Synthesis of spiro[dihydropyridine-oxindoles] via three-component reaction of arylamine, isatin and cyclopentane-1,3-dione

Yan Sun,
Jing Sun and
Chao-Guo Yan

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Published 03 Jan 2013

986 Accesses

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1. Graphical Abstract
2. Scheme 1: The four-component reactions containing dimedone (a) and cyclopentane-1,3-dione (b).
  
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3. Figure 1: Molecular structure of spiro[dihydropyridine-oxindole] 1b.
  
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4. Figure 2: The two kinds of spiro compounds from reactions of isatins with arylamines and cyclic 1,3-diketones....
  
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5. Figure 3: Molecular structure of spiro[dihydropyridine-oxindole] 2f.
  
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6. Scheme 2: Condensation reactions of isatins with cyclopentane-1,3-dione.
  
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7. Figure 4: Molecular structure of compound 3d.
  
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8. Scheme 3: Proposed reaction mechanism for the three-component reaction.
  
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Beilstein J. Org. Chem. 2013, 9, 8–14, doi:10.3762/bjoc.9.2

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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

942 Accesses

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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

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Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

Shahboz Yakubov and
Joshua P. Barham

Review
Published 03 Sep 2020

863 Accesses

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1. Graphical Abstract
2. Figure 1: Fluorine-containing drugs.
  
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3. Figure 2: Fluorinated agrochemicals.
  
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4. Scheme 1: Selectivity of fluorination reactions.
  
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5. Scheme 2: Different mechanisms of photocatalytic activation. Sub = substrate.
  
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6. Figure 3: Jablonski diagram showing visible-light-induced energy transfer pathways: a) absorption, b) IC, c) ...
  
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7. Figure 4: Schematic illustration of TTET.
  
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8. Figure 5: Organic triplet PSCats.
  
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9. Figure 6: Additional organic triplet PSCats.
  
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10. Figure 7: A) Further organic triplet PSCats and B) transition metal triplet PSCats.
  
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11. Figure 8: Different fluorination reagents grouped by generation.
  
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12. Scheme 3: Synthesis of Selectfluor^®.
  
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13. Scheme 4: General mechanism of PS TTET C(sp³)–H fluorination.
  
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14. Scheme 5: Selective benzylic mono- and difluorination using 9-fluorenone and xanthone PSCats, respectively.
  
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15. Scheme 6: Chen’s photosensitized monofluorination: reaction scope.
  
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16. Scheme 7: Chen’s photosensitized benzylic difluorination reaction scope.
  
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17. Scheme 8: Photosensitized monofluorination of ethylbenzene on a gram scale.
  
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18. Scheme 9: Substrate scope of Tan’s AQN-photosensitized C(sp³)–H fluorination.
  
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19. Scheme 10: AQN-photosensitized C–H fluorination reaction on a gram scale.
  
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20. Scheme 11: Reaction mechanism of the AQN-assisted fluorination.
  
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21. Figure 9: 3D structures of the singlet ground and triplet excited states of Selectfluor^®.
  
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22. Scheme 12: Associated transitions for the activation of acetophenone by violet light.
  
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23. Scheme 13: Ethylbenzene C–H fluorination with various PSCats and conditions.
  
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24. Scheme 14: Effect of different PSCats on the C(sp³)–H fluorination of cyclohexane (39).
  
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25. Scheme 15: Reaction scope of Chen’s acetophenone-photosensitized C(sp³)–H fluorination reaction.
  
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26. Figure 10: a) Site-selectivity of Chen’s acetophenone-photosensitized C–H fluorination reaction [201]. b) Site-sele...
  
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27. Scheme 16: Formation of the AQN–Selectfluor^® exciplex Int1.
  
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28. Scheme 17: Generation of the C3 2° pentane radical and the Selectfluor^® N-radical cation from the exciplex.
  
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29. Scheme 18: Hydrogen atom abstraction by the Selectfluor^® N-radical cation from pentane to give the C3 2° penta...
  
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30. Scheme 19: Fluorine atom transfer from Selectfluor^® to the C3 2° pentane radical to yield 3-fluoropentane and ...
  
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31. Scheme 20: Barrierless fluorine atom transfer from Int1 to the C3 2° pentane radical to yield 3-fluoropentane,...
  
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32. Scheme 21: Ketone-directed C(sp³)–H fluorination.
  
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33. Scheme 22: Ketone-directed fluorination through a 5- and a 6-membered transition state, respectively.
  
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34. Scheme 23: Effect of different PSCats on the photosensitized C(sp³)–H fluorination of 47.
  
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35. Scheme 24: Substrate scope of benzil-photoassisted C(sp³)–H fluorinations.
  
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36. Scheme 25: A) Benzil-photoassisted enone-directed C(sp³)–H fluorination. B) Classification of the reaction mod...
  
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37. Scheme 26: A) Xanthone-photoassisted ketal-directed C(sp³)–H fluorination. B) Substrate scope. C) C–H fluorina...
  
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38. Scheme 27: Rationale for the selective HAT at the C2 C–H bond of galactose acetonide.
  
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39. Scheme 28: Photosensitized C(sp³)–H benzylic fluorination of a peptide using different PSCats.
  
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40. Scheme 29: Peptide scope of 5-benzosuberenone-photoassisted C(sp³)–H fluorinations.
  
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41. Scheme 30: Continuous flow PS TTET monofluorination of 72.
  
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42. Scheme 31: Photosensitized C–H fluorination of N-butylphthalimide as a PSX.
  
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43. Scheme 32: Substrate scope and limitations of the PSX C(sp³)–H monofluorination.
  
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44. Scheme 33: Substrate crossover monofluorination experiment.
  
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45. Scheme 34: PS TTET mechanism proposed by Hamashima and co-workers.
  
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46. Scheme 35: Photosensitized TFM of 78 to afford α-trifluoromethylated ketone 80.
  
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47. Scheme 36: Substrate scope for photosensitized styrene TFM to give α-trifluoromethylated ketones.
  
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48. Scheme 37: Control reactions for photosensitized TFM of styrenes.
  
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49. Scheme 38: Reaction mechanism for photosensitized TFM of styrenes to afford α-trifluoromethylated ketones.
  
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50. Scheme 39: Reaction conditions for TFMs to yield the cis- and the trans-product, respectively.
  
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51. Scheme 40: Substrate scope of trifluoromethylated (E)-styrenes.
  
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52. Scheme 41: Strategies toward trifluoromethylated (Z)-styrenes.
  
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53. Scheme 42: Substrate scope of trifluoromethylated (Z)-styrenes.
  
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54. Scheme 43: Reaction mechanism for photosensitized TFM of styrenes to afford E- or Z-products.
  
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Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

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High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

Eric Yu,
Hari P. R. Mangunuru,
Nakul S. Telang,
Caleb J. Kong,
Jenson Verghese,
Stanley E. Gilliland III,
Saeed Ahmad,
Raymond N. Dominey and
B. Frank Gupton

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Published 08 Mar 2018

575 Accesses

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1. Graphical Abstract
2. Figure 1: Commercially available antimalarial drugs.
  
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3. Scheme 1: Current batch syntheses of the key intermediate 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (6).
  
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4. Scheme 2: Retrosynthetic strategy to hydroxychloroquine (1).
  
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5. Scheme 3: Schematic representation for continuous in-line extraction of 10.
  
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6. Scheme 4: Optimization of the flow process for the synthesis of 12.
  
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Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

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

Marcus Baumann and
Ian R. Baxendale

Review
Published 17 Jul 2015

484 Accesses

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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

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Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

Benjamin Jeffries,
Zhong Wang,
Robert I. Troup,
Anaïs Goupille,
Jean-Yves Le Questel,
Charlene Fallan,
James S. Scott,
Elisabetta Chiarparin,
Jérôme Graton and
Bruno Linclau

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Published 02 Sep 2020

433 Accesses

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1. Graphical Abstract
2. Figure 1: Examples of lipophilicity modulation for geminal dimethyl to cyclopropyl and oxetane modifications ...
  
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3. Figure 2: Lipophilicity modulation examples involving fluorinated cyclopropane derivatives (measured experime...
  
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4. Figure 3: Lipophilicity changes upon fluorination of isopropyl, cyclopropane and oxetane rings (Series A, C: ...
  
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5. Figure 4: Lipophilicity modulations discussed in this contribution.
  
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6. Figure 5: Distribution of the experimental lipophilicity values of series D, E and F (* denotes an estimated ...
  
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7. Figure 6: Comparison of lipophilicities between the linear alkyl, isopropyl, cyclopropyl, and 3-oxetanyl subs...
  
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8. Figure 7: Comparison of lipophilicities between isopropyl and cyclopropyl substituents grouped by exchange of...
  
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9. Figure 8: Carbon extensions.
  
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10. Figure 9: Experimental and theoretical (in blue) values (calculated at the MN15/aug-cc-pVTZ//MN15/cc-pVTZ lev...
  
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11. Figure 10: Correlation of the DFT-calculated lipophilicities with the experimental values. A) fluorinated seri...
  
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12. Figure 11: Experimental (in black) and theoretical (in blue) values (calculated at the MN15/aug-cc-pVTZ//MN15/...
  
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Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

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Computational methods in drug discovery

Sumudu P. Leelananda and
Steffen Lindert

Review
Published 12 Dec 2016

414 Accesses

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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

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Synthesis of 6,13-difluoropentacene

Matthias W. Tripp and
Ulrich Koert

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Published 02 Sep 2020

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1. Graphical Abstract
2. Figure 1: Structures of pentacene and fluorinated pentacenes.
  
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3. Scheme 1: Retrosynthetic analysis of F2PEN 5.
  
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4. Scheme 2: Synthesis of F2PEN 5.
  
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5. Scheme 3: Decomposition of diol 13 in solution.
  
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6. Figure 2: UV–vis spectrum of F2PEN 5 in CH₂Cl₂.
  
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Beilstein J. Org. Chem. 2020, 16, 2136–2140, doi:10.3762/bjoc.16.181

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Regioselective cobalt(II)-catalyzed [2 + 3] cycloaddition reaction of fluoroalkylated alkynes with 2-formylphenylboronic acids: easy access to 2-fluoroalkylated indenols

Tatsuya Kumon,
Miroku Shimada,
Jianyan Wu,
Shigeyuki Yamada and
Tsutomu Konno

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Published 04 Sep 2020

354 Accesses

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1. Graphical Abstract
2. Figure 1: Indenol skeleton.
  
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3. Scheme 1: Synthesis of 2,3-disubstituted indene derivatives.
  
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4. Scheme 2: Cobalt-catalyzed [2 + 3] cycloaddition reaction of the fluorinated alkynes 1 with various 2-formylp...
  
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5. Scheme 3: Synthesis of the fluoroalkylated indenone 6 and the indanone 7 from the indenol 3aA. The yields wer...
  
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6. Scheme 4: Stereochemical assignment of 5aA and 7 based on NMR techniques. The cross-peaks were observed throu...
  
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7. Scheme 5: Proposed reaction mechanism.
  
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Beilstein J. Org. Chem. 2020, 16, 2193–2200, doi:10.3762/bjoc.16.184

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The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

Patrizia Andreozzi,
Lorenza Tamberi,
Elisamaria Tasca,
Gina Elena Giacomazzo,
Marta Martinez,
Mirko Severi,
Marco Marradi,
Stefano Cicchi,
Sergio Moya,
Giacomo Biagiotti and
Barbara Richichi

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Published 11 Sep 2020

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1. Graphical Abstract
2. Figure 1: Structure of PBA-BODIPY (1) and schematic representation of dextran (Dex) and PBA-BODIPY conjugated...
  
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3. Scheme 1: Schematic representation of dextran/PBA-BODIPY bioconjugations in: A. conventional solution-based c...
  
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4. Figure 2: A) Amount of recovered PBA-BODIPY (1, i.e., nonreacted 1) in the mixtures DMSO/EtOH and in the seri...
  
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5. Figure 3: A) UV–vis absorption and B) fluorescence emission spectra (λ_exc = 380 nm) of the BODIPY-dextran con...
  
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6. Figure 4: A) Hydrodynamic diameter of (nm) conjugate Dex-1b (at 1 mg/mL in H₂O, black curve) and PBS (red cur...
  
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7. Figure 5: Fluorescence emission spectra of pyrene (4.4 × 10⁻⁸ M) in water and in a water solution in the pres...
  
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Beilstein J. Org. Chem. 2020, 16, 2272–2281, doi:10.3762/bjoc.16.188

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The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

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