An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

Marcus Baumann and
Ian R. Baxendale

Review
Published 30 Oct 2013

1172 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
  
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3. Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
  
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4. Scheme 3: Synthesis of 3-picoline and nicotinic acid.
  
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5. Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
  
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6. Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
  
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7. Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
  
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8. Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
  
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9. Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
  
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10. Scheme 8: Synthesis of rosiglitazone.
  
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11. Scheme 9: Syntheses of 2-pyridones.
  
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12. Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
  
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13. Scheme 11: Polymer-assisted synthesis of rosiglitazone.
  
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14. Scheme 12: Synthesis of pioglitazone.
  
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15. Scheme 13: Meerwein arylation reaction towards pioglitazone.
  
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16. Scheme 14: Route towards pioglitazone utilising tyrosine.
  
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17. Scheme 15: Route towards pioglitazone via Darzens ester formation.
  
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18. Scheme 16: Syntheses of the thiazolidinedione moiety.
  
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19. Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
  
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20. Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
  
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21. Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
  
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22. Scheme 19: Synthesis of moxifloxacin.
  
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23. Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
  
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24. Scheme 21: Synthesis of levofloxacin.
  
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25. Scheme 22: Alternative approach to the levofloxacin core 1.125.
  
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26. Figure 3: Structures of nifedipine, amlodipine and clevidipine.
  
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27. Scheme 23: Mg₃N₂-mediated synthesis of nifedipine.
  
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28. Scheme 24: Synthesis of rac-amlodipine as besylate salt.
  
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29. Scheme 25: Aza Diels–Alder approach towards amlodipine.
  
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30. Scheme 26: Routes towards clevidipine.
  
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31. Figure 4: Examples of piperidine containing drugs.
  
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32. Figure 5: Discovery of tiagabine based on early leads.
  
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33. Scheme 27: Synthetic sequences to tiagabine.
  
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34. Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
  
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35. Scheme 28: Enantioselective synthesis of solifenacin.
  
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36. Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
  
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37. Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
  
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38. Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
  
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39. Scheme 30: Improved route to carmegliptin.
  
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40. Figure 9: Structures of lamivudine and zidovudine.
  
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41. Scheme 31: Typical routes accessing uracil, thymine and cytosine.
  
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42. Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
  
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43. Scheme 33: Synthesis of lamivudine.
  
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44. Scheme 34: Synthesis of raltegravir.
  
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45. Scheme 35: Mechanistic studies on the formation of 3.22.
  
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46. Figure 10: Structures of selected pyrimidine containing drugs.
  
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47. Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
  
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48. Scheme 37: Synthesis of imatinib.
  
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49. Scheme 38: Flow synthesis of imatinib.
  
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50. Scheme 39: Syntheses of erlotinib.
  
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51. Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
  
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52. Scheme 41: Synthesis of lapatinib.
  
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53. Scheme 42: Synthesis of rosuvastatin.
  
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54. Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
  
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55. Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
  
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56. Scheme 44: Syntheses of varenicline and its key building block 4.5.
  
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57. Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
  
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58. Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
  
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59. Scheme 46: Asymmetric synthesis of bortezomib.
  
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60. Figure 13: Structures of some prominent piperazine containing drugs.
  
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61. Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
  
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62. Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
  
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63. Scheme 48: Syntheses of azelastine (5.1).
  
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64. Figure 15: Structures of captopril, enalapril and cilazapril.
  
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65. Scheme 49: Synthesis of cilazapril.
  
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66. Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
  
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67. Scheme 50: Synthesis of lamotrigine.
  
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68. Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
  
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69. Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
  
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70. Scheme 52: Conventional synthesis of imiquimod (no yields reported).
  
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71. Scheme 53: Synthesis of imiquimod.
  
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72. Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
  
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73. Figure 18: Structures of various anti HIV-medications.
  
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74. Scheme 55: Synthesis of abacavir.
  
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75. Figure 19: Structures of diazepam compared to modern replacements.
  
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76. Scheme 56: Synthesis of ocinaplon.
  
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77. Scheme 57: Access to zaleplon and indiplon.
  
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78. Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
  
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79. Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
  
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80. Scheme 60: Early synthetic route to sildenafil.
  
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81. Scheme 61: Convergent preparations of sildenafil.
  
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82. Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
  
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83. Scheme 62: Short route to imidazotriazinones.
  
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84. Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
  
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85. Scheme 64: Bayer’s approach to the vardenafil core.
  
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86. Scheme 65: Large scale synthesis of vardenafil.
  
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87. Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
  
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88. Scheme 67: Different routes to temozolomide.
  
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89. Scheme 68: Safer route towards temozolomide.
  
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90. Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
  
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Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Full Text

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

Marcus Baumann and
Ian R. Baxendale

Review
Published 17 Jul 2015

555 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Pharmaceutical structures targeted in early flow syntheses.
  
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3. Scheme 1: Flow synthesis of 6-hydroxybuspirone (9). Inserted photograph reprinted with permission from [45]. Copy...
  
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4. Figure 2: Configuration of a baffled reactor tube (left) and its schematic working principle (right).
  
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5. Scheme 2: McQuade’s flow synthesis of ibuprofen (16).
  
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6. Scheme 3: Jamison’s flow synthesis of ibuprofen sodium salt (17).
  
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7. Scheme 4: Flow synthesis of imatinib (23).
  
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8. Scheme 5: Flow synthesis of the potent 5HT1B antagonist 28.
  
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9. Scheme 6: Flow synthesis of a selective δ-opioid receptor agonist 33.
  
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10. Scheme 7: Flow synthesis of a casein kinase I inhibitor library (38).
  
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11. Scheme 8: Flow synthesis of fluoxetine (46).
  
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12. Scheme 9: Flow synthesis of artemisinin (55).
  
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13. Scheme 10: Telescoped flow synthesis of artemisinin (55) and derivatives (62–64).
  
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14. Scheme 11: Flow approach towards AZD6906 (65).
  
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15. Scheme 12: Pilot scale flow synthesis of key intermediate 73.
  
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16. Scheme 13: Semi-flow synthesis of vildagliptine (77).
  
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17. Scheme 14: Pilot scale asymmetric flow hydrogenation towards 83. Inserted photograph reprinted with permission...
  
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18. Figure 3: Schematic representation of the ‘tube-in-tube’ reactor.
  
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19. Scheme 15: Flow synthesis of fanetizole (87) via tube-in-tube system.
  
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20. Scheme 16: Flow synthesis of diphenhydramine^.HCl (92).
  
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21. Scheme 17: Flow synthesis of rufinamide (95).
  
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22. Scheme 18: Large scale flow synthesis of rufinamide precursor 102.
  
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23. Scheme 19: First stage in the flow synthesis of meclinertant (103).
  
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24. Scheme 20: Completion of the flow synthesis of meclinertant (103).
  
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25. Scheme 21: Flow synthesis of olanzapine (121) utilising inductive heating techniques.
  
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26. Scheme 22: Flow synthesis of amitriptyline·HCl (127).
  
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27. Scheme 23: Flow synthesis of E/Z-tamoxifen (132) using peristaltic pumping modules.
  
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28. Figure 4: Container sized portable mini factory (photograph credit: INVITE GmbH, Leverkusen Germany).
  
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29. Scheme 24: Flow synthesis of imidazo[1,2-a]pyridines 136 linked to frontal affinity chromatography (FAC).
  
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30. Figure 5: Structures of zolpidem (142) and alpidem (143).
  
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31. Scheme 25: Synthesis and screening loops in the discovery of new Abl kinase inhibitors.
  
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32. Figure 6: Schotten–Baumann approach towards LY573636^.Na (147).
  
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33. Scheme 26: Pilot scale flow synthesis of LY2886721 (146).
  
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34. Scheme 27: Continuous flow manufacture of alikiren hemifumarate 152.
  
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Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

Full Text

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann,
Ian R. Baxendale,
Steven V. Ley and
Nikzad Nikbin

Review
Published 18 Apr 2011

507 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Structures of atorvastatin and other commercial statins.
  
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3. Figure 2: Structure of compactin.
  
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4. Scheme 1: Synthesis of pentasubstituted pyrroles.
  
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5. Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.
  
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6. Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.
  
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7. Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.
  
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8. Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.
  
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9. Scheme 6: Convergent synthesis towards atorvastatin.
  
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10. Figure 3: Binding pocket of sunitinib in the TRK KIT.
  
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11. Scheme 7: Synthesis of sunitinib.
  
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12. Scheme 8: Alternative synthesis of sunitinib.
  
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13. Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.
  
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14. Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.
  
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15. Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.
  
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16. Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
  
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17. Scheme 13: Alternative introduction of the sulfonamide.
  
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18. Scheme 14: Negishi-type coupling to benzylic sulfonamides.
  
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19. Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.
  
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20. Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.
  
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21. Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.
  
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22. Scheme 18: Improved synthesis of rizatriptan.
  
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23. Scheme 19: Larock-type synthesis of rizatriptan.
  
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24. Scheme 20: Synthesis of eletriptan.
  
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25. Scheme 21: Heck coupling for the indole system in eletriptan.
  
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26. Scheme 22: Attempted Fischer indole synthesis of elatriptan.
  
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27. Scheme 23: Successful Fischer indole synthesis for eletriptan.
  
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28. Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction.
  
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29. Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis.
  
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30. Scheme 26: Palladium-mediated synthesis of ondansetron.
  
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31. Scheme 27: Fischer indole synthesis of ondansetron.
  
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32. Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.
  
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33. Figure 4: Structures of carvedilol 136 and propranolol 137.
  
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34. Scheme 29: Synthesis of the carbazole core of carvedilol.
  
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35. Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.
  
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36. Scheme 31: Convergent synthesis of etodolac.
  
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37. Scheme 32: Alternative synthesis of etodolac.
  
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38. Figure 5: Structures of imidazole-containing drugs.
  
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39. Scheme 33: Synthesis of functionalised imidazoles towards losartan.
  
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40. Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.
  
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41. Scheme 35: Synthesis of trisubstituted imidazoles.
  
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42. Scheme 36: Preparation of the imidazole ring in olmesartan.
  
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43. Scheme 37: Synthesis of ondansetron.
  
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44. Scheme 38: Alternative route to ondansetron and its analogues.
  
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45. Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.
  
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46. Scheme 40: Synthesis of benzimidazole core pantoprazole.
  
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47. Figure 6: Structure of rabeprazole 194.
  
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48. Scheme 41: Synthesis of candesartan.
  
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49. Scheme 42: Alternative access to the candesartan key intermediate 216.
  
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50. Scheme 43: .Medicinal chemistry route to telmisartan.
  
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51. Scheme 44: Improved synthesis of telmisartan.
  
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52. Scheme 45: Synthesis of zolpidem.
  
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53. Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.
  
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54. Figure 7: Structure of celecoxib.
  
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55. Scheme 47: Preparation of celecoxib.
  
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56. Scheme 48: Alternative synthesis of celecoxib.
  
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57. Scheme 49: Regioselective access to celecoxib.
  
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58. Scheme 50: Synthesis of pazopanib.
  
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59. Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.
  
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60. Scheme 52: Regioselective synthesis of anastrozole.
  
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61. Scheme 53: Triazine-mediated triazole formation towards anastrozole.
  
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62. Scheme 54: Alternative routes to 1,2,4-triazoles.
  
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63. Scheme 55: Initial synthetic route to sitagliptin.
  
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64. Figure 8: Binding of sitagliptin within DPP-IV.
  
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65. Scheme 56: The process route to sitagliptin key intermediate 280.
  
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66. Scheme 57: Synthesis of maraviroc.
  
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67. Scheme 58: Synthesis of alprazolam.
  
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68. Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.
  
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69. Figure 9: Structures of itraconazole, ravuconazole and voriconazole.
  
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70. Scheme 60: Synthesis of itraconazole.
  
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71. Scheme 61: Synthesis of rufinamide.
  
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72. Scheme 62: Representative tetrazole formation in valsartan.
  
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73. Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.
  
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74. Scheme 63: Early stage introduction of the tetrazole in losartan.
  
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75. Scheme 64: Synthesis of cilostazol.
  
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76. Figure 11: Structure of cefdinir.
  
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77. Scheme 65: Semi-synthesis of cefdinir.
  
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78. Scheme 66: Thiazole syntheses towards ritonavir.
  
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79. Scheme 67: Synthesis towards pramipexole.
  
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80. Scheme 68: Alternative route to pramipexole.
  
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81. Scheme 69: Synthesis of famotidine.
  
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82. Scheme 70: Efficient synthesis of the hyperuricemic febuxostat.
  
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83. Scheme 71: Synthesis of ziprasidone.
  
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84. Figure 12: Structure of mometasone.
  
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85. Scheme 72: Industrial access to 2-furoic acid present in mometasone.
  
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86. Scheme 73: Synthesis of ranitidine from furfuryl alcohol.
  
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87. Scheme 74: Synthesis of nitrofurantoin.
  
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88. Scheme 75: Synthesis of benzofuran.
  
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89. Scheme 76: Synthesis of amiodarone.
  
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90. Scheme 77: Synthesis of raloxifene.
  
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91. Scheme 78: Alternative access to the benzo[b]thiophene core of raloxifene.
  
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92. Scheme 79: Gewald reaction in the synthesis of olanzapine.
  
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93. Scheme 80: Alternative synthesis of olanzapine.
  
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94. Figure 13: Access to simple thiophene-containing drugs.
  
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95. Scheme 81: Synthesis of clopidogrel.
  
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96. Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).
  
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97. Scheme 83: Alternative synthesis of key intermediate 422.
  
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98. Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.
  
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99. Scheme 84: Synthesis of timolol.
  
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100. Scheme 85: Synthesis of tizanidine 440.
  
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101. Scheme 86: Synthesis of leflunomide.
  
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102. Scheme 87: Synthesis of sulfamethoxazole.
  
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103. Scheme 88: Synthesis of risperidone.
  
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104. Figure 15: Relative abundance of selected transformations.
  
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105. Figure 16: The abundance of heterocycles within top 200 drugs (5-membered rings).
  
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Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

Full Text

A review of new developments in the Friedel–Crafts alkylation – From green chemistry to asymmetric catalysis

Magnus Rueping and
Boris J. Nachtsheim

Review
Published 20 Jan 2010

427 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: AlCl₃-mediated reaction between amyl chloride and benzene as developed by Friedel and Crafts.
  
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3. Figure 1: Most often used metal salts for catalytic FC alkylations and hydroarylations of arenes.
  
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4. Figure 2: 1,1-diarylalkanes with biological activity.
  
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5. Scheme 2: Alkylating reagents and side products produced.
  
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6. Scheme 3: Initially reported TeCl₄-mediated FC alkylation of 1-penylethanol with toluene.
  
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7. Scheme 4: Sc(OTf)₃-catalyzed FC benzylation of arenes.
  
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8. Scheme 5: Reductive FC alkylation of arenes with arenecarbaldehydes.
  
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9. Scheme 6: Iron(III)-catalyzed FC benzylation of arenes and heteroarenes.
  
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10. Scheme 7: A gold(III)-catalyzed route to beclobrate.
  
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11. Scheme 8: Catalytic FC-type alkylations of 1,3-dicarbonyl compounds.
  
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12. Scheme 9: Iron(III)-catalyzed synthesis of phenprocoumon.
  
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13. Scheme 10: Bi(OTf)₃-catalyzed FC alkylation of benzyl alcohols developed by Rueping et al.
  
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14. Scheme 11: (A) Bi(OTf)₃-catalyzed intramolecular FC alkylation as an efficient route to substituted fulvenes. ...
  
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15. Scheme 12: FC-type glycosylation of 1,2-dimethylindole and trimethoxybenzene.
  
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16. Scheme 13: FC alkylation with highly reactive ferrocenyl- and benzyl alcohols. The reaction proceeds even with...
  
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17. Scheme 14: Reductive FC alkylation of arenes with benzaldehyde and acetophenone catalyzed by the Ir-carbene co...
  
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18. Scheme 15: Formal synthesis of 1,1-diarylalkanes from benzyl alcohols and styrenes.
  
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19. Scheme 16: (A) Mo-catalyzed hydroarylation of styrenes and cyclohexenes. (B) Hydroalkylation–cyclization casca...
  
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20. Scheme 17: Bi(III)-catalyzed hydroarylation of styrenes with arenes and heteroarenes.
  
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21. Scheme 18: BiCl₃-catalyzed ene/FC alkylation reaction cascade – A fast access to highly arylated dihydroindene...
  
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22. Scheme 19: Au(I)/Ag(I)-catalyzed hydroarylation of indoles with styrenes, aliphatic and cyclic alkenes.
  
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23. Scheme 20: First transition-metal-catalyzed ortho-hydroarylation developed by Beller et al.
  
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24. Scheme 21: (A) Ti(IV)-mediated rearrangement of an N-benzylated aniline to the corresponding ortho-alkylated a...
  
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25. Scheme 22: Dibenzylation of aniline gives potentially useful amine-based ligands in a one-step procedure.
  
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26. Scheme 23: FC-type alkylations with allyl alcohols as alkylating reagents – linear vs. branched product format...
  
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27. Scheme 24: (A) First catalytic FC allylation and cinnamylation using allyl alcohols and its derivatives. (B) E...
  
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28. Scheme 25: FC allylation/cyclization reaction yielding substituted chromanes.
  
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29. Scheme 26: Synthesis of (all-rac)-α-tocopherol utilizing Lewis- and strong Brønsted-acids.
  
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30. Scheme 27: Au(III)-catalyzed cinnamylation of arenes.
  
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31. Scheme 28: “Exhaustive” allylation of benzene-1,3,5-triol.
  
  Jump to Scheme 28
32. Scheme 29: Palladium-catalyzed allylation of indole.
  
  Jump to Scheme 29
33. Scheme 30: Pd-catalyzed synthesis of pyrroloindoles from L-tryptophane.
  
  Jump to Scheme 30
34. Scheme 31: Ru(IV)-catalyzed allylation of indole and pyrroles with unique regioselectivity.
  
  Jump to Scheme 31
35. Scheme 32: Silver(I)-catalyzed intramolecular FC-type allylation of arenes and heteroarenes.
  
  Jump to Scheme 32
36. Scheme 33: FC-type alkylations of arenes using propargyl alcohols.
  
  Jump to Scheme 33
37. Scheme 34: (A) Propargylation of arenes with stoichiometric amounts of the Ru-allenylidene complex 86. (B) Fir...
  
  Jump to Scheme 34
38. Scheme 35: Diruthenium-catalyzed formation of chromenes and 1H-naphtho[2,1-b]pyrans.
  
  Jump to Scheme 35
39. Scheme 36: Rhenium(V)-catalyzed FC propargylations as a first step in the total synthesis of podophyllotoxin, ...
  
  Jump to Scheme 36
40. Scheme 37: Scandium-catalyzed arylation of 3-sulfanyl- and 3-selanylpropargyl alcohols.
  
  Jump to Scheme 37
41. Scheme 38: Synthesis of 1,3-diarylpropynes via direct coupling of propargyl trichloracetimidates and arenes.
  
  Jump to Scheme 38
42. Scheme 39: Diastereoselective substitutions of benzyl alcohols.
  
  Jump to Scheme 39
43. Scheme 40: (A) First diastereoselective FC alkylations developed by Bach et al. (B) anti-Selective FC alkylati...
  
  Jump to Scheme 40
44. Scheme 41: Diastereoselective AuCl₃-catalyzed FC alkylation.
  
  Jump to Scheme 41
45. Scheme 42: Bi(OTf)₃-catalyzed alkylation of α-chiral benzyl acetates with silyl enol ethers.
  
  Jump to Scheme 42
46. Scheme 43: Bi(OTf)₃-catalyzed diastereoselective substitution of propargyl acetates.
  
  Jump to Scheme 43
47. Scheme 44: Nucelophilic substitution of enantioenriched ferrocenyl alcohols.
  
  Jump to Scheme 44
48. Scheme 45: First catalytic enantioselective propargylation of arenes.
  
  Jump to Scheme 45

Beilstein J. Org. Chem. 2010, 6, No. 6, doi:10.3762/bjoc.6.6

Full Text

Computational methods in drug discovery

Sumudu P. Leelananda and
Steffen Lindert

Review
Published 12 Dec 2016

404 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Schematic representation of a computer-aided drug discovery (CADD) pipeline. CADD methods are broad...
  
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3. Figure 2: FDA approved drugs Saquinavir and Amprenavir for the treatment of HIV infections. (a) The structure...
  
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4. Figure 3: (a) The crystal structure showing the binding of Dorzolamide (orange) to carbonic anhydrase II (pur...
  
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5. Figure 4: The best ligand binding site identified by SiteHound in HIV-1 protease. The ligand binding pocket i...
  
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6. Figure 5: Binding mode prediction. The known inhibitor Dorzolamide is docked into Carbonic anhydrase II cryst...
  
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7. Figure 6: The molecular structure of Raltegravir. Raltegravir is an FDA approved drug used in the treatment o...
  
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8. Figure 7: An example alchemical thermodynamic cycle for a protein–ligand binding free energy calculation. The...
  
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9. Figure 8: Schematic diagram showing the steps involved in QSAR. Known drug molecule activity and descriptor d...
  
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10. Figure 9: A few drugs discovered with the help of ligand-based drug discovery tools. (a) Zolmitriptan: used a...
  
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Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

Full Text

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

Xiaowei Li,
Xiaolin Shi,
Xiangqian Li and
Dayong Shi

Review
Published 23 Sep 2019

380 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: The main three strategies of fluorination: nucleophilic, electrophilic and radical fluorination.
  
  Jump to Scheme 1
3. Scheme 2: Doyle’s Pd-catalyzed fluorination of allylic chlorides.
  
  Jump to Scheme 2
4. Scheme 3: Allylic fluorination of 2- and 3-substituted propenyl esters.
  
  Jump to Scheme 3
5. Scheme 4: Regioselective allylic fluorination of cinnamyl phosphorothioate esters.
  
  Jump to Scheme 4
6. Scheme 5: Palladium-catalyzed aliphatic C–H fluorination reported by Doyle.
  
  Jump to Scheme 5
7. Scheme 6: Pd-catalyzed enantioselective fluorination of α-ketoesters followed by stereoselective reduction to...
  
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8. Scheme 7: Pd-catalyzed C(sp³)–H fluorination of oxindoles.
  
  Jump to Scheme 7
9. Scheme 8: C–H fluorination of 8-methylquinoline derivatives with F⁻ reagents.
  
  Jump to Scheme 8
10. Scheme 9: Fluorination of α-cyano acetates reported by van Leeuwen.
  
  Jump to Scheme 9
11. Scheme 10: The catalytic enantioselective electrophilic C–H fluorination of α-chloro-β-keto phosphonates.
  
  Jump to Scheme 10
12. Scheme 11: Fluorination of unactivated C(sp³)–H bonds directed by the bidentate PIP auxiliary.
  
  Jump to Scheme 11
13. Scheme 12: Fluorination of C(sp³)–H bonds at the β-position of carboxylic acids.
  
  Jump to Scheme 12
14. Scheme 13: Enantioselective benzylic C–H fluorination with a chiral transient directing group.
  
  Jump to Scheme 13
15. Scheme 14: Microwave-heated Pd-catalyzed fluorination of aryl alcohols.
  
  Jump to Scheme 14
16. Scheme 15: Fluorination of aryl potassium trifluoroborates.
  
  Jump to Scheme 15
17. Scheme 16: C(sp²)–F bond formation using precatalyst [L·Pd]₂(cod).
  
  Jump to Scheme 16
18. Scheme 17: Pd-catalyzed fluorination of (hetero)aryl triflates and bromides.
  
  Jump to Scheme 17
19. Scheme 18: The Pd-catalyzed C–H fluorination of arenes with Selectfluor/NFSI.
  
  Jump to Scheme 18
20. Scheme 19: Pd(II)-catalyzed ortho-monofluorination protocol for benzoic acids.
  
  Jump to Scheme 19
21. Scheme 20: Pd-catalyzed C(sp²)–H bond fluorination of 2-arylbenzothiazoles.
  
  Jump to Scheme 20
22. Scheme 21: Nitrate-promoted fluorination of aromatic and olefinic C(sp²)–H bonds and proposed mechanism.
  
  Jump to Scheme 21
23. Scheme 22: Fluorination of oxalyl amide-protected benzylamine derivatives.
  
  Jump to Scheme 22
24. Scheme 23: C–H fluorination of benzaldehydes with orthanilic acids as transient directing group.
  
  Jump to Scheme 23
25. Scheme 24: Pd(II)-catalyzed aryl C–H fluorination with various directing groups.
  
  Jump to Scheme 24
26. Scheme 25: Cu-catalyzed aliphatic, allylic, and benzylic fluorination.
  
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27. Scheme 26: Cu-catalyzed S_N2 fluorination of primary and secondary alkyl bromides.
  
  Jump to Scheme 26
28. Scheme 27: Copper-catalyzed fluorination of alkyl triflates.
  
  Jump to Scheme 27
29. Scheme 28: Cu-catalyzed fluorination of allylic bromides and chlorides.
  
  Jump to Scheme 28
30. Scheme 29: Synthetic strategy for the fluorination of active methylene compounds.
  
  Jump to Scheme 29
31. Scheme 30: Fluorination of β-ketoesters using a tartrate-derived bidentate bisoxazoline-Cu(II) complex.
  
  Jump to Scheme 30
32. Scheme 31: Highly enantioselective fluorination of β-ketoesters and N-Boc-oxindoles.
  
  Jump to Scheme 31
33. Scheme 32: Amide group-assisted site-selective fluorination of α-bromocarbonyl compounds.
  
  Jump to Scheme 32
34. Scheme 33: Cu-mediated aryl fluorination reported by Sanford [77].
  
  Jump to Scheme 33
35. Scheme 34: Mono- or difluorination reactions of benzoic acid derivatives.
  
  Jump to Scheme 34
36. Scheme 35: Cu-catalyzed fluorination of diaryliodonium salts with KF.
  
  Jump to Scheme 35
37. Scheme 36: Copper(I)-catalyzed cross-coupling of 2-pyridylaryl bromides.
  
  Jump to Scheme 36
38. Scheme 37: AgNO₃-catalyzed decarboxylative fluorination of aliphatic carboxylic acids.
  
  Jump to Scheme 37
39. Scheme 38: The Mn-catalyzed aliphatic and benzylic C–H fluorination.
  
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40. Scheme 39: Iron(II)-promoted C–H fluorination of benzylic substrates.
  
  Jump to Scheme 39
41. Scheme 40: Ag-catalyzed fluorodecarboxylation of carboxylic acids.
  
  Jump to Scheme 40
42. Scheme 41: Vanadium-catalyzed C(sp³)–H fluorination.
  
  Jump to Scheme 41
43. Scheme 42: AgNO₃-catalyzed radical deboronofluorination of alkylboronates and boronic acids.
  
  Jump to Scheme 42
44. Scheme 43: Selective heterobenzylic C–H fluorination with Selectfluor reported by Van Humbeck.
  
  Jump to Scheme 43
45. Scheme 44: Fe(II)-catalyzed site-selective fluorination guided by an alkoxyl radical.
  
  Jump to Scheme 44
46. Scheme 45: Fluorination of allylic trichloroacetimidates reported by Nguyen et al.
  
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47. Scheme 46: Iridium-catalyzed fluorination of allylic carbonates with TBAF(t-BuOH)₄.
  
  Jump to Scheme 46
48. Scheme 47: Iridium-catalyzed asymmetric fluorination of allylic trichloroacetimidates.
  
  Jump to Scheme 47
49. Scheme 48: Cobalt-catalyzed α-fluorination of β-ketoesters.
  
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50. Scheme 49: Nickel-catalyzed α-fluorination of various α-chloro-β-ketoesters.
  
  Jump to Scheme 49
51. Scheme 50: Ni(II)-catalyzed enantioselective fluorination of oxindoles and β-ketoesters.
  
  Jump to Scheme 50
52. Scheme 51: Scandium(III)-catalyzed asymmetric C–H fluorination of unprotected 3-substituted oxindoles.
  
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53. Scheme 52: Iron-catalyzed directed C–H fluorination.
  
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54. Scheme 53: Electrophilic silver-catalyzed Ar–F bond-forming reaction from arylstannanes.
  
  Jump to Scheme 53
55. Figure 1: Nucleophilic, electrophilic and radical CF₃ sources.
  
  Jump to Figure 1
56. Scheme 54: Cu(I)-catalyzed allylic trifluoromethylation of unactivated terminal olefins.
  
  Jump to Scheme 54
57. Scheme 55: Direct copper-catalyzed trifluoromethylation of allylsilanes.
  
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58. Scheme 56: Cupper-catalyzed enantioselective trifluoromethylation of five and six-membered ring β-ketoesters.
  
  Jump to Scheme 56
59. Scheme 57: Cu-catalyzed highly stereoselective trifluoromethylation of secondary propargyl sulfonates.
  
  Jump to Scheme 57
60. Scheme 58: Remote C(sp³)–H trifluoromethylation of carboxamides and sulfonamides.
  
  Jump to Scheme 58
61. Scheme 59: Trifluoromethylation of allylsilanes with photoredox catalysis.
  
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62. Scheme 60: Ag-catalyzed decarboxylative trifluoromethylation of aliphatic carboxylic acids in aqueous CH₃CN.
  
  Jump to Scheme 60
63. Scheme 61: Decarboxylative trifluoromethylation of aliphatic carboxylic acids via combined photoredox and copp...
  
  Jump to Scheme 61
64. Scheme 62: Palladium-catalyzed Ar–CF₃ bond-forming reaction.
  
  Jump to Scheme 62
65. Scheme 63: Palladium-catalyzed trifluoromethylation of arenes with diverse heterocyclic directing groups.
  
  Jump to Scheme 63
66. Scheme 64: Pd-catalyzed trifluoromethylation of indoles as reported by Liu.
  
  Jump to Scheme 64
67. Scheme 65: Pd-catalyzed trifluoromethylation of vinyl triflates and vinyl nonaflates.
  
  Jump to Scheme 65
68. Scheme 66: Pd(II)-catalyzed ortho-trifluoromethylation of aromatic C–H bonds.
  
  Jump to Scheme 66
69. Scheme 67: Visible-light-induced Pd(OAc)₂-catalyzed ortho-trifluoromethylation of acetanilides with CF₃SO₂Na.
  
  Jump to Scheme 67
70. Scheme 68: CuI-catalyzed trifluoromethylation of aryl- and alkenylboronic acids.
  
  Jump to Scheme 68
71. Scheme 69: Cu-catalyzed trifluoromethylation of aryl- and vinylboronic acids.
  
  Jump to Scheme 69
72. Scheme 70: Copper-catalyzed trifluoromethylation of α,β-unsaturated carboxylic acids.
  
  Jump to Scheme 70
73. Scheme 71: Formation of C(sp²)–CF₃ bond catalyzed by copper(I) complex.
  
  Jump to Scheme 71
74. Scheme 72: Loh’s Cu(I)-catalyzed trifluoromethylation of enamides and electron-deficient alkenes.
  
  Jump to Scheme 72
75. Scheme 73: Copper and iron-catalyzed decarboxylative tri- and difluoromethylation.
  
  Jump to Scheme 73
76. Scheme 74: Cu-catalyzed trifluoromethylation of hydrazones developed by Bouyssi.
  
  Jump to Scheme 74
77. Scheme 75: Cu(I)-catalyzed trifluoromethylation of terminal alkenes.
  
  Jump to Scheme 75
78. Scheme 76: Cu/Ag-catalyzed decarboxylative trifluoromethylation of cinnamic acids.
  
  Jump to Scheme 76
79. Scheme 77: Copper-catalyzed direct alkenyl C–H trifluoromethylation.
  
  Jump to Scheme 77
80. Scheme 78: Copper(I/II)-catalyzed direct trifluoromethylation of styrene derivatives.
  
  Jump to Scheme 78
81. Scheme 79: Regioselective trifluoromethylation of pivalamido arenes and heteroarenes.
  
  Jump to Scheme 79
82. Scheme 80: Synthesis of trifluoromethylquinones in the presence of copper(I).
  
  Jump to Scheme 80
83. Scheme 81: Oxidative trifluoromethylation of imidazoheterocycles in ionic liquid/water.
  
  Jump to Scheme 81
84. Scheme 82: A mild and fast continuous-flow trifluoromethylation of coumarins using a CuI/CF₃SO₂Na/TBHP system.
  
  Jump to Scheme 82
85. Scheme 83: Copper-catalyzed oxidative trifluoromethylation of various 8-aminoquinolines.
  
  Jump to Scheme 83
86. Scheme 84: PA-directed copper-catalyzed trifluoromethylation of anilines.
  
  Jump to Scheme 84
87. Scheme 85: Trifluoromethylation of potassium vinyltrifluoroborates catalyzed by Fe(II).
  
  Jump to Scheme 85
88. Scheme 86: Alkenyl trifluoromethylation catalyzed by Ru(phen)₃Cl₂ as photocatalyst.
  
  Jump to Scheme 86
89. Scheme 87: Ru-catalyzed trifluoromethylation of alkenes by Akita’s group.
  
  Jump to Scheme 87
90. Scheme 88: Ir-catalyzed C_vinyl–CF₃ bond formation of α,β-unsaturated carboxylic acids.
  
  Jump to Scheme 88
91. Scheme 89: Ag(I)-catalyzed denitrative trifluoromethylation of β-nitrostyrenes.
  
  Jump to Scheme 89
92. Scheme 90: Photocatalyzed direct trifluoromethylation of aryl and heteroaryl C–H bonds.
  
  Jump to Scheme 90
93. Scheme 91: Rhenium (MTO)-catalyzed direct trifluoromethylation of aromatic substrates.
  
  Jump to Scheme 91
94. Scheme 92: Trifluoromethylation of unprotected anilines under [Ir(ppy)₃] catalyst.
  
  Jump to Scheme 92
95. Scheme 93: Oxidative trifluoromethylation of imidazopyridines and imidazoheterocycles.
  
  Jump to Scheme 93
96. Scheme 94: Ruthenium-catalyzed trifluoromethylation of (hetero)arenes with trifluoroacetic anhydride.
  
  Jump to Scheme 94
97. Scheme 95: Phosphovanadomolybdic acid-catalyzed direct C–H trifluoromethylation.
  
  Jump to Scheme 95
98. Scheme 96: Picolinamide-assisted ortho-trifluoromethylation of arylamines.
  
  Jump to Scheme 96
99. Scheme 97: A nickel-catalyzed C–H trifluoromethylation of free anilines.
  
  Jump to Scheme 97
100. Scheme 98: Cu-mediated trifluoromethylation of terminal alkynes reported by Qing.
  
  Jump to Scheme 98
101. Scheme 99: Huang’s C(sp)–H trifluoromethylation using Togni’s reagent.
  
  Jump to Scheme 99
102. Scheme 100: Cu-catalyzed methods for trifluoromethylation with Umemoto’s reagent.
  
  Jump to Scheme 100
103. Scheme 101: The synthesis of alkynyl-CF₃ compounds in the presence of fac-[Ir(ppy)₃] under visible-light irradi...
  
  Jump to Scheme 101
104. Scheme 102: Pd-catalyzed Heck reaction reported by Reutrakul.
  
  Jump to Scheme 102
105. Scheme 103: Difluoromethylation of enamides and ene-carbamates.
  
  Jump to Scheme 103
106. Scheme 104: Difluoromethylation of α,β-unsaturated carboxylic acids.
  
  Jump to Scheme 104
107. Scheme 105: Copper-catalyzed direct C(sp²)–H difluoroacetylation reported by Pannecoucke and co-workers.
  
  Jump to Scheme 105
108. Scheme 106: Difluoroalkylation of aldehyde-derived hydrazones with functionalized difluoromethyl bromides.
  
  Jump to Scheme 106
109. Scheme 107: Photoredox-catalyzed C–H difluoroalkylation of aldehyde-derived hydrazones.
  
  Jump to Scheme 107
110. Scheme 108: Synergistic ruthenium(II)-catalyzed C–H difluoromethylation reported by Ackermann.
  
  Jump to Scheme 108
111. Scheme 109: Visible-light photocatalytic decarboxylation of α,β-unsaturated carboxylic acids.
  
  Jump to Scheme 109
112. Scheme 110: Synthesis of difluorinated ketones via S-alkyl dithiocarbamates obtained from acyl chlorides and po...
  
  Jump to Scheme 110
113. Scheme 111: Synthesis of aryl and heteroaryl difluoromethylated phosphonates.
  
  Jump to Scheme 111
114. Scheme 112: Difluoroalkylation of secondary propargyl sulfonates using Cu as the catalyst.
  
  Jump to Scheme 112
115. Scheme 113: Ru(II)-mediated para-selective difluoromethylation of anilides and their derivatives.
  
  Jump to Scheme 113
116. Scheme 114: Bulky diamine ligand promoted cross-coupling of difluoroalkyl bromides.
  
  Jump to Scheme 114
117. Scheme 115: Copper-catalyzed C3–H difluoroacetylation of quinoxalinones.
  
  Jump to Scheme 115
118. Scheme 116: Copper(I) chloride-catalyzed trifluoromethylthiolation of enamines, indoles and β-ketoesters.
  
  Jump to Scheme 116
119. Scheme 117: Copper-boxmi-catalyzed asymmetric trifluoromethylthiolation of β-ketoesters.
  
  Jump to Scheme 117
120. Scheme 118: Direct Cu-catalyzed trifluoromethylthiolation of boronic acids and alkynes.
  
  Jump to Scheme 118
121. Scheme 119: Cu-catalyzed synthesis of α-trifluoromethylthio-substituted ketones.
  
  Jump to Scheme 119
122. Scheme 120: Trifluoromethylthiolation reactions promoted by diazotriflone and copper.
  
  Jump to Scheme 120
123. Scheme 121: Halide activation of N-(trifluoromethylthio)phthalimide.
  
  Jump to Scheme 121
124. Scheme 122: The visible light-promoted trifluoromethylthiolation reported by Glorius.
  
  Jump to Scheme 122
125. Scheme 123: Synthesis of α-trifluoromethylthioesters via Goossen’s approach.
  
  Jump to Scheme 123
126. Scheme 124: Photoinduced trifluoromethylthiolation of diazonium salts.
  
  Jump to Scheme 124
127. Scheme 125: Ag-mediated trifluoromethoxylation of aryl stannanes and arylboronic acids.
  
  Jump to Scheme 125
128. Scheme 126: Catalytic (hetero)aryl C–H trifluoromethoxylation under visible light.
  
  Jump to Scheme 126
129. Scheme 127: Photoinduced C–H-bond trifluromethoxylation of (hetero)arenes.
  
  Jump to Scheme 127

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

Full Text

Aggregation-induced emission effect on turn-off fluorescent switching of a photochromic diarylethene

Luna Kono,
Yuma Nakagawa,
Ayako Fujimoto,
Ryo Nishimura,
Yohei Hattori,
Toshiki Mutai,
Nobuhiro Yasuda,
Kenichi Koizumi,
Satoshi Yokojima,
Shinichiro Nakamura and
Kingo Uchida

Full Research Paper
Published 20 Sep 2019

372 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Synthetic procedure for a diarylethene (1o).
  
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3. Figure 2: Photochromic reaction of diarylethene 1o having an ESIPT moiety.
  
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4. Figure 3: Absorption spectral changes of diarylethene 1o having an ESIPT moiety in THF (c = 1.3×10^-5 M). Blac...
  
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5. Figure 4: Fluorescent spectra of 1o in several solvents (λ_ex = 370 nm). Hexane (black line), chloroform (red ...
  
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6. Figure 5: (a) The energy diagram of the ESIPT process of 1. (b) ESIPT fluorescence quenching upon UV light (λ...
  
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7. Figure 6: (a) Fluorescence photographs of solutions/suspensions of 1o (1.2×10^-4 M) in THF/water mixtures with...
  
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8. Figure 7: (a) Crystals of 1o before UV light irradiation, (b) Green fluorescence of 1o observed under UV ligh...
  
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Beilstein J. Org. Chem. 2019, 15, 2204–2212, doi:10.3762/bjoc.15.217

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The chemistry of amine radical cations produced by visible light photoredox catalysis

Jie Hu,
Jiang Wang,
Theresa H. Nguyen and
Nan Zheng

Review
Published 01 Oct 2013

369 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: Amine radical cations’ mode of reactivity.
  
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3. Scheme 2: Reductive quenching of photoexcited Ru complexes by Et₃N.
  
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4. Scheme 3: Photoredox aza-Henry reaction.
  
  Jump to Scheme 3
5. Scheme 4: Formation of iminium ions using BrCCl₃ as stoichiometric oxidant.
  
  Jump to Scheme 4
6. Scheme 5: Oxidative functionalization of N-aryltetrahydroisoquinolines using Eosin Y.
  
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7. Scheme 6: Synthetic and mechanistic studies of Eosin Y-catalyzed aza-Henry reaction.
  
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8. Scheme 7: Oxidative functionalization of N-aryltetrahydroisoquinolines using RB and GO.
  
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9. Scheme 8: Merging Ru-based photoredox catalysis and Lewis base catalysis for the Mannich reaction.
  
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10. Scheme 9: Merging Au-based photoredox catalysis and Lewis base catalysis for the Mannich reaction.
  
  Jump to Scheme 9
11. Scheme 10: Merging Ru-based photoredox catalysis and Cu-catalyzed alkynylation reaction.
  
  Jump to Scheme 10
12. Scheme 11: Merging Ru-based photoredox catalysis and NHC catalysis.
  
  Jump to Scheme 11
13. Scheme 12: 1,3-Dipolar cycloaddition of photogenically formed azomethine ylides.
  
  Jump to Scheme 12
14. Scheme 13: Plausible mechanism for photoredox 1,3-dipolar cycloaddition.
  
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15. Scheme 14: Photoredox-catalyzed cascade reaction for the synthesis of fused isoxazolidines.
  
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16. Scheme 15: Plausible mechanism for the photoredox-catalyzed cascade reaction.
  
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17. Scheme 16: Photoredox-catalyzed α-arylation of glycine derivatives.
  
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18. Scheme 17: Photoredox-catalyzed α-arylation of amides.
  
  Jump to Scheme 17
19. Scheme 18: Intramolecular interception of iminium ions by sulfonamides.
  
  Jump to Scheme 18
20. Scheme 19: Intramolecular interception of iminium ions by alcohols and sulfonamides.
  
  Jump to Scheme 19
21. Scheme 20: Intermolecular interception of iminium ions by phosphites.
  
  Jump to Scheme 20
22. Scheme 21: Photoredox-catalyzed oxidative phosphonylation by Eosin Y.
  
  Jump to Scheme 21
23. Scheme 22: Conjugated addition of α-amino radicals to Michael acceptors.
  
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24. Scheme 23: Conjugated addition of α-amino radicals to Michael acceptors assisted by a Brønsted acid.
  
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25. Scheme 24: Conjugated addition of α-amino radicals derived from anilines to Michael acceptors.
  
  Jump to Scheme 24
26. Scheme 25: Oxygen switch between two pathways involving α-amino radicals.
  
  Jump to Scheme 25
27. Scheme 26: Interception of α-amino radicals by azodicarboxylates.
  
  Jump to Scheme 26
28. Scheme 27: α-Arylation of amines.
  
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29. Scheme 28: Plausible mechanism for α-arylation of amines.
  
  Jump to Scheme 28
30. Scheme 29: Photoinduced C–C bond cleavage of tertiary amines.
  
  Jump to Scheme 29
31. Scheme 30: Photoredox cleavage of C–C bonds of 1,2-diamines.
  
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32. Scheme 31: Proposed mechanism photoredox cleavage of C–C bonds.
  
  Jump to Scheme 31
33. Scheme 32: Intermolecular [3 + 2] annulation of cyclopropylamines with olefins.
  
  Jump to Scheme 32
34. Scheme 33: Proposed mechanism for intermolecular [3 + 2] annulation.
  
  Jump to Scheme 33
35. Scheme 34: Photoinduced clevage of N–N bonds of aromatic hydrazines and hydrazides.
  
  Jump to Scheme 34

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

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Synthesis of acremines A, B and F and studies on the bisacremines

Nils Winter and
Dirk Trauner

Full Research Paper
Published 23 Sep 2019

348 Accesses

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1. Graphical Abstract
2. Figure 1: Selected members of the acremine family [3-5].
  
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3. Scheme 1: Retrosynthetic analysis of acremine F (5).
  
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4. Scheme 2: Total synthesis of acremine F (5).
  
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5. Scheme 3: Synthesis of acremines A and B through selective oxidation of acremine F.
  
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6. Scheme 4: Proposed biomimetic dimerization of 5.
  
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7. Scheme 5: Attempted intramolecular cyclization of 23.
  
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8. Scheme 6: Attempted photochemical cyclization of 25.
  
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Beilstein J. Org. Chem. 2019, 15, 2271–2276, doi:10.3762/bjoc.15.219

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Fluorescent phosphorus dendrimers excited by two photons: synthesis, two-photon absorption properties and biological uses

Anne-Marie Caminade,
Artem Zibarov,
Eduardo Cueto Diaz,
Aurélien Hameau,
Maxime Klausen,
Kathleen Moineau-Chane Ching,
Jean-Pierre Majoral,
Jean-Baptiste Verlhac,
Olivier Mongin and
Mireille Blanchard-Desce

Review
Published 24 Sep 2019

327 Accesses

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1. Graphical Abstract
2. Figure 1: Jablonski-type diagram displaying the classical one-photon excited fluorescence (left), and the les...
  
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3. Figure 2: Two ways to represent schematized structures of dendrimers, showing the different generations (laye...
  
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4. Scheme 1: Synthesis of phosphorhydrazone dendrimers, from the core to generation 2. Generation 1 dendrimers w...
  
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5. Scheme 2: Full structure of the generation 1 dendrimer bearing 12 blue-emitting TPA fluorophores on the surfa...
  
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6. Figure 3: Linear structure of the generation 2 dendrimer bearing 24 green-emitting TPA fluorophores on the su...
  
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7. Scheme 3: Synthesis of the dioxaborine-functionalized dendrimer of generation 4.
  
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8. Figure 4: Diverse structures of multistilbazole compounds, and graph of the σ₂^max/ε^max response, depending on...
  
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9. Figure 5: Nile Red derivatives: monomer (M) and two generations of dendrimers.
  
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10. Scheme 4: Dumbbell-like dendrimers (third generation) having one TPA fluorophore at the core, and ammonium te...
  
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11. Scheme 5: Another example of dumbbell-like dendrimers having one TPA fluorophore at the core, and P(S)Cl₂ or ...
  
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12. Scheme 6: The 12 steps needed to synthesize a sophisticated TPA fluorophore, to be used as branches of dendri...
  
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13. Scheme 7: Synthesis of dendrimers having TPA fluorophores as branches and water-solubilizing functions on the...
  
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14. Figure 6: Other types of dendrimers having TPA fluorophores as branches and water-solubilizing functions on t...
  
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15. Figure 7: Generations 0, 1, and 2 of dumbbell-like dendrimers having one fluorophore at the core and either 1...
  
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16. Figure 8: Double layer fluorescent dendrimer.
  
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17. Figure 9: Dumbbell-like dendrimer used for two-photon imaging of the blood vessels of a living rat olfactory ...
  
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18. Figure 10: Fluorescent gold complex having high antiproliferative activities against different tumor cell line...
  
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19. Figure 11: A fluorescent water-soluble dendrimer, applicable for two-photon photodynamic therapy and imaging.
  
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20. Figure 12: Schematization of the different types of TPA fluorescent phosphorus dendrimers and dendritic struct...
  
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Beilstein J. Org. Chem. 2019, 15, 2287–2303, doi:10.3762/bjoc.15.221

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