Download PDF
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 
a   Almac Group Ltd., Craigavon BT63 5QD, UK
,
Thomas S. Moody
a   Almac Group Ltd., Craigavon BT63 5QD, UK
b   Arran Chemical Company, Roscommon N37 DN24, Ireland
,
Scott Wharry
a   Almac Group Ltd., Craigavon BT63 5QD, UK
,
Marcus Baumann  ∗
c   School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Dublin, Ireland
› Author AffiliationsFunding was provided by Science Foundation Ireland via the Industry Fellowship Program for the project entitled ‘Development of Continuous Biocatalysed Processes, Continuous Biocatalysed Chemicals (CATCH)’ (19/IFA/7420 to M.B.) and a Frontiers for the Future award (20/FFP-P/8712, to M.B.).
› Further Information
    Permissions and Reprints All articles of this category


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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2086-0630.
  • Supporting Information


Publication History

Received: 19 March 2023

Accepted after revision: 04 May 2023

Accepted Manuscript online:
04 May 2023

Article published online:
06 June 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References and Notes

  • 7 Childs RF, Johnson AW. J. Chem. Soc. C 1967; 874
    Crossref
  • 11 Dimeric species have been reported in maleimide-based cycloadditions, please see: von Sonntag J., Knolle W., Naumov S., Mehnert R.; Chem. Eur. J. 2002; 8: 4199 , see also ref. 10f
    CrossrefPubMed
  • 12 Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre. CCDC 2246538 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures. Please see: Groom C. R., Bruno I. J., Lightfoot M. P., Ward S. C.; Acta Crystallogr., Sect. B Struct. Sci., Cryst. Eng. Mater. 2016; 72: 171
    CrossrefPubMed
  • 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.