Continuous-Flow Synthesis of Cyclobutenes Using LED Technology

Megan Smyth; Thomas S. Moody; Scott Wharry; Marcus Baumann

doi:10.1055/a-2086-0630

Synlett, Inhaltsverzeichnis

Synlett 2024; 35(03): 285-290
DOI: 10.1055/a-2086-0630

cluster

Organic Chemistry Under Visible Light: Photolytic and Photocatalytic Organic Transformations

Continuous-Flow Synthesis of Cyclobutenes Using LED Technology

Megan Smyth

^aAlmac Group Ltd., Craigavon BT63 5QD, UK

,

Thomas S. Moody

^aAlmac Group Ltd., Craigavon BT63 5QD, UK

^bArran Chemical Company, Roscommon N37 DN24, Ireland

,

Scott Wharry

^aAlmac Group Ltd., Craigavon BT63 5QD, UK

,

Marcus Baumann ∗

^cSchool of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Dublin, Ireland

› Institutsangaben

Abstract

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Abstract

Cyclobutenes are highly strained ring systems of considerable synthetic interest that can be accessed via cycloaddition reactions between alkenes and alkynes. However, their traditional preparation relies on photochemical [2+2] cycloadditions that exploit low-wavelength UV radiation emitted from inefficient medium-pressure Hg lamps. This paper reports on the development of a modern approach using a high-power LED set-up emitting at the boundary of UV-A and visible light in conjunction with a continuous-flow reactor. The resulting flow process renders a series of cyclobutenes from maleimides and various commercial alkynes. This provides a more energy-efficient approach that is readily scalable to access multigram quantities of cyclobutenes in high chemical yields and short residence times. The value of these products is exemplified by flow-based hydrogenations yielding highly substituted cyclobutanes which represent sought after building blocks in modern medicinal chemistry programs.

Key words

photochemistry - cycloaddition - cyclobutene - light-emitting diode (LED) - flow chemistry

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Referenzen

References and Notes

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14 Synthesis of Substrates 2a and 2bTo a solution of maleic anhydride (1 equiv.) in chloroform (1 M) and acetic acid (10 equiv.) was added either cyclopentyl amine (1.5 equiv.) or 4-trifluoromethoxyaniline (1.5 equiv.). The resulting mixture was then heated at reflux for ca. 10 h when sampling by ¹H NMR indicated near-quantitative formation of the desired maleimide product. The pure products were isolated by column chromatography (10–30% EtOAc in cyclohexane) after neutralization with K₂CO₃ and aqueous extraction.1-Cyclopentyl-1H-pyrrole-2,5-dione (2a)Yield 76% (7.6 mmol, 1.25 g), colorless solid, melting range 68–71 °C. ¹H NMR (400 MHz, CDCl₃): δ = 6.61 (s, 2 H), 4.39 (p, J = 8.3 Hz, 1 H), 2.03–1.75 (m, 6 H), 1.63–1.51 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.9 (2 C), 134.0 (2 CH), 50.9 (CH), 29.4 (2 CH₂), 24.8 (2 CH₂). IR: ν = 3443 (w), 3092 (w), 2967 (m), 2874 (w), 1691 (s), 1373 (s), 1208 (m), 1128 (m), 837 (s), 689 (s), 432 (s). HRMS (ES-TOF)⁺: m/z calcd for C₉H₁₂NO₂: 165.0790; found: 165.0786.1-[4-(Trifluoromethoxy)phenyl]-1H-pyrrole-2,5-dione (2b)Yield 70% (1.8 mmol, 460 mg), off-white powder, melting range 75–77 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.39 (d, J = 9.2 Hz, 2 H), 7.29 (d, J = 9.2 Hz, 2 H), 6.84 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.1 (2 C), 148.2 (q, J = 4 Hz, C), 134.3 (2 CH), 129.7 (C), 127.2 (2 CH), 121.6 (2 CH), 119.7 (q, J = 258 Hz, CF₃). ¹⁹F NMR (376 MHz, CDCl₃): δ = –58.0 (s). IR: ν = 3072 (w), 1720 (s), 1703 (s), 1514 (m), 1265 (s), 1214 (m), 1160 (s), 819 (m), 691 (m). HRMS (ES-TOF)⁺: m/z calcd for C₁₁H₇F₃NO₃: 258.0373; found: 258.0374.Synthesis of Cyclobutenes 3a–iA stock solution of the maleimide (1.0 equiv.) and alkyne (1.2 equiv.) was prepared in MeCN (0.2 M) and pumped through the reactor coil (10 mL, PFA, 15 min residence time) of a Vapourtec flow reactor combined with its UV150 unit. As light source an adjustable high-intensity LED emitting at 365 nm was used with a set input power of 75 W. After collection of the product solution, the volatiles were removed by evaporation and the pure product was isolated after silica column chromatography (eluent 10–20% EtOAc/cyclohexane).(rac)-(1S,5S)-6-(Hydroxymethyl)-3-azabicyclo[3.2.0]hept-6-ene-2,4-dione (3a)Yield 77% (3.9 mmol, 590 mg), pale yellow wax. ¹H NMR (500 MHz, CDCl₃): δ = 7.83 (s, 1 H), 6.33 (d, J = 1.8 Hz, 1 H), 4.27 (s, 2 H), 3.86 (br s, 1 H), 3.74 (br s, 1 H), 1.99 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 174.6 (C), 174.3 (C), 151.1 (C), 130.4 (CH), 59.5 (CH₂), 48.7 (CH), 45.6 (CH). IR: δ = 3435 (m), 3218 (m), 3078 (m), 2985 (w), 1763 (m), 1691 (s), 1338 (m), 1248 (m), 1171 (s), 1036 (m), 973 (m), 791 (m), 630 (m). HRMS (ES-TOF)⁺: m/z calcd for C₇H₈NO₃: 154.0499; found: 154.0500.(rac)-(1S,5S)-6-Butyl-3-azabicyclo[3.2.0]hept-6-ene-2,4-dione (3b)Yield 77% (3.1 mmol, 550 mg), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.42 (br s, 1 H), 6.05 (d, J = 1.5 Hz, 1 H), 3.66 (dd, J = 3.0, 1.4 Hz, 1 H), 3.64–3.56 (m, 1 H), 2.15 (dddd, J = 8.2, 6.4, 3.8, 2.0 Hz, 2 H), 1.56–1.42 (m, 2 H), 1.31 (dt, J = 14.8, 7.3 Hz, 2 H), 0.87 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.3 (C), 175.3 (C), 154.0 (C), 129.0 (CH), 49.9 (CH), 45.3 (CH), 29.6 (CH₂), 28.0 (CH₂), 22.2 (CH₂), 13.7 (CH₃). IR: ν = 3221 (br m), 2958 (m), 2930 (m), 1764 (m), 1694 (s), 1337 (m), 1247 (m), 1170 (m), 957 (m), 781 (m), 676 (m), 625 (m). HRMS (ES-TOF)⁺: m/z calcd for C₁₀H₁₄NO₂: 180.1019; found: 180.1020. (rac)-(1R,5S)-6,7-Diethyl-3-azabicyclo[3.2.0]hept-6-ene-2,4-dione (3c)Yield 81% (2.7 mmol, 480 mg), white solid, melting range 72–75 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.55 (br s, 1 H), 3.52 (s, 2 H), 2.24–2.05 (m, 4 H), 1.03 (t, J = 7.6 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.6 (2 C), 144.3 (2 C), 46.4 (2 CH), 21.1 (2 CH₂), 11.7 (2 CH₃). IR: ν = 3280 (br), 2971 (m), 2914 (w), 1758 (w), 1703 (s), 1460 (w), 1334 (m), 1247 (m), 1181 (m), 1145 (m), 754 (m), 700 (w). HRMS (ES-TOF)⁺: m/z calcd for C₁₀H₁₄NO₂: 180.1019; found: 180.1020.(rac)-(1S,5S)-3-Cyclopentyl-6-(hydroxymethyl)-3-azabicyclo-[3.2.0]hept-6-ene-2,4-dione (3d)Yield 76% (2.9 mmol, 639 mg), waxy solid. ¹H NMR (500 MHz, CDCl₃): δ = 6.27 (d, J = 1.4 Hz, 1 H), 4.40 (p, J = 8.6 Hz, 1 H), 4.21 (d, J = 5.1 Hz, 2 H), 3.72 (d, J = 3.1 Hz, 1 H), 3.63–3.54 (m, 1 H), 2.62 (t, J = 5.8 Hz, 1 H), 1.99–1.84 (m, 4 H), 1.83–1.70 (m, 2 H), 1.61–1.47 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 175.2 (C), 175.0 (C), 151.7 (C), 130.5 (CH), 59.4 (CH₂), 51.4 (CH), 46.7 (CH), 43.7 (CH), 28.5 (CH₂), 28.4 (CH₂), 25.3 (2 CH₂). IR: ν = 3438 (br), 2956 (w), 2870 (w), 1762 (w), 1687 (s), 1395 (m), 1250 (w), 1218 (m), 1039 (w), 668 (w). HRMS (ES-TOF)⁺: m/z calcd for C₁₂H₁₆NO₃: 222.1125; found: 222.1124.(rac)-(1S,5S)-6-Butyl-3-cyclopentyl-3-azabicyclo[3.2.0]hept-6-ene-2,4-dione (3e)Yield 82% (2.5 mmol, 620 mg), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 6.05 (d, J = 1.5 Hz, 1 H), 4.40 (p, J = 8.4 Hz, 1 H), 3.57 (d, J = 3.4 Hz, 1 H), 3.49 (dd, J = 2.7, 1.1 Hz, 1 H), 2.17–2.11 (m, 2 H), 1.98–1.82 (m, 4 H), 1.77 (qt, J = 8.2, 2.3 Hz, 2 H), 1.58–1.52 (m, 2 H), 1.49–1.40 (m, 2 H), 1.29 (dq, J = 14.7, 7.3 Hz, 2 H), 0.88 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.0 (C), 175.1 (C), 154.4 (C), 129.4 (CH), 51.2 (CH), 48.1 (CH), 43.4 (CH), 29.6 (CH₂), 28.4 (2 CH₂), 28.1 (CH₂), 25.3 (2 CH₂), 22.2 (CH₂), 13.7 (CH₃). IR: ν = 2956 (m), 2932 (w), 2871 (w), 1764 (w), 1697 (s), 1365 (m), 1217 (w), 1154 (m). HRMS (ES-TOF)⁺: m/z calcd for C₁₅H₂₂NO₂: 248.1645; found: 248.1646.(rac)-(1R,5S)-3-Cyclopentyl-6,7-diethyl-3-azabicyclo[3.2.0]-hept-6-ene-2,4-dione (3f)Yield 87% (4.1 mmol, 1.0 g), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 4.38 (p, J = 8.5 Hz, 1 H), 3.41 (s, 2 H), 2.14 (qd, J = 7.6, 5.1 Hz, 4 H), 1.97–1.80 (m, 4 H), 1.79–1.71 (m, 2 H), 1.56–1.47 (m, 2 H), 1.03 (t, J = 7.6 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.1 (2 C), 144.7 (2 C), 51.0 (CH), 44.6 (2 CH), 28.4 (2 CH₂), 25.3 (2 CH₂), 21.1 (2 CH₂), 12.0 (2 CH₃). IR: ν = 2966 (m), 2874 (w), 1762 (w), 1693 (s), 1460 (w), 1394 (w), 1366 (m), 1215 (m), 1156 (m), 1139 (m). HRMS (ES-TOF)⁺: m/z calcd for C₁₅H₂₂NO₂: 248.1645; found: 248.1648.(rac)-(1S,5S)-6-Cyclopropyl-3-azabicyclo[3.2.0]hept-6-ene-2,4-dione (3g)Yield 76% (7.2 mmol, 1.17 g), waxy solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.59 (br s, 1 H), 5.99 (s, 1 H), 3.57–3.48 (m, 2 H), 1.55–1.39 (m, 1 H), 0.92–0.70 (m, 3 H), 0.66–0.54 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.2 (C), 175.4 (C), 154.5 (C), 126.3 (CH₂), 48.4 (CH), 44.5 (CH), 11.3 (CH), 6.5 (CH₂), 6.1 (CH₂). IR: ν = 3221 (br), 3078 (w), 3009 (w), 1765 (w), 1703 (s), 1338 (w), 1250 (w), 1184 (w), 792 (w). HRMS (ES-TOF)⁺: m/z calcd for C₉H₁₀NO₂: 164.0706; found: 164.0708.(rac)-(1S,5S)-6-(Hydroxymethyl)-3-[4-(trifluoromethoxy)phenyl]-3-azabicyclo[3.2.0]hept-6-ene-2,4-dione (3h)Yield 71% (2.0 mmol, 625 mg), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.38–7.27 (m, 4 H), 6.39 (app q, J = 1.7 Hz, 1 H), 4.30 (d, J = 5.2 Hz, 2 H), 3.97 (d, J = 3.1 Hz, 1 H), 3.87–3.82 (m, 1 H), 1.89 (t, J = 5.9 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5 (C), 173.3 (C), 151.5 (C), 148.8 (C), 130.6 (CH), 130.1 (C), 128.0 (2 CH), 121.6 (2 CH), 120.3 (q, J = 252 Hz, CF₃), 59.5 (CH₂), 47.1 (CH), 44.1 (CH). ¹⁹F NMR (376 MHz, CDCl₃): δ = –57.9 (s). IR: ν = 3467 (br), 2923 (w), 1773 (w), 1707 (s), 1510 (m), 1379 (w), 1259 (s), 1214 (s), 1170 (s), 1021 (w). HRMS (ES-TOF)⁺: m/z calcd for C₁₄H₁₁NF₃NO₄: 314.0635; found: 314.0634.(rac)-{(1S,5S)-2,4-Dioxo-3-azabicyclo[3.2.0]hept-6-en-6-yl}methyl Cinnamate (4a)Quantitative yield, white solid, melting range 145–148 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.29 (br s, 1 H), 7.73 (d, J = 15.9 Hz, 1 H), 7.65–7.50 (m, 2 H), 7.40–7.33 (m, 3 H), 6.43 (d, J = 15.9 Hz, 1 H), 6.35 (s, 1 H), 4.77 (d, J = 2.5 Hz, 2 H), 3.84 (d, J = 3.1 Hz, 1 H), 3.72 (d, J = 2.7 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.6 (C), 173.7 (C), 166.3 (C), 146.7 (C), 146.0 (CH), 134.1 (C), 132.8 (CH), 130.6 (CH), 128.9 (2 CH), 128.2 (2 CH), 116.9 (CH), 60.0 (CH₂), 49.0 (CH), 46.0 (CH). IR: ν = 3188 (br), 3061 (w), 2960 (w), 1770 (w), 1696 (s), 1633 (s), 1337 (m), 1312 (m), 1161 (s), 963 (m), 821 (s), 768 (s), 689 s), 630 (s), 414 (s). X-ray data: P1 (2), a = 5.6738(3) Å, b = 10.4380(4) Å, c = 11.8262(2) Å, α = 104.359(3), β = 101.334(4), γ = 96.871(4). HRMS (ES-TOF)⁺: m/z calcd for C₁₆H₁₄NO₄: 284.0917; found: 284.0913.Synthesis of Cyclobutanes 5a, 5g, and 5iA solution of the desired cyclobutene (3a, 3g, 3i) was prepared (0.1 M in EtOAc/EtOH, 50/50 by volume) and pumped into an H-Cube^® Mini reactor equipped with a catalyst cartridge (10% Pd/C, 30 °C) using a flow rate of 1 mL/min. The reaction solution was collected, evaporated under reduced pressure, and subjected to purification via silica gel chromatography (10–25% EtOAc/cyclohexane) to obtain the pure products prior to analysis and characterization. (rac)-(1S,5R,6R)-6-(Hydroxymethyl)-3-azabicyclo[3.2.0]-heptane-2,4-dione (5a)Yield 94% (0.94 mmol, 145 mg), waxy solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.62 (br s, 1 H), 3.73 (dd, J = 12.1, 4.5 Hz, 1 H), 3.63 (dd, J = 11.9, 7.7 Hz, 1 H), 3.43 (dd, J = 10.2, 6.6 Hz, 1 H), 3.28–3.23 (m, 1 H), 3.10 (ttd, J = 10.1, 7.8, 4.6 Hz, 1 H), 2.68 (dtd, J = 13.1, 10.2, 1.3 Hz, 1 H), 2.48 (br s, 1 H), 2.16 (ddd, J = 13.4, 8.1, 5.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 179.8 (C), 179.7 (C), 62.7 (CH₂), 42.4 (CH), 36.6 (CH), 36.0 (CH), 25.0 (CH₂). IR: ν = 3444 (br), 3230 (br), 2950 (w), 1760 (m), 1701 (s), 1349 (w), 1180 (w), 1029 (w), 605 (w). HRMS (ES-TOF)⁺: m/z calcd for C₇H₉NO₃Na: 178.0475; found: 178.0474.(rac)-(1S,5R,6R)-6-Propyl-3-azabicyclo[3.2.0]heptane-2,4-dione (5g)Yield 93% (0.93 mmol, 155 mg), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.02 (br s, 1 H), 3.40–3.33 (m, 1 H), 3.18 (dt, J = 10.2, 6.2 Hz, 1 H), 2.87–2.70 (m, 2 H), 1.87 (ddd, J = 12.5, 6.7, 4.9 Hz, 1 H), 1.67–1.56 (m, 1 H), 1.33–1.20 (m, 3 H), 0.86 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 180.3 (C), 177.8 (C), 43.8 (CH), 36.9 (CH), 35.0 (CH₂), 34.1 (CH), 29.7 (CH₂), 19.8 (CH₂), 13.8 (CH₃). IR: ν = 3206 (br), 2958 (m), 2931 (m), 1758 (m), 1706 (s), 1338 (m), 1167 (m), 977 (m), 826 (m), 599 (m). (rac)-Ethyl (1S,5S,6R)-3-Cyclopentyl-2,4-dioxo-3-azabicyclo-[3.2.0]heptane-6-carboxylate (5i)Yield 90% (0.90 mmol, 237 mg), colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 4.48 (p, J = 8.5 Hz, 1 H), 4.20–4.03 (m, 2 H), 3.58 (td, J = 10.0, 7.4 Hz, 1 H), 3.42 (dd, J = 10.4, 6.7 Hz, 1 H), 3.15 (ddd, J = 10.3, 6.8, 5.3 Hz, 1 H), 2.71 (dtd, J = 13.3, 9.8, 1.2 Hz, 1 H), 2.48 (ddd, J = 12.9, 7.4, 5.2 Hz, 1 H), 2.06–1.95 (m, 2 H), 1.94–1.75 (m, 4 H), 1.59–1.51 (m, 2 H), 1.23 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 178.8 (C), 176.3 (C), 171.2 (C), 61.3 (CH₂), 51.9 (CH), 40.2 (CH), 37.4 (CH), 35.1 (CH), 28.6 (CH₂), 28.3 (CH₂), 25.4 (CH₂), 25.3 (CH₂), 25.2 (CH₂), 14.1 (CH₃). IR: ν = 2957 (m), 2872 (w), 1770 (m), 1729 (m), 1697 (s), 1396 (m), 1195 (m), 1146 (m), 855 (w). HRMS (ES-TOF)⁺: m/z calcd for C₁₄H₁₉NO₄Na: 288.1206; found: 288.1207.

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