Photocatalytic Carbamoyl Radical Transfer to Alkenyl Azaarenes

Zi-xuan Yu; Shi-Wei Ma; Guang-xun Li; Long-jun Ma

doi:10.1055/a-2256-3096

Synlett, Table of Contents

Synlett 2024; 35(16): 1883-1888
DOI: 10.1055/a-2256-3096

letter

Photocatalytic Carbamoyl Radical Transfer to Alkenyl Azaarenes

Zi-xuan Yu

^aSchool of Chemistry and Chemical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, P. R. of China

^bNatural Product Research Center, Chengdu Institute of Biology, Chinese Academy of Science, Chengdu, Sichuan 610041, P. R. of China

,

Shi-Wei Ma

^aSchool of Chemistry and Chemical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, P. R. of China

,

Guang-xun Li ∗

^bNatural Product Research Center, Chengdu Institute of Biology, Chinese Academy of Science, Chengdu, Sichuan 610041, P. R. of China

,

Long-jun Ma∗

^aSchool of Chemistry and Chemical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, P. R. of China

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Abstract

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Abstract

1-Phenyl-3-azaarenyl-propan-1-amine structural moieties have been widely incorporated in pharmaceuticals and biologically active compounds; however, current synthetic methods to access these compounds need multiple steps and proceed with low efficiency. Herein, we reported an efficient photocatalytic carbamoyl radical transfer approach that allows the preparation of these compounds in high yields (up to 88%). The reaction easily runs on a gram-scale and was applied for the preparation of pheniramine in two steps with 72% total yield.

Key words

azaarene - photocatalysis - carbamoyl radical - 1,4-dihydropyridine

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References

References and Notes

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10 Carbamoyl Transfer Reaction; General Procedure: A test tube equipped with a magnetic stirrer was charged with 4-carbamoyl-1,4-dihydropyridine 1 (0.1 mmol, 1 equiv) and α-branched 2-vinylquinoline 2 (0.1 mmol, 1 equiv) followed by addition of [Ir(dtbbpy)(ppy)₂][PF₆] (0.002 mmol, 0.01 equiv) and dichloromethane (1.5 mL) under air. The tube was sealed and three vacuum/argon cycles were made, then the mixture was then irradiated with a 60 W, 390 nm Kessil lamp and stirred at room temperature for 12 hours. Upon completion, the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (petrol ether/EtOAc = 5:1–3:1) to give the desired product. N-Isopropyl-3-phenyl-3-(quinolin-2-yl)propanamide (3a): Yield: 85%; white solid; mp 131–133 ℃. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.73–7.67 (m, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.30 (d, J = 7.1 Hz, 2 H), 7.25 (t, J = 7.4 Hz, 2 H), 7.19 (dd, J = 15.8, 7.8 Hz, 2 H), 6.06 (d, J = 6.4 Hz, 1 H), 4.80 (dd, J = 9.4, 5.5 Hz, 1 H), 3.90 (m, J = 13.2, 6.6 Hz, 1 H), 3.46 (dd, J = 13.7, 9.5 Hz, 1 H), 2.83 (dd, J = 13.7, 5.5 Hz, 1 H), 0.96 (d, J = 6.5 Hz, 3 H), 0.82 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.1, 162.1, 147.2, 143.1, 136.3, 129.3, 128.8, 128.6, 128.2, 127.6, 126.9, 126.8, 126.1, 122.6, 50.3, 42.4, 40.9, 22.6, 22.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₃N₂O⁺: 319.1804; found: 319.1782. N-Isopropyl-3-(2-methoxyphenyl)-3-(quinolin-2-yl)propanamide (3b): Yield: 61%; yellow solid; mp 142–146 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.73 (t, J = 7.7 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.84 (t, J = 7.4 Hz, 1 H), 6.46 (d, J = 6.6 Hz, 1 H), 5.30 (dd, J = 9.8, 4.5 Hz, 1 H), 3.99–3.90 (m, 1 H), 3.90 (d, J = 7.0 Hz, 3 H), 3.46 (dd, J = 13.6, 10.1 Hz, 1 H), 2.84 (dd, J = 13.8, 4.5 Hz, 1 H), 1.03 (d, J = 6.5 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 171.5, 162.7, 156.5, 147.0, 136.2, 131.3, 129.2, 129.0, 128.6, 127.9, 127.6, 126.9, 125.9, 122.6, 120.6, 110.7, 55.5, 42.6, 40.9, 40.6, 22.7, 22.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O₂ ⁺: 349.1910; found: 349.1910. 3-(2-Isopropoxyphenyl)-N-isopropyl-3-(quinolin-2-yl)propanamide (3c): Yield: 85%; yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.05 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 1 H), 7.14 (t, J = 7.8 Hz, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.80 (t, J = 7.4 Hz, 1 H), 6.46 (d, J = 7.0 Hz, 1 H), 5.20 (dd, J = 9.7, 4.5 Hz, 1 H), 4.57 (m, J = 12.0, 6.0 Hz, 1 H), 3.91 (m, J = 13.3, 6.6 Hz, 1 H), 3.47 (dd, J = 13.6, 9.9 Hz, 1 H), 2.81 (dd, J = 13.7, 4.5 Hz, 1 H), 1.32 (d, J = 6.0 Hz, 3 H), 1.25 (d, J = 6.0 Hz, 3 H), 1.01 (d, J = 6.5 Hz, 3 H), 0.84 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.6, 162.9, 154.8, 147.0, 135.9, 132.2, 129.4, 129.1, 128.7, 127.7, 127.5, 126.9, 125.8, 122.6, 120.3, 112.9, 69.9, 43.5, 40.8, 40.5, 22.7, 22.5, 22.2, 21.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₉N₂O₂ ⁺: 377.2223; found: 377.2228. N-Isopropyl-3-(quinolin-2-yl)-3-(o-tolyl)propanamide (3d): Yield: 62%; white solid; mp 121–130 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.74 (t, J = 7.7 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.21 (d, J = 7.4 Hz, 1 H), 7.12 (dd, J = 9.8, 5.9 Hz, 2 H), 7.07 (d, J = 3.0 Hz, 2 H), 6.23 (d, J = 7.1 Hz, 1 H), 5.08 (dd, J = 9.5, 4.9 Hz, 1 H), 3.95 (m, J = 13.4, 6.6 Hz, 1 H), 3.46 (dd, J = 13.8, 9.6 Hz, 1 H), 2.76 (dd, J = 13.8, 4.9 Hz, 1 H), 2.56 (s, 3 H), 1.03 (d, J = 6.5 Hz, 3 H), 0.90 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.3, 162.4, 147.1, 141.5, 136.3, 135.9, 130.7, 129.3, 128.8, 128.1, 127.6, 126.9, 126.6, 126.2, 126.1, 122.5, 46.0, 41.6, 41.0, 22.6, 22.5, 19.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O⁺: 333.1961; found: 333.1964. N-Isopropyl-3-(3-methoxyphenyl)-3-(quinolin-2-yl)propanamide (3e): Yield: 71%; colorless oil; mp 121–130 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.71 (t, J = 7.7 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 7.18 (t, J = 7.9 Hz, 1 H), 6.88 (d, J = 8.3 Hz, 2 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.05 (d, J = 7.1 Hz, 1 H), 4.77 (dd, J = 9.6, 5.3 Hz, 1 H), 3.90 (dd, J = 13.2, 6.6 Hz, 1 H), 3.74 (s, 3 H), 3.46 (dd, J = 13.7, 9.7 Hz, 1 H), 2.81 (dd, J = 13.7, 5.3 Hz, 1 H), 0.99 (d, J = 6.5 Hz, 3 H), 0.81 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.1, 161.9, 159.7, 147.1, 144.6, 136.4, 129.6, 129.4, 128.8, 127.6, 127.0, 126.1, 122.6, 120.5, 114.0, 112.0, 55.1, 50.3, 42.3, 40.9, 22.6, 22.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O₂ ⁺: 349.1910; found: 349.1912. N-Isopropyl-3-(4-methoxyphenyl)-3-(quinolin-2-yl)propanamide (3f): Yield: 82%; yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.74 (t, J = 7.6 Hz, 1 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.24 (d, J = 8.5 Hz, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), 6.10 (d, J = 7.2 Hz, 1 H), 4.77 (dd, J = 9.4, 5.5 Hz, 1 H), 3.92 (m, J = 13.3, 6.6 Hz, 1 H), 3.77 (s, 3 H), 3.45 (dd, J = 13.7, 9.5 Hz, 1 H), 2.82 (dd, J = 13.7, 5.5 Hz, 1 H), 1.00 (d, J = 6.5 Hz, 3 H), 0.84 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.2, 162.4, 158.4, 136.4, 135.1, 129.4, 129.1, 128.7, 127.6, 126.9, 126.1, 122.6, 114.0, 55.2, 49.5, 42.5, 40.9, 22.6, 22.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₄N₂O₂Na⁺: 371.1730; found: 371.1737. 3-(4-Fluorophenyl)-N-isopropyl-3-(quinolin-2-yl)propanamide (3g): Yield: 72%; white solid; mp 108–113 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.29 (t, J = 6.7 Hz, 3 H), 7.21 (dd, J = 15.1, 6.4 Hz, 2 H), 6.02 (d, J = 6.6 Hz, 1 H), 4.79 (dd, J = 9.3, 5.5 Hz, 1 H), 3.90 (m, J = 13.5, 6.7 Hz, 1 H), 3.46 (dd, J = 13.6, 9.6 Hz, 1 H), 2.82 (dd, J = 13.7, 5.4 Hz, 1 H), 0.97 (d, J = 6.5 Hz, 3 H), 0.82 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.14, 167.2, 162.1, 157.0, 147.2, 143.0, 136.3, 129.3, 128.8, 128.6, 128.2, 127.6, 126.9, 126.8, 126.1, 122.6, 50.3, 42.4, 40.9, 22.6, 22.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₂FN₂O⁺: 337.1710; found: 337.1758. 3-(4-Chlorophenyl)-N-isopropyl-3-(quinolin-2-yl)propanamide (3h): Yield: 81%; white solid; mp 134–136 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.07 (d, J = 8.1 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 7.77 (d, J = 7.9 Hz, 1 H), 7.72 (t, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.1 Hz, 1 H), 7.25–7.16 (m, 4 H), 5.95 (d, J = 3.7 Hz, 1 H), 4.84–4.74 (m, 1 H), 3.97–3.85 (m, 1 H), 3.42 (dd, J = 12.6, 10.3 Hz, 1 H), 2.79 (dd, J = 13.0, 3.1 Hz, 1 H), 0.99 (d, J = 3.5 Hz, 3 H), 0.83 (d, J = 3.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 170.7, 161.6, 161.5, 147.2, 141.5, 136.5, 132.6, 129.5, 129.5, 128.9, 128.7, 127.6, 127.0, 126.2, 122.4, 49.6, 42.3, 41.0, 22.6, 22.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₂ClN₂O⁺: 353.1415; found: 353.1429. N-Isopropyl-3-(quinolin-2-yl)-3-(p-tolyl)propanamide (3i): Yield: 82%; yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.71 (t, J = 7.7 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.21 (d, J = 8.6 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.06 (d, J = 7.9 Hz, 2 H), 6.10 (d, J = 7.4 Hz, 1 H), 4.76 (dd, J = 9.6, 5.3 Hz, 1 H), 3.95–3.84 (m, 1 H), 3.44 (dd, J = 13.7, 9.7 Hz, 1 H), 2.80 (dd, J = 13.7, 5.3 Hz, 1 H), 2.28 (s, 3 H), 0.98 (d, J = 6.5 Hz, 3 H), 0.81 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.2, 167.1, 164.6, 162.3, 157.0, 147.2, 140.1, 136.3, 136.3, 129.3, 128.8, 128.0, 127.6, 126.9, 126.0, 122.6, 49.9, 42.4, 40.9, 22.6, 22.4, 21.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O⁺: 333.1961; found: 333.1968.

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