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

672 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

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

480 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

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

Marcus Baumann and
Ian R. Baxendale

Review
Published 17 Jul 2015

379 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

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

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

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Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

Nicholas G. Jentsch,
Jared D. Hume,
Emily B. Crull,
Samer M. Beauti,
Amy H. Pham,
Julie A. Pigza,
Jacques J. Kessl and
Matthew G. Donahue

Full Research Paper
Published 28 Sep 2018

360 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Investigational non-catalytic HIV-1 Integrase inhibitors.
  
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3. Scheme 1: Boehringer Ingelheim retrosynthesis of quinoline 1.
  
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4. Scheme 2: Quinoline ring condensation strategies.
  
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5. Scheme 3: Isatoic anhydrides from anthranilic acids with triphosgene.
  
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6. Scheme 4: Substituted 2-methyl-4-hydroxyquinolines from isatoic anhydrides and ethyl acetoacetate.
  
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7. Scheme 5: Mechanistic hypothesis for the cyclocondensation reaction.
  
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8. Scheme 6: Quinoline synthesis with ethyl acetylpyruvate.
  
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9. Scheme 7: Elaboration of the benzoic acid ethyl ester to the acetic acid residue.
  
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10. Scheme 8: Umpolung addition of ethoxycarbonyl via a MAC strategy.
  
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Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

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Expedient syntheses of the N-heterocyclic carbene precursor imidazolium salts IPr·HCl, IMes·HCl and IXy·HCl

Lukas Hintermann

Full Research Paper
Published 28 Aug 2007

343 Accesses

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1. Graphical Abstract
2. Figure 1: The carbenes IPr, IMes, IXy and their imidazolium salt precursors
  
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3. Scheme 1: Synthetic routes to and diazadiene precursors for imidazolium salts.
  
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4. Scheme 2: The imidazolium salt synthesis as a 1, 5-dipolar electrocyclization.
  
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5. Scheme 3: Potential side-reactions in the imidazolium salt synthesis.
  
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Beilstein J. Org. Chem. 2007, 3, No. 22, doi:10.1186/1860-5397-3-22

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Synthesis of aryl sulfides via radical–radical cross coupling of electron-rich arenes using visible light photoredox catalysis

Amrita Das,
Mitasree Maity,
Simon Malcherek,
Burkhard König and
Julia Rehbein

Full Research Paper
Published 27 Sep 2018

337 Accesses

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1. Graphical Abstract
2. Figure 1: Selected examples of sulfenylated heterocycles used in pharmaceuticals and material chemistry.
  
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3. Scheme 1: Synthetic routes to organosulfur compounds.
  
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4. Scheme 2: Aryl sulfide synthesis.
  
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5. Scheme 3: Substrate scope for arylthiol syntheses. The reaction was performed with 1a–g (0.1 mmol) and 2a–d (...
  
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6. Figure 2: Crystal structures of compounds 3a, 3d, 3e and 3i.
  
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7. Scheme 4: Radical trapping experiments.
  
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8. Figure 3: (a) Changes in the fluorescence spectra (in this case intensity, λ_Ex = 455 nm) of [Ir(dF(CF₃)ppy)₂(...
  
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9. Scheme 5: Proposed mechanism for visible light mediated direct C–H sulfenylation.
  
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10. Figure 4: Black line: UV–vis spectrum of the degassed [Ir] + 1,3,5-TMB mixture (solution A) in ACN. Blue and ...
  
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Beilstein J. Org. Chem. 2018, 14, 2520–2528, doi:10.3762/bjoc.14.228

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Synergistic approach to polycycles through Suzuki–Miyaura cross coupling and metathesis as key steps

Sambasivarao Kotha,
Milind Meshram and
Chandravathi Chakkapalli

Review
Published 21 Sep 2018

308 Accesses

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1. Graphical Abstract
2. Figure 1: Various catalysts used for metathesis reactions.
  
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3. Scheme 1: SM coupling and RCM protocol to substituted indene derivative 10.
  
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4. Scheme 2: Synthesis of polycycles via SM and RCM approach.
  
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5. Figure 2: Various angucyclines.
  
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6. Scheme 3: SM coupling and RCM protocol to the benz[a]anthracene skeleton 26.
  
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7. Scheme 4: Synthesis of substituted spirocycles via RCM and SM sequence.
  
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8. Scheme 5: Synthesis of highly functionalized bis-spirocyclic derivative 37.
  
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9. Scheme 6: Synthesis of spirofluorene derivatives via RCM and SM coupling sequence.
  
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10. Scheme 7: Synthesis of truxene derivatives via RCM and SM coupling.
  
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11. Scheme 8: Synthesis of substituted isoquinoline derivative via SM and RCM protocol.
  
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12. Scheme 9: Synthesis to 8-aryl substituted coumarin 64 via RCM and SM sequence.
  
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13. Scheme 10: Synthesis of cyclic sulfoximine 70 via SM and RCM as key steps.
  
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14. Scheme 11: Synthesis of 1-benzazepine derivative 75 via SM and RCM as key steps.
  
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15. Scheme 12: Synthesis of naphthoxepine derivative 79 via RCM followed by SM coupling.
  
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16. Scheme 13: Sequential CM and SM coupling approach to Z-stilbene derivative 85.
  
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17. Scheme 14: Synthesis of substituted trans-stilbene derivatives via SM coupling and RCM.
  
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18. Scheme 15: Synthesis of biaryl derivatives via sequential EM, DA followed by SM coupling.
  
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19. Scheme 16: Synthesis of the dibenzocyclooctadiene core of schisandrene.
  
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20. Scheme 17: Synthesis of cyclophane 115 via SM coupling and RCM as key steps.
  
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21. Scheme 18: Synthesis of cyclophane 120 and 122 via SM coupling and RCM as key steps.
  
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22. Scheme 19: Synthesis of cyclophanes via SM and RCM.
  
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23. Scheme 20: Synthesis of MK-6325 (141) via RCM and SM coupling.
  
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Beilstein J. Org. Chem. 2018, 14, 2468–2481, doi:10.3762/bjoc.14.223

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Carbonylonium ions: the onium ions of the carbonyl group

Daniel Blanco-Ania and
Floris P. J. T. Rutjes

Commentary
Published 04 Oct 2018

281 Accesses

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1. Graphical Abstract
2. Figure 1: Protonated (or organylated) carbonyl (1) and hydroxy (or organyloxy) carbenium ion (2): two possibl...
  
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3. Scheme 1: Acid-catalyzed interconversion of carbonyls, hydrates, hemiacetals and acetals.
  
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4. Figure 2: Oxacarbenium, oxocarbenium, oxycarbenium and carboxonium ions.
  
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Beilstein J. Org. Chem. 2018, 14, 2568–2571, doi:10.3762/bjoc.14.233

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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

268 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.
  
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5. Scheme 4: Formation of iminium ions using BrCCl₃ as stoichiometric oxidant.
  
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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.
  
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11. Scheme 10: Merging Ru-based photoredox catalysis and Cu-catalyzed alkynylation reaction.
  
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12. Scheme 11: Merging Ru-based photoredox catalysis and NHC catalysis.
  
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13. Scheme 12: 1,3-Dipolar cycloaddition of photogenically formed azomethine ylides.
  
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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.
  
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19. Scheme 18: Intramolecular interception of iminium ions by sulfonamides.
  
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20. Scheme 19: Intramolecular interception of iminium ions by alcohols and sulfonamides.
  
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21. Scheme 20: Intermolecular interception of iminium ions by phosphites.
  
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22. Scheme 21: Photoredox-catalyzed oxidative phosphonylation by Eosin Y.
  
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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.
  
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26. Scheme 25: Oxygen switch between two pathways involving α-amino radicals.
  
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27. Scheme 26: Interception of α-amino radicals by azodicarboxylates.
  
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28. Scheme 27: α-Arylation of amines.
  
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29. Scheme 28: Plausible mechanism for α-arylation of amines.
  
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30. Scheme 29: Photoinduced C–C bond cleavage of tertiary amines.
  
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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.
  
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33. Scheme 32: Intermolecular [3 + 2] annulation of cyclopropylamines with olefins.
  
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34. Scheme 33: Proposed mechanism for intermolecular [3 + 2] annulation.
  
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35. Scheme 34: Photoinduced clevage of N–N bonds of aromatic hydrazines and hydrazides.
  
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Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

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