9, 143.3, 130.4, 129.6, 121.6, 113.2, 107.1 ppm. MS (ESI⁺): m/z = 161.03 [M + H]⁺. 2-(1H-Pyrazol-1-yl)benzonitrile (3j)⁴⁵ Yield: 0.118 g (87%), yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.15 (d, J = 2.5 Hz, 1 H), 7.81–7.70 (m, 3 H), 7.73–7.69 (dt, J = 7.6 Hz, 1.5 Hz, 1 H), 7.45–7.41 (dt, J = 7.6 Hz, 1.0 Hz, 1 H), 6.55 (t, J = 2.1 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 142.3, 142.1, 134.5, 134.0, 129.5, 127.2, 124.3, 117.0, 108.5, 105.4 ppm. MS (ESI⁺): m/z = 170.07 [M + H]⁺. 1-(4-Chlorophenyl)-1H-indole-2-carboxylic Acid (3k) Yield: 0.160 g (74%), white to pale grey solid; mp 227–230 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.75–7.73 (dt, J = 8.4 Hz, 0.9 Hz, 1 H), 7.57 (d, J = 0.7 Hz, 1 H), 7.50–7.47 (m, 2 H), 7.33–7.26 (m, 3 H), 7.23–7.19 (m, 1 H), 7.09–7.06 (m, 1 H) ppm. ¹³C NMR (150 MHz, DMSO-d ₆): δ = 162.2, 140.4, 137.5, 132.7, 130.1, 129.4, 126.6, 125.9, 121.7, 111.6 ppm. MS (ESI^–): m/z = 270.02 [M – H]^–. 1-(Thiophen-2-yl)-1H-indole-2-carboxylic Acid (3l) Yield: 0.169 g (87%), white solid; mp 175–176 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.02 (s, 1 H), 8.55 (s, 1 H), 8.41–8.38 (m, 2 H), 8.23 (s, 1 H), 7.97–7.94 (m, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 165.8, 142.4, 138.9, 128.9, 126.5, 126.0, 125.9,125.5, 125.0, 122.6, 121.9, 114.6, 111.8 ppm. MS (ESI^–): m/z = 241.99 [M – H]^–. 1-(Thiophen-3-yl)-1H-indole-2-carboxylic Acid (3m) Yield: 0.177 g (91%), white to a pale grey solid; mp 190–192 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.74–7.71 (dt, J = 7.9 Hz, 1.0 Hz, 1 H), 7.55 (d, J = 0.6 Hz, 1 H), 7.43–7.41 (m, 1 H), 7.34–7.30 (m, 2 H), 7.22–7.17 (m, 2 H), 7.09–7.07 (q, J = 5.2 Hz, 1.4 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 165.8, 141.2, 135.8, 127.8, 126.8, 126.2, 125.9, 124.9, 122.6, 121.5, 121.2, 113.7, 111.7 ppm. MS (ESI^–): m/z = 242.02 [M – H]^–. 1-Phenyl-1H-indole-3-carbaldehyde (3n)⁴⁶ Yield: 0.157 g (89%), brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 10.12 (s, 1 H), 8.40–8.38 (m, 1 H), 7.92 (s, 1 H), 7.61–7.57 (m, 2 H), 7.54–7.47 (m, 4 H), 7.39–7.32 (m, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 184.9, 138.2, 138.1, 137.5, 130.0, 128.3, 125.6, 124.9, 124.6, 123.5, 122.3, 119.7, 111.1 ppm. MS (ESI⁺): m/z = 222.07 [M + H]⁺. Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (3o) Yield: 0.124 g (70%), yellow solid; mp 238–240 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.10 (s, 1 H), 8.69–8.66 (dd, J = 7.8 Hz, 1.6 Hz, 1 H), 8.49-8.48 (dd, J = 4.8 Hz, 1.6 Hz, 1 H), 8.12 (s, 1 H), 7.76–7.74 (m, 2 H), 7.62–7.57 (m, 2 H), 7.49–7.45 (m, 1 H), 7.36–7.33 (q, J = 7.8 Hz, 4.8 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 184.8, 148.5, 145.7, 137.5, 137.0, 130.8, 129.6, 128.0, 124.5, 119.5, 118.2, 117.6 ppm. MS (ESI⁺): m/z = 223.12 [M + H]⁺. 2-Chloro-4-(1H-pyrazol-1-yl)aniline (3p) Yield: 0.133 g (86%), light yellow solid; mp 70–73 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.77 (d, J = 2.4 Hz, 1 H), 7.70 (d, J = 1.5 Hz, 1 H), 7.61 (d, J = 2.5 Hz, 1 H), 7.39–7.36 (dd, J = 8.6 Hz, 2.5 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 6.42 (t, J = 2.1 Hz, 1 H), 4.09 (br, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 144.5, 141.2, 131.4, 128.4, 120.7, 119.9, 118.2, 116.7, 108.3 ppm. MS (ESI⁺): m/z = 194.05 [M + H]⁺. 2-(1H-Pyrazol-1-yl)benzoic Acid (3q)⁴⁷ Yield: 0.134 g (89%), white solid; mp 128–129 °C. ¹H NMR (400 MHz, CDCl₃): δ = 11.41 (br, 1 H), 8.06–8.04 (dd, J = 7.8 Hz, 1.1 Hz, 1 H), 7.77–7.75 (m, 2 H), 7.63–7.59 (m, 1 H), 7.50–7.46 (t, J = 7.5 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 6.49–6.48 (t, J = 2.1 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 168.8, 141.0, 138.6, 132.7, 132.3, 131.0, 128.2, 127.1, 125.7, 107.6 ppm. MS (ESI^–): m/z = 187.06 [M – H]^–. 1-(4-Nitrophenyl)-1H-pyrazole (3r)³⁶ Yield: 0.130 g (86%), yellow solid; mp 167–168 °C (lit. mp 168.5–169 °C). ¹H NMR (400 MHz, CDCl₃): δ = 8.37–8.33 (m, 2 H), 8.04 (d, J = 2.6 Hz, 1 H), 7.91–7.87 (m, 2 H), 7.81 (d, J = 1.5 Hz, 1 H), 6.57–5.56 (q, J = 2.4 Hz, 1.9 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 140.8, 129.6, 125.6, 120.6, 119.3, 110.4 ppm. MS (ESI⁺): m/z = 190.08 [M + H]⁺. 3-Nitro-4-(1H-pyrazol-1-yl)aniline (3s) Yield: 0.156 g (96%), yellow solid; mp 135–136 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 1.0 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 2.6 Hz, 1 H), 6.88–6.85 (dd, J = 8.6 Hz, 2.6 Hz, 1 H), 6.44 (t, J = 2.0 Hz, 1 H), 3.85 (br, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 147.0, 145.7, 141.3, 130.3, 128.4, 124.3, 118.1, 109.9, 107.1 ppm. MS (ESI⁺): m/z = 205.06 [M + H]⁺. 4-Chloro-2-(1H-pyrazol-1-yl)benzoic Acid (3t) Yield: 0.172 g (97%), pale grey solid; mp 237–240 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.20 (d, J = 2.4 Hz, 1 H), 7.73–7.71 (m, 3 H), 7.57–7.54 (dd, J = 8.3 Hz, 2.0 Hz, 1 H), 6.51–6.50 (q, J = 2.4 Hz, 1.9 Hz, 1 H) ppm. ¹³C NMR (150 MHz, DMSO-d ₆): δ = 168.5, 142.3, 140.4, 136.7, 132.5, 131.8, 128.5, 128.4, 125.4, 108.8 ppm. MS (ESI⁺): m/z = 220.94 [M + H]⁺, 222.93 [M + H]⁺. 1-(4-Nitrophenyl)-1H-indol-5-ol (3u) Yield: 0.216 g (85%), yellow solid; mp 188–191 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.40 (d, J = 9.0 Hz, 2 H), 7.67 (d, J = 9.0 Hz, 2 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.36 (d, J = 3.3 Hz, 1 H), 7.09 (d, J = 2.4 Hz, 1 H), 6.87–6.84 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 6.66 (d, J = 3.2 Hz, 1 H), 4.60 (br, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 152.8, 145.2, 144.2, 131.5, 129.2, 128.6, 125.9, 122.8, 113.2, 111.9, 105.8, 105.7 ppm. MS (ESI^–): m/z = 253.06 [M – H]^–. Ethyl 5-Hydroxy-2-methyl-1-phenyl-1H-indole-3-carboxylate (3v)⁴⁸ Yield: 0.174 g (59%), brown solid; mp 203–205 °C (lit. mp 203–204 °C). ¹H NMR (600 MHz, DMSO-d ₆): δ = 9.06 (s, 3 H), 7.63 (t, J = 7.4 Hz, 2 H), 7.57 (t, J = 7.3 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H), 7.45 (d, J = 7.3 Hz, 2 H), 6.78 (d, J = 8.7 Hz, 1 H), 6.65–6.63 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 4.33–4.30 (q, J = 14.2 Hz, 7.1 Hz, 2 H), 2.49 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (150 MHz, DMSO-d ₆): δ = 165.6, 153.6, 145.3, 136.5, 131.9, 130.3, 129.3, 128.4, 127.5, 112.5, 111.2, 105.9, 104.0, 59.4, 15.0, 13.3 ppm. MS (ESI⁺): m/z = 296.12 [M + H]⁺. Ethyl 1-(4-Ethoxyphenyl)-5-hydroxy-2-methyl-1H-indole-3-carboxylate (3w) Yield: 0.210 g (62%), brown solid; mp 225–226 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 9.02 (s, 1 H), 7.45 (d, J = 2.2 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.13 (d, J = 8.8 Hz, 2 H), 6.75 (d, J = 8.6 Hz, 1 H), 6.63–6.61 (dd, J = 8.7 Hz, 2.3 Hz, 1 H), 4.32–4.29 (q, J = 14.2 Hz, 7.1 Hz, 2 H), 4.13–4.10 (q, J = 13.7 Hz, 6.9 Hz, 2 H), 2.46 (s, 3 H), 1.39–1.36 (q, J = 14.1 Hz, 7.0 Hz, 6 H) ppm. ¹³C NMR (150 MHz, DMSO-d ₆): δ = 165.6, 159.0, 153.5, 145.6, 132.3, 129.6, 128.8, 127.4, 115.8, 112.4, 111.2, 105.9, 103.6, 63.9, 59.3, 15.1, 15.0, 13.3 ppm. MS (ESI⁺): m/z = 340.16 [M + H]⁺. Ethyl 5-Hydroxy-2-methyl-1-(p-tolyl)-1H-indole-3-carboxylate (3x)⁴⁹ Yield: 0.170 g (55%), yellow solid; mp 190–192 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 9.03 (s, 1 H), 7.45–7.41 (m, 3 H), 7.31 (d, J = 7.5 Hz, 2 H), 6.77 (d, J = 8.5 Hz, 1 H), 6.63 (d, J = 8.1 Hz, 1 H), 4.32–4.29 (q, J = 14.0 Hz, 7.1 Hz, 2 H), 2.47 (s, 3 H), 2.43 (s, 3 H), 1.37 (t, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (150 MHz, DMSO-d ₆): δ = 165.6, 153.5, 145.4, 138.9, 133.9, 132.0, 130.8, 128.2, 127.5, 112.4, 111.2, 105.9, 103.8, 59.4, 21.2, 15.0, 13.3 ppm. MS (ESI⁺): m/z = 310.13 [M + H]⁺. Ethyl 5-Hydroxy-2-methyl-1-[3-(trifluoromethyl)phenyl]-1H-indole-3-carboxylate (3y) Yield: 0.229 g (63%), white solid; mp 199–201 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 9.09 (s, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.92 (s, 1 H), 7.87 (t, J = 7.9 Hz, 1 H), 7.82 (d, J = 7.9 Hz, 1 H), 7.47 (d, J = 2.1 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 6.67–6.65 (dd, J = 8.7 Hz, 2.2 Hz, 1 H), 4.34–4.31 (q, J = 14.2 Hz, 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (150 MHz, DMSO-d ₆): δ = 165.5, 153.7, 145.4, 137.3, 132.9, 131.7, 131.6, 131.1 (J = 31.9 Hz), 127.6, 126.1 (J = 3.5 Hz), 125.4 (J = 3.8 Hz), 125.0, 123.2, 112.7, 111.0, 106.0, 104.5, 59.5, 15.0, 13.3 ppm. MS (ESI⁺): m/z = 364.15 [M + H]⁺. 4-(1H-Pyrazol-1-yl)phenol (3z)⁵⁰ Yield: 0.158 g (99%), white solid; mp 99–101 °C (lit. mp 94–96 °C) ¹H NMR (400 MHz, CDCl₃): δ = 7.77–7.72 (m, 2 H), 7.41–7.37 (m, 2 H), 6.82–6.78 (m, 2 H), 6.45 (t, J = 2.1 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 155.6, 140.3, 132.9, 127.8, 121.9, 116.2, 107.1 ppm. MS (ESI⁺): m/z = 161.02 [M + H]⁺. N-[2-(1-phenyl-1H-indol-3-yl)ethyl]aniline (3aa) Yield: 0.271 g (87%), yellow solid; mp 85–87 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.67–7.65 (m, 1 H), 7.58–7.56 (m, 1 H), 7.53–7.46 (m, 1 H), 7.35–7.30 (m, 1 H), 7.26–7.16 (m, 5 H), 6.73–6.69 (m, 1 H), 6.66–6.63 (m, 2 H), 3.98 (br, 1 H), 3.53 (t, J = 6.9 Hz, 2 H), 3.16–3.12 (m, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 148.0, 139.7, 136.1, 129.6, 128.8, 126.2, 125.7, 124.1, 122.6, 120.0, 119.1, 117.4, 114.4, 113.0, 110.6, 43.9, 25.0 ppm. MS (ESI⁺): m/z = 313.18 [M + H]⁺. 3-(1H-Pyrazol-1-yl)aniline (3ab)⁵¹ Yield: 0.141 g (89%), brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.89 (d, J = 2.3 Hz, 1 H), 7.70 (d, J = 1.5 Hz, 1 H), 7.20 (t, J = 8.0 Hz, 1 H), 7.10 (t, J = 2.2 Hz, 1 H), 7.01–6.99 (m, 1 H), 6.61–6.58 (m, 1 H), 6.44 (t, J = 2.0 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 147.6, 140.8, 130.2, 126.8, 113.1, 109.0, 107.3, 106.1 ppm. MS (ESI⁺): m/z = 160.07 [M + H]⁺. 5-Methoxy-2-phenylbenzo[d]oxazole (3ac)⁵² Yield: 0.129 g (72%), white solid; mp 66–69 °C (lit. mp 60–61 °C). ¹H NMR (400 MHz, CDCl₃): δ = 8.24–8.22 (m, 2 H), 7.52–7.51 (m, 3 H), 7.45 (d, J = 8.8 Hz, 1 H), 7.27 (d, J = 2.5 Hz, 1 H), 6.96–6.93 (dd, J = 2.6 Hz, 8.9 Hz, 1 H), 3.87 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 163.7, 157.3, 145.3, 142.8, 131.3, 128.8, 128.7, 127.4, 127.2, 113.7, 110.6, 102.8, 55.9 ppm. MS (ESI⁺): m/z = 226.10 [M + H]⁺. 3 -Nitro-5a,6,7,8,9,10-hexahydro-5H-benzo[4,5]imidazo[1,2-a]azepine (3ad) Yield: 0.160 g (86%), yellow solid; mp 171 °C (lit. mp 170–171 °C). ¹H NMR (400 MHz, CDCl₃): δ = 8.58 (d, J = 2.1 Hz, 1 H), 8.18 (dd, J = 9.0, 2.2 Hz, 1 H), 7.32 (d, J = 9.0 Hz, 1 H), 4.24–4.21 (m, 2 H), 3.17–3.14 (m, 2 H), 2.02–1.96 (m, 2 H), 1.92–1.82 (m, 4 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 161.2, 143.1, 141.6, 117.9, 115.8, 108.5, 45.1, 30.5, 30.1, 28.5, 25.1 ppm. MS (ESI⁺): m/z = 232.14 [M + H]⁺. 2-Methyl-1-phenyl-1H-benzo[d]imidazole (3ae)⁵³ Yield: 0.116 g (70%), white solid; mp 62–65 ^°C (lit. mp 68 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, J = 7.9 Hz, 1 H), 7.60–7.56 (m, 2 H), 7.54–7.49 (m, 1 H), 7.38–7.35 (m, 2 H), 7.29–7.24 (m, 1 H), 7.21–7.17 (m, 1 H), 7.14–7.12 (m, 1 H), 2.51 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 151.6, 142.7, 136.5, 136.1, 129.9, 128.8, 127.1, 122.6, 122.4, 119.0, 109.9, 14.5 ppm. MS (ESI⁺): m/z = 209.11 [M + H]⁺. 5-Nitro-2-(1H-pyrazol-1-yl)aniline (3af) Yield: 0.081 g (50%), red solid; mp 100 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.83–7.80 (m, 2 H), 7.69 (d, J = 2.4 Hz, 1 H), 7.63–7.60 (dd, J = 8.7 Hz, 2.5 Hz, 1 H), 7.33 (d, J = 8.7 Hz, 1 H), 6.52 (t, J = 2.3 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 147.0, 141.3, 141.2, 129.9, 129.7, 123.1, 112.5, 111.9, 107.5 ppm. MS (ESI⁺): m/z = 205.10 [M + H]⁺. 2-Phenyl-5-(trifluoromethyl)benzo[d]oxazole (3ag)⁵² Yield: 0.185 g (88%), white solid; mp 83 °C (lit. mp 86–87 °C). ¹H NMR (400 MHz, CDCl₃): δ = 8.95 (d, J = 1.9 Hz, 1 H), 8.56 (br, 1 H), 7.96–7.93 (m, 2 H), 7.73–7.70 (m, 1 H), 7.64–7.60 (m, 1 H), 7.57–7.51 (m, 2 H), 7.29–7.26 (m, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 136.4, 133.9, 132.6, 132.5, 131.0 (J = 33.0 Hz), 129.0, 128.8, 127.0, 123.5 (J = 271.0 Hz), 121.5 (J = 3.5 Hz), 118.3 (J = 3.7 Hz), 116.8 ppm. MS (ESI⁺): m/z = 264.05 [M + H]⁺. 5-(1H-Pyrazol-1-yl)-2-(trifluoromethyl)pyridine (3ah) Yield: 0.198 g (93%), white solid; mp 115–117 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.10 (d, J = 2.4 Hz, 1 H), 8.26–8.23 (dd, J = 8.5 Hz, 2.2 Hz, 1 H), 8.04 (d, J = 2.6 Hz, 1 H), 7.82 (d, J = 1.6 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 6.58–6.57 (q, J = 2.4 Hz, 1.8 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 145.4 (J = 36.0 Hz), 142.8, 140.1, 138.2, 126.8, 126.7, 121.3 (J = 273.1 Hz), 121.2 (J = 2.3 Hz), 109.3 ppm. MS (ESI⁺): m/z = 214.08 [M + H]⁺. 1-[3-(Trifluoromethyl)phenyl]-1H-pyrazole (3ai)⁵⁴ Yield: 0.201 g (95%), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (br, 1 H), 7.98 (d, J = 1.9 Hz, 1 H), 7.90–7.88 (dt, J = 7.8 Hz, 0.9 Hz, 1 H), 7.76 (d, J = 1.4 Hz, 1 H), 7.60–7.53 (m, 2 H), 6.51 (t, J = 1.9 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 141.7, 140.4, 131.9 (J = 32.7 Hz), 130.0, 126.7, 123.6 (J = 271.2 Hz), 122.8 (J = 3.4 Hz), 121.9, 115.9 (J = 3.6 Hz), 108.3 ppm. MS (ESI⁺): m/z = 213.05 [M + H]⁺. 1-(3-Chlorophenyl)-1H-pyrazole (3aj)⁵⁵ Yield: 0.171 g (96%), white solid; mp 27–29 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (br, 1 H), 7.75 (t, J = 1.9 Hz, 1 H), 7.74 (br, 1 H), 7.60–7.57 (m, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.27–7.24 (m, 1 H), 6.49 (br, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 141.4, 141.0, 135.2, 130.4, 126.7, 126.3, 119.3, 116.9, 108.1 ppm. MS (ESI⁺): m/z = 179.02 [M + H]⁺, 181.03 [M + H]⁺. 1-(3-Methoxyphenyl)-1H-pyrazole (3ak)³⁶ Yield: 0.156 g (90%), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.92–791 (dd, J = 2.4 Hz, 0.4 Hz, 1 H), 7.72 (d, J = 1.5 Hz, 1 H), 7.36–7.31 (m, 2 H), 7.24–7.21 (m, 1 H), 6.85–6.82 (m, 1 H), 6.46–6.45 (q, J = 2.4 Hz, 1.9 Hz, 1 H), 3.87 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 160.5, 141.3, 140.9, 130.1, 126.9, 112.3, 111.1, 107.5, 105.0, 55.4 ppm. MS (ESI⁺): m/z = 175.10 [M + H]⁺. 5-(1H-Pyrazol-1-yl)pyrimidine (3al)⁵⁶ Yield: 0.140 g (96%), white solid; mp 88–90 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.16 (s, 1 H), 8.00 (d, J = 2.5 Hz, 1 H), 7.83 (d, J = 1.6 Hz, 1 H), 6.59 (t, J = 1.9 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 156.1, 147.0, 142.8, 134.6, 126.6, 109.2 ppm. MS (ESI⁺): m/z = 147.05 [M + H]⁺. 2,5-Di(1H-pyrazol-1-yl)pyridine (3am)⁵⁷ Yield: 0.202 g (96%), white solid; mp 160–161 °C (lit. mp 162 °C). ¹H NMR (400 MHz, CDCl₃): δ = 8.78 (d, J = 1.5 Hz, 1 H), 8.59 (d, J = 2.4 Hz, 1 H), 8.19–8.10 (m, 2 H), 7.96 (d, J = 2.4 Hz, 1 H), 7.79 (d, J = 1.6 Hz, 1 H), 7.77 (s, 1 H), 6.54 (t, J = 2.1 Hz, 1 H), 6.50 (t, J = 2.0 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 149.6, 142.2, 141.8, 138.5, 134.8, 129.5, 127.1, 126.7, 112.8, 108.3, 108.0 ppm. MS (ESI⁺): m/z = 212.10 [M + H]⁺. 4-(1H-Pyrazol-1-yl)pyridine (3an)⁵⁵ Yield: 0.143 g (99%), white solid; mp 72–74 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.71 (br, 2 H), 8.05 (d, J = 2.4 Hz, 1 H), 7.79 (d, J = 1.5 Hz, 1 H), 7.67 (d, J = 4.0 Hz, 2 H), 6.55–6.54 (q, J = 2.6 Hz, 1.8 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 151.1, 145.9, 142.5, 126.5, 112.5, 109.0 ppm. MS (ESI⁺): m/z = 146.02 [M + H]⁺. 1-(2-(Allyloxy)phenyl)-1H-pyrazole (3ao)⁵⁸ Yield: 0.160 g (84%), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (s, 1 H), 7.77–7.74 (dd, J = 7.9 Hz, 1.4 Hz, 1 H), 7.73 (s, 1 H), 7.30–7.25 (m, 1 H), 7.10–7.03 (m, 2 H), 6.44 (s, 1 H), 6.06–5.96 (m, 1 H), 5.39–5.33 (m, 1 H), 5.29–5.25 (m, 1 H), 4.61–4.59 (dt, J = 5.1 Hz, 1.5 Hz, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 148.6, 140.6, 140.2, 131.4, 128.8, 127.6, 125.0, 123.1, 116.4, 108.4, 106.5, 69.7 ppm. MS (ESI⁺): m/z = 201.12 [M + H]⁺.