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

1095 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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Computational methods in drug discovery

Sumudu P. Leelananda and
Steffen Lindert

Review
Published 12 Dec 2016

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

Yan Sun,
Jing Sun and
Chao-Guo Yan

Full Research Paper
Published 03 Jan 2013

511 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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A chromatography-free and aqueous waste-free process for thioamide preparation with Lawesson’s reagent

Ke Wu,
Yichen Ling,
An Ding,
Liqun Jin,
Nan Sun,
Baoxiang Hu,
Zhenlu Shen and
Xinquan Hu

Full Research Paper
Published 09 Apr 2021

464 Accesses

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1. Graphical Abstract
2. Figure 1: Generation of the six-membered byproduct A from thionation reactions using Lawesson’s reagent.
  
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3. Figure 2: Work-up procedure for the reaction with LR.
  
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4. Figure 3: Modified process for the synthesis of 2e via phase separation.
  
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5. Scheme 1: Modified process for the synthesis of pincer ligand 4.
  
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6. Scheme 2: Modified process for the synthesis of pincer-type ligand 6.
  
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Beilstein J. Org. Chem. 2021, 17, 805–812, doi:10.3762/bjoc.17.69

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Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

Shivani Gulati,
Stephy Elza John and
Nagula Shankaraiah

Review
Published 19 Apr 2021

447 Accesses

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1. Graphical Abstract
2. Figure 1: Marketed drugs with acridine moiety.
  
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3. Scheme 1: Synthesis of 4-arylacridinediones.
  
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4. Scheme 2: Proposed mechanism for acridinedione synthesis.
  
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5. Scheme 3: Synthesis of tetrahydrodibenzoacridinones.
  
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6. Scheme 4: Synthesis of naphthoacridines.
  
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7. Scheme 5: Plausible mechanism for naphthoacridines.
  
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8. Figure 2: Benzoazepines based potent molecules.
  
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9. Scheme 6: Synthesis of azepinone.
  
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10. Scheme 7: Proposed mechanism for azepinone formation.
  
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11. Scheme 8: Synthesis of benzoazulenen-1-one derivatives.
  
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12. Scheme 9: Proposed mechanism for benzoazulene-1-one synthesis.
  
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13. Figure 3: Indole-containing pharmacologically active molecules.
  
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14. Scheme 10: Synthesis of functionalized indoles.
  
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15. Scheme 11: Plausible mechanism for the synthesis of functionalized indoles.
  
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16. Scheme 12: Synthesis of spirooxindoles.
  
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17. Scheme 13: Synthesis of substituted spirooxindoles.
  
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18. Scheme 14: Plausible mechanism for the synthesis of substituted spirooxindoles.
  
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19. Scheme 15: Synthesis of pyrrolidinyl spirooxindoles.
  
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20. Scheme 16: Proposed mechanism for pyrrolidinyl spirooxindoles.
  
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21. Figure 4: Pyran-containing biologically active molecules.
  
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22. Scheme 17: Synthesis of functionalized benzopyrans.
  
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23. Scheme 18: Plausible mechanism for synthesis of benzopyran.
  
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24. Scheme 19: Synthesis of indoline-spiro-fused pyran derivatives.
  
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25. Scheme 20: Proposed mechanism for indoline-spiro-fused pyran.
  
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26. Scheme 21: Synthesis of substituted naphthopyrans.
  
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27. Figure 5: Marketed drugs with pyrrole ring.
  
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28. Scheme 22: Synthesis of tetra-substituted pyrroles.
  
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29. Scheme 23: Mechanism for silica-supported PPA-SiO₂-catalyzed pyrrole synthesis.
  
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30. Scheme 24: Synthesis of pyrrolo[1,10]-phenanthrolines.
  
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31. Scheme 25: Proposed mechanism for pyrrolo[1,10]-phenanthrolines.
  
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32. Figure 6: Marketed drugs and molecules containing pyrimidine and pyrimidinones skeletons.
  
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33. Scheme 26: MWA-MCR pyrimidinone synthesis.
  
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34. Scheme 27: Two proposed mechanisms for pyrimidinone synthesis.
  
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35. Scheme 28: MWA multicomponent synthesis of dihydropyrimidinones.
  
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36. Scheme 29: Proposed mechanism for dihydropyrimidinones.
  
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37. Figure 7: Biologically active fused pyrimidines.
  
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38. Scheme 30: MWA- MCR for the synthesis of pyrrolo[2,3-d]pyrimidines.
  
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39. Scheme 31: Proposed mechanism for pyrrolo[2,3-d]pyrimidines.
  
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40. Scheme 32: Synthesis of substituted pyrrolo[2,3-d]pyrimidine-2,4-diones.
  
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41. Scheme 33: Probable pathway for pyrrolo[2,3-d]pyrimidine-2,4-diones.
  
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42. Scheme 34: Synthesis of pyridopyrimidines.
  
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43. Scheme 35: Plausible mechanism for the synthesis of pyridopyrimidines.
  
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44. Scheme 36: Synthesis of dihydropyridopyrimidine and dihydropyrazolopyridine.
  
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45. Scheme 37: Proposed mechanism for the formation of dihydropyridopyrimidine.
  
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46. Scheme 38: Synthesis of thiopyrano[4,3-d]pyrimidines.
  
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47. Scheme 39: Plausible mechanism for the synthesis of thiopyrano[4,3-d]pyrimidines.
  
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48. Scheme 40: Synthesis of decorated imidazopyrimidines.
  
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49. Scheme 41: Proposed mechanism for imidazopyrimidine synthesis.
  
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50. Figure 8: Pharmacologically active molecules containing purine bases.
  
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51. Scheme 42: Synthesis of aza-adenines.
  
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52. Scheme 43: Synthesis of 5-aza-7-deazapurines.
  
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53. Scheme 44: Proposed mechanism for deazapurines synthesis.
  
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54. Figure 9: Biologically active molecules containing pyridine moiety.
  
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55. Scheme 45: Synthesis of steroidal pyridines.
  
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56. Scheme 46: Proposed mechanism for steroidal pyridine.
  
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57. Scheme 47: Synthesis of N-alkylated 2-pyridones.
  
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58. Scheme 48: Two possible mechanisms for pyridone synthesis.
  
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59. Scheme 49: Synthesis of pyridone derivatives.
  
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60. Scheme 50: Postulated mechanism for synthesis of pyridone.
  
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61. Figure 10: Biologically active fused pyridines.
  
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62. Scheme 51: Benzimidazole-imidazo[1,2-a]pyridines synthesis.
  
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63. Scheme 52: Mechanism for the synthesis of benzimidazole-imidazo[1,2-a]pyridines.
  
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64. Scheme 53: Synthesis of pyrazolo[3,4-b]pyridine-5-spirocycloalkanedione derivatives.
  
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65. Scheme 54: Proposed mechanism for spiro-pyridines.
  
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66. Scheme 55: Functionalized macrocyclane-fused pyrazolo[3,4-b]pyridine derivatives.
  
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67. Scheme 56: Mechanism postulated for macrocyclane-fused pyrazolo[3,4-b]pyridine.
  
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68. Scheme 57: Generation of pyrazolo[3,4-b]pyridines.
  
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69. Scheme 58: Proposed mechanism for the synthesis of pyrazolo[3,4-b]pyridines.
  
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70. Scheme 59: Proposed mechanism for the synthesis of azepinoindole.
  
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71. Figure 11: Pharmaceutically important molecules with quinoline moiety.
  
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72. Scheme 60: Povarov-mediated quinoline synthesis.
  
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73. Scheme 61: Proposed mechanism for Povarov reaction.
  
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74. Scheme 62: Synthesis of pyrazoloquinoline.
  
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75. Scheme 63: Plausible mechanism for pyrazoloquinoline synthesis.
  
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76. Figure 12: Quinazolinones as pharmacologically significant scaffolds.
  
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77. Scheme 64: Four-component reaction for dihydroquinazolinone.
  
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78. Scheme 65: Proposed mechanism for dihydroquinazolinones.
  
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79. Scheme 66: Synthesis purine quinazolinone and PI3K-δ inhibitor.
  
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80. Scheme 67: Synthesis of fused benzothiazolo/benzoimidazoloquinazolinones.
  
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81. Scheme 68: Proposed mechanism for fused benzothiazolo/benzoimidazoloquinazolinones.
  
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82. Scheme 69: On-water reaction for synthesis of thiazoloquinazolinone.
  
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83. Scheme 70: Proposed mechanism for the thiazoloquinazolinone synthesis.
  
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84. Scheme 71: β-Cyclodextrin-mediated synthesis of indoloquinazolinediones.
  
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85. Scheme 72: Proposed mechanism for synthesis of indoloquinazolinediones.
  
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86. Figure 13: Triazoles-containing marketted drugs and pharmacologically active molecules.
  
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87. Scheme 73: Cu(I) DAPTA-catalyzed 1,2,3-triazole formation.
  
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88. Scheme 74: Mechanism for Cu(I) DAPTA-catalyzed triazole formation.
  
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89. Scheme 75: Synthesis of β-hydroxy-1,2,3-triazole.
  
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90. Scheme 76: Proposed mechanism for synthesis of β-hydroxy-1,2,3-triazoles.
  
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91. Scheme 77: Synthesis of bis-1,2,4-triazoles.
  
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92. Scheme 78: Proposed mechanism for bis-1,2,4-triazoles synthesis.
  
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93. Figure 14: Thiazole containing drugs.
  
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94. Scheme 79: Synthesis of a substituted thiazole ring.
  
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95. Scheme 80: Synthesis of pyrazolothiazoles.
  
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96. Figure 15: Chromene containing drugs.
  
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97. Scheme 81: Magnetic nanocatalyst-mediated aminochromene synthesis.
  
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98. Scheme 82: Proposed mechanism for the synthesis of chromenes.
  
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Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

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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

430 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

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The chemistry of isoindole natural products

Klaus Speck and
Thomas Magauer

Review
Published 10 Oct 2013

421 Accesses

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Album
1. Graphical Abstract
2. Figure 1: a) Structural features and b) selected examples of non-natural congeners.
  
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3. Scheme 1: Synthesis of isoindole 18.
  
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4. Scheme 2: Staining amines with 1,4-diketone 19 (R = H).
  
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5. Figure 2: Representative members of the indolocarbazole alkaloid family.
  
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6. Figure 3: Staurosporine (26) bound to the adenosine-binding pocket [19] (from pdb1stc).
  
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7. Figure 4: Structure of imatinib (34) and midostaurin (35).
  
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8. Scheme 3: Biosynthesis of staurosporine (26).
  
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9. Scheme 4: Wood’s synthesis of K-252a via the common intermediate 48.
  
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10. Scheme 5: Synthesis of 26, 27, 49 and 50 diverging from the common intermediate 48.
  
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11. Figure 5: Selected members of the cytochalasan alkaloid family.
  
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12. Scheme 6: Biosynthesis of chaetoglobosin A (57) [56].
  
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13. Scheme 7: Synthesis of cytochalasin D (70) by Thomas [63].
  
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14. Scheme 8: Synthesis of L-696,474 (78).
  
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15. Scheme 9: Synthesis of aldehyde 85 (R = TBDPS).
  
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16. Scheme 10: Synthesis of (+)-aspergillin PZ (79) by Tanis.
  
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17. Figure 6: Representative Berberis alkaloids.
  
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18. Scheme 11: Proposed biosynthetic pathway to chilenine (93).
  
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19. Scheme 12: Synthesis of magallanesine (97) by Danishefsky [84].
  
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20. Scheme 13: Kurihara’s synthesis of magallanesine (85).
  
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21. Scheme 14: Proposed biosynthesis of 113, 117 and 125.
  
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22. Scheme 15: DNA lesion caused by aristolochic acid I (117) [102].
  
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23. Scheme 16: Snieckus’ synthesis of piperolactam C (131).
  
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24. Scheme 17: Synthesis of aristolactam BII (104).
  
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25. Figure 7: Representative cularine alkaloids.
  
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26. Scheme 18: Proposed biosynthesis of 136.
  
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27. Scheme 19: The syntheses of 136 and 137 reported by Castedo and Suau.
  
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28. Scheme 20: Synthesis of 136 by Couture.
  
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29. Figure 8: Representative isoindolinone meroterpenoids.
  
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30. Scheme 21: Postulated biosynthetic pathway for the formation of 156 (adopted from George) [143].
  
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31. Scheme 22: Synthesis of stachyflin (156) by Katoh [144].
  
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32. Figure 9: Selected examples of spirodihydrobenzofuranlactams.
  
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33. Scheme 23: Synthesis of stachybotrylactam I (157).
  
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34. Scheme 24: Synthesis of pestalachloride A (193) by Schmalz.
  
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35. Scheme 25: Proposed mechanism for the BF₃-catalyzed metal-free carbonyl–olefin metathesis [149].
  
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36. Scheme 26: Preparation of the isoindoline core of muironolide A (204).
  
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37. Scheme 27: Proposed biosynthesis of 208.
  
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38. Scheme 28: Model for the biosynthesis of 215 and 217.
  
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39. Scheme 29: Synthesis of lactonamycin (215) and lactonamycin Z (217).
  
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40. Figure 10: Hetisine alkaloids 225–228.
  
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41. Scheme 30: Biosynthetic proposal for the formation of the hetisine core [167].
  
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42. Scheme 31: Synthesis of nominine (225).
  
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Video

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

Full Text

Synthesis of bis(aryloxy)fluoromethanes using a heterodihalocarbene strategy

Carl Recsei and
Yaniv Barda

Letter
Published 12 Apr 2021

414 Accesses

PDF
Album
1. Graphical Abstract
2. Scheme 1: Retrosynthesis of compound 1.
  
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3. Scheme 2: Reported bis(aryloxy)fluoromethane syntheses. Reagents and conditions: (a) Cl₂FCH, NaOH, 1,4-dioxan...
  
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4. Scheme 3: Attempted synthesis of 4. Reagents and conditions: (a) Ca(OH)₂, 1,4-dioxane/water, reflux, 72 h, 5%...
  
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5. Scheme 4: Synthesis of 10. Reagents and conditions: (a) BrFCHCO₂Et, Cs₂CO₃, DMF, 35 °C, 16 h then H₂O, 35 °C,...
  
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6. Scheme 5: Synthesis of 1. Reagents and conditions: (a) 1,3-dibromo-5,5-dimethylhydantoin, benzoyl peroxide, (...
  
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7. Scheme 6: Synthesis of 11–13. Reagents and conditions: ArOH (1.3 mmol), Br₂FCH (1.3 mmol), KOH (4 mmol), MeCN...
  
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8. Scheme 7: Proposed mechanism for the formation of compound 11.
  
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Supp. Info

Beilstein J. Org. Chem. 2021, 17, 813–818, doi:10.3762/bjoc.17.70

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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

Full Research Paper
Published 08 Mar 2018

411 Accesses

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Album
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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Supp. Info

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

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

400 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.
  
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32. Scheme 29: Palladium-catalyzed allylation of indole.
  
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33. Scheme 30: Pd-catalyzed synthesis of pyrroloindoles from L-tryptophane.
  
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34. Scheme 31: Ru(IV)-catalyzed allylation of indole and pyrroles with unique regioselectivity.
  
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35. Scheme 32: Silver(I)-catalyzed intramolecular FC-type allylation of arenes and heteroarenes.
  
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36. Scheme 33: FC-type alkylations of arenes using propargyl alcohols.
  
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37. Scheme 34: (A) Propargylation of arenes with stoichiometric amounts of the Ru-allenylidene complex 86. (B) Fir...
  
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38. Scheme 35: Diruthenium-catalyzed formation of chromenes and 1H-naphtho[2,1-b]pyrans.
  
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39. Scheme 36: Rhenium(V)-catalyzed FC propargylations as a first step in the total synthesis of podophyllotoxin, ...
  
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40. Scheme 37: Scandium-catalyzed arylation of 3-sulfanyl- and 3-selanylpropargyl alcohols.
  
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41. Scheme 38: Synthesis of 1,3-diarylpropynes via direct coupling of propargyl trichloracetimidates and arenes.
  
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42. Scheme 39: Diastereoselective substitutions of benzyl alcohols.
  
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43. Scheme 40: (A) First diastereoselective FC alkylations developed by Bach et al. (B) anti-Selective FC alkylati...
  
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44. Scheme 41: Diastereoselective AuCl₃-catalyzed FC alkylation.
  
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45. Scheme 42: Bi(OTf)₃-catalyzed alkylation of α-chiral benzyl acetates with silyl enol ethers.
  
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46. Scheme 43: Bi(OTf)₃-catalyzed diastereoselective substitution of propargyl acetates.
  
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47. Scheme 44: Nucelophilic substitution of enantioenriched ferrocenyl alcohols.
  
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48. Scheme 45: First catalytic enantioselective propargylation of arenes.
  
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