Microwave-Assisted Bohlmann–Rahtz Synthesis of Highly Substituted 2-Aminonicotinates

Abstract

Microwave irradiation of 2-carbethoxyacetamidine and an ethynyl ketone under acidic or basic conditions in ethanol at 150 °C for 1.5 hours facilitated Bohlmann–Rahtz pyridine synthesis to give highly substituted ethyl 2-aminonicotinates with total regiocontrol and in reasonable to excellent yield, following purification by immobilization upon an acidic resin.

Key words

2-aminopyridines - heterocycles - ethynyl ketones - microwave synthesis - catch-and-release

• References and Notes

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• 42 Typical Procedure for Microwave-Assisted Synthesis of 2-Aminonicotinates Using Hydrochloride Salt 6·HCl: A solution of ethyl 3-amino-3-iminopropionate hydrochloride (6·HCl; 1 equiv) and the ethynyl ketone (1.05 equiv) in EtOH (3 mL) was irradiated at 150 °C for 1.5 h (hold time) in a pressure-rated glass tube (10 mL) using a CEM Discover® microwave synthesizer by moderation of the initial magnetron power (200 W). After cooling in a flow of compressed air, the solution was immobilized on a Biotage ISOLUTE SCX-2 column and eluted with EtOH–NH₄OH (aq, 35%; 5:1) to give the title compound.
• 43 Typical Procedure for Microwave-Assisted Synthesis of 2-Aminonicotinates Using Free Base 6: An ethanolic solution of ethyl 3-amino-3-iminopropionate hydrochloride (6·HCl; 1 equiv) was pretreated with Na₂CO₃ (1 equiv) for 10 min. After filtering, the ethynyl ketone (1.05 equiv) was added and the mixture in EtOH (3.5 mL) was irradiated at 150 °C for 1.5 h (hold time) in a pressure-rated glass tube (10 mL) using a CEM Discover® microwave synthesizer by moderation of the initial magnetron power (200 W). After cooling in a flow of compressed air, the solution was immobilized on a Biotage ISOLUTE SCX-2 column and eluted with EtOH–NH₄OH (aq; 35%; 5:1) or ethanolic NH₃ (2 M) to give the title compound.
• 44 See Supporting Information for detailed experimental procedures and characterization data for known compounds. Ethyl 2-amino-6-methyl-4-phenylnicotinate (12b) was prepared using the above procedure,⁴³ with ethyl 3-amino-3-iminopropionate hydrochloride (6·HCl; 270 mg, 1.62 mmol), 4-phenyl-3-butyn-2-one (11b; 270 mg, 1.70 mmol) and Na₂CO₃ (270 mg, 1.62 mmol), in EtOH (3.5 mL), to give the title compound (216 mg, 52%) as a brown solid; mp 139 °C. IR (neat): 3443, 3272, 2977, 1682, 1606, 1582, 1241 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.30–7.33 (3 H, 3′-H, 4′-H, 5′-H), 7.20 (m, 2 H, 2′-Η, 6′-H), 6.41 (s, 1 H, 5-H), 6.29 (br s, 2 H, NH₂), 3.88 (q, J = 7.1 Hz, 2 H, OCH₂), 2.37 (s, 3 H, Me), 0.69 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 168.5 (C), 160.3 (C), 158.7 (C), 153.8 (C), 141.5 (C), 127.9 (CH/CH), 127.4 (CH), 115.2 (CH), 104.7 (C), 60.4 (CH₂), 24.2 (Me), 13.1 (Me). MS (EI): m/z = 256 [M·⁺]. HRMS: m/z [M + H] calcd for C₁₅H₁₇N₂O₂: 257.1285; found: 257.1278. Ethyl 2-amino-4-ethyl-6-methylnicotinate (12c) was prepared using the above procedure,⁴³ with ethyl 3-amino-3-iminopropionate hydrochloride (6·HCl) (200 mg, 1.26 mmol), 3-hexyn-2-one (128 mg, 1.32 mmol), and Na₂CO₃ (200 mg, 1.26 mmol) in EtOH (3.5 mL), to give the title compound (133 mg, 54%) as a brown solid; mp 141 °C. IR (neat): 3450, 3269, 3147, 2972, 1686, 1619, 1586 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.33 (s, 1 H, 5-H), 6.19 (br s, 2 H, NH₂), 4.33 (q, J = 7.0 Hz, 2 H, OCH₂), 2.78 (q, J = 7.0 Hz, 2 H, 4-CH ₂CH₃), 2.30 (s, 3 H, 6-Me), 1.36 (t, J = 7.0 Hz, 3 H, Me), 1.16 (t, J = 7.0 Hz, 3 H, 4-CH₂Me). ¹³C NMR (125 MHz, CDCl₃): δ = 168.3 (C), 160.3 (C), 159.4 (C), 157.2 (C), 114.8 (CH), 104.6 (C), 60.7 (CH₂), 28.6 (CH₂), 23.9 (Me), 15.1 (Me), 14.0 (Me). HRMS: m/z [M + H] calcd for C₁₁H₁₇N₂O₂: 209.1285; found: 209.1282.