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

853 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

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

485 Accesses

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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

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

447 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

Recent advances on organic blue thermally activated delayed fluorescence (TADF) emitters for organic light-emitting diodes (OLEDs)

Thanh-Tuân Bui,
Fabrice Goubard,
Malika Ibrahim-Ouali,
Didier Gigmes and
Frédéric Dumur

Review
Published 30 Jan 2018

424 Accesses

PDF
Album
1. Graphical Abstract
2. Figure 1: Radiative deactivation pathways existing in fluorescent, phosphorescent and TADF materials.
  
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3. Figure 2: Boron-containing TADF emitters B1–B10.
  
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4. Figure 3: Diphenylsulfone-based TADF emitters D1–D7.
  
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5. Figure 4: Triazine-based TADF emitters T1–T3, T5–T7 and azasiline derivatives T3 and T4.
  
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6. Figure 5: Triazine-based TADF emitters T8, T9, T11–T14 and carbazole derivative T10.
  
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7. Figure 6: Triazine-based TADF emitters T15–T19.
  
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8. Figure 7: Triazine- and pyrimidine-based TADF emitters T20–T26.
  
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9. Figure 8: Pyrimidine-based TADF emitters T27–T30.
  
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10. Figure 9: Triazine-based TADF polymers T31–T32.
  
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11. Figure 10: Phenoxaphosphine oxide and phenoxathiin dioxide-based TADF emitters P1 and P2.
  
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12. Figure 11: CN-Substituted pyridine and pyrimidine derivatives CN-P1–CN-P8.
  
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13. Figure 12: CN-Substituted pyridine derivatives CN-P9 and CN-P10.
  
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14. Figure 13: Phosphine oxide-based TADF blue emitters PO-1–PO-3.
  
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15. Figure 14: Phosphine oxide-based TADF blue emitters PO-4–PO-9.
  
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16. Figure 15: Benzonitrile-based emitters BN-1–BN-5.
  
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17. Figure 16: Benzonitrile-based emitters BN-6–BN-11.
  
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18. Figure 17: Benzoylpyridine-carbazole hybrid emitters BP-1–BP-6.
  
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19. Figure 18: Benzoylpyridine-carbazole hybrid emitters BP-7–BP-10.
  
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20. Figure 19: Triazole-based emitters Trz-1 and Trz-2.
  
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21. Figure 20: Triarylamine-based emitters TPA-1–TPA-3.
  
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22. Figure 21: Distribution of the CIE coordinates of ca. 90 blue TADF emitters listed in this review.
  
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Beilstein J. Org. Chem. 2018, 14, 282–308, doi:10.3762/bjoc.14.18

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Reusable and highly enantioselective water-soluble Ru(II)-Amm-Pheox catalyst for intramolecular cyclopropanation of diazo compounds

Hamada S. A. Mandour,
Yoko Nakagawa,
Masaya Tone,
Hayato Inoue,
Nansalmaa Otog,
Ikuhide Fujisawa,
Soda Chanthamath and
Seiji Iwasa

Letter
Published 06 Feb 2019

419 Accesses

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1. Graphical Abstract
2. Figure 1: A comparison of the solubility of Ru(II)-Pheox (cat. 1) and Ru(II)-Amm-Pheox (cat. 2).
  
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3. Scheme 1: Intramolecular cyclopropanation of various trans-allylic diazo Weinreb amide derivatives catalyzed....
  
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4. Scheme 2: Synthetic transformation of cyclopropane products 2d and 2f.
  
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Beilstein J. Org. Chem. 2019, 15, 357–363, doi:10.3762/bjoc.15.31

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Synthesis of nonracemic hydroxyglutamic acids

Dorota G. Piotrowska,
Iwona E. Głowacka,
Andrzej E. Wróblewski and
Liwia Lubowiecka

Review
Published 25 Jan 2019

365 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Structure of L-glutamic acid.
  
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3. Figure 2: 3-Hydroxy- (2), 4-hydroxy- (3) and 3,4-dihydroxyglutamic acids (4).
  
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4. Figure 3: Enantiomers of 3-hydroxyglutamic acid (2).
  
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5. Scheme 1: Synthesis of (2S,3R)-2 from (R)-Garner's aldehyde. Reagents and conditions: a) MeOCH=CH–CH(OTMS)=CH₂...
  
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6. Scheme 2: Synthesis of (2S,3R)-2 and (2S,3S)-2 from (R)-Garner’s aldehyde. Reagents and conditions: a) H₂C=CH...
  
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7. Scheme 3: Two-carbon homologation of the protected L-serine. Reagents and conditions: a) Fmoc-succinimide, Na₂...
  
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8. Scheme 4: Synthesis of di-tert-butyl ester of (2R,3S)-2 from L-serine. Reagents and conditions: a) PhSO₂Cl, K₂...
  
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9. Scheme 5: Synthesis of (2R,3S)-2 from O-benzyl-L-serine. Reagents and conditions: a) (CF₃CH₂O)₂P(O)CH₂COOMe, ...
  
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10. Scheme 6: Synthesis of (2S,3R)-2 employing a one-pot cis-olefination–conjugate addition sequence. Reagents an...
  
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11. Scheme 7: Synthesis of the orthogonally protected (2S,3R)-2 from a chiral aziridine. Reagents and conditions:...
  
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12. Scheme 8: Synthesis of N-Boc-protected (2S,3R)-2 from D-phenylglycine. Reagents and conditions: a) BnMgCl, et...
  
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13. Scheme 9: Synthesis of (2S,3R)-2 employing ketopinic acid as chiral auxiliary. Reagents and conditions: a) Br₂...
  
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14. Scheme 10: Synthesis of dimethyl ester of (2S,3R)-2 employing (1S)-2-exo-methoxyethoxyapocamphane-1-carboxylic...
  
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15. Scheme 11: Synthesis of N-Boc-protected dimethyl ester of (2S,3R)-2 from (S)-N-(1-phenylethyl)thioacetamide. R...
  
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16. Scheme 12: Synthesis of N-Boc-protected dimethyl ester of (2S,3R)-2 via Sharpless epoxidation. Reagents and co...
  
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17. Scheme 13: Synthesis of (2S,3S)-2 from the imide 51. Reagents and conditions: a) NaBH₄, MeOH/CH₂Cl₂; b) Ac₂O, ...
  
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18. Scheme 14: Synthesis of (2R,3S)-2 and (2S,3S)-2 from the acetolactam 55 (PMB = p-methoxybenzyl). Reagents and ...
  
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19. Scheme 15: Synthesis of (2S,3R)-2 from D-glucose. Reagents and conditions: a) NaClO₂, 30% H₂O₂, NaH₂PO₄, MeCN;...
  
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20. Figure 4: Enantiomers of 3-hydroxyglutamic acid (3).
  
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21. Scheme 16: Synthesis of (4S)-4-hydroxy-L-glutamic acid [(2S,4S)-3] by electrophilic hydroxylation. Reagents an...
  
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22. Scheme 17: Synthesis of all stereoisomers of 4-hydroxyglutamic acid (3). Reagents and conditions: a) Br₂, PBr₅...
  
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23. Scheme 18: Synthesis of the orthogonally protected 4-hydroxyglutamic acid (2S,4S)-73. Reagents and conditions:...
  
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24. Scheme 19: Synthesis of (2S,4R)-4-acetyloxyglutamic acid as a component of a dipeptide. Reagents and condition...
  
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25. Scheme 20: Synthesis of N-Boc-protected dimethyl esters of (2S,4R)- and (2S,4S)-3 from (2S,4R)-4-hydroxyprolin...
  
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26. Scheme 21: Synthesis of orthogonally protected (2S,4S)-3 from (2S,4R)-4-hydroxyproline. Reagents and condition...
  
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27. Scheme 22: Synthesis of the protected (4R)-4-hydroxy-L-pyroglutamic acid (2S,4R)-87 by electrophilic hydroxyla...
  
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28. Figure 5: Enantiomers of 3,4-dihydroxy-L-glutamic acid (4).
  
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29. Scheme 23: Synthesis of (2S,3S,4R)-4 from the epoxypyrrolidinone 88. Reagents and conditions: a) MeOH, THF, KC...
  
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30. Scheme 24: Synthesis of (2S,3R,4R)-4 from the orthoester 92. Reagents and conditions: a) OsO₄, NMO, acetone/wa...
  
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31. Scheme 25: Synthesis of (2S,3S,4S)-4 from the aziridinolactone 95. Reagents and conditions: a) BnOH, BF₃·OEt₂,...
  
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32. Scheme 26: Synthesis of (2S,3S,4R)-4 and (2R,3S,4R)-4 from cyclic imides 106. Reagents and conditions: a) NaBH₄...
  
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33. Scheme 27: Synthesis of (2R,3R,4R)-4 and (2S,3R,4R)-4 from the cyclic meso-imide 110. Reagents and conditions:...
  
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34. Scheme 28: Synthesis of (2S,3S,4S)-4 from the protected serinal (R)-23. Reagents and conditions: a) Ph₃P=CHCOO...
  
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35. Scheme 29: Synthesis of (2S,3S,4S)-4 from O-benzyl-N-Boc-D-serine. Reagents and conditions: a) ClCOOiBu, TEA, ...
  
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36. Scheme 30: Synthesis of (2S,3S,4R)-127 by enantioselective conjugate addition and asymmetric dihydroxylation. ...
  
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37. Figure 6: Structures of selected compounds containing hydroxyglutamic motives (in blue).
  
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Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

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Oxidative radical ring-opening/cyclization of cyclopropane derivatives

Yu Liu,
Qiao-Lin Wang,
Zan Chen,
Cong-Shan Zhou,
Bi-Quan Xiong,
Pan-Liang Zhang,
Chang-An Yang and
Quan Zhou

Review
Published 28 Jan 2019

357 Accesses

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1. Graphical Abstract
2. Scheme 1: The oxidative radical ring-opening/cyclization of cyclopropane derivatives.
  
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3. Scheme 2: Mn(OAc)₃-mediated oxidative radical ring-opening and cyclization of MCPs with malonates.
  
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4. Scheme 3: Mn(III)-mediated oxidative radical ring-opening and cyclization of MCPs with 1,3-dicarbonyl compoun...
  
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5. Scheme 4: Heat-promoted ring-opening/cyclization of MCPs with elemental chalgogens.
  
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6. Scheme 5: Copper(II) acetate-mediated oxidative radical ring-opening and cyclization of MCPs with diphenyl di...
  
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7. Scheme 6: AIBN-promoted oxidative radical ring-opening and cyclization of MCPs with benzenethiol.
  
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8. Scheme 7: AIBN-mediated oxidative radical ring-opening and cyclization of MCPs with diethyl phosphites.
  
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9. Scheme 8: Organic-selenium induced radical ring-opening and cyclization of MCPs derivatives (cyclopropylaldeh...
  
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10. Scheme 9: Copper(I)-catalyzed oxidative radical trifluoromethylation/ring-opening/cyclization of MCPs with To...
  
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11. Scheme 10: Ag(I)-mediated trifluoromethylthiolation/ring-opening/cyclization of MCPs with AgSCF₃.
  
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12. Scheme 11: oxidative radical ring-opening and cyclization of MCPs with α-C(sp³)-–H of ethers.
  
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13. Scheme 12: Oxidative radical ring-opening and cyclization of MCPs with aldehydes.
  
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14. Scheme 13: Cu(I) or Fe(II)-catalyzed oxidative radical trifluoromethylation/ring-opening/cyclization of MCPs d...
  
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15. Scheme 14: Rh(II)-catalyzed oxidative radical ring-opening and cyclization of MCPs.
  
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16. Scheme 15: Ag(I)-catalyzed oxidative radical amination/ring-opening/cyclization of MCPs derivatives.
  
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17. Scheme 16: Heating-promoted radical ring-opening and cyclization of MCP derivatives (arylvinylidenecyclopropan...
  
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18. Scheme 17: Bromine radical-mediated ring-opening of alkylidenecyclopropanes.
  
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19. Scheme 18: Fluoroalkyl (Rf) radical-mediated ring-opening of MCPs.
  
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20. Scheme 19: Visible-light-induced alkylation/ring-opening/cyclization of cyclopropyl olefins with bromides.
  
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21. Scheme 20: Mn(III)-mediated ring-opening and [3 + 3]-annulation of cyclopropanols and vinyl azides.
  
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22. Scheme 21: Ag(I)-catalyzed oxidative ring-opening of cyclopropanols with quinones.
  
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23. Scheme 22: Ag(I)-catalyzed oxidative ring-opening of cyclopropanols with heteroarenes.
  
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24. Scheme 23: Cu(I)-catalyzed oxidative ring-opening/trifluoromethylation of cyclopropanols.
  
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25. Scheme 24: Cu(I)-catalyzed oxidative ring-opening and trifluoromethylation/trifluoromethylthiolation of cyclop...
  
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26. Scheme 25: Ag(I)-mediated oxidative ring-opening/fluorination of cyclopropanols with Selectfluor.
  
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27. Scheme 26: Photocatalyzed ring-opening/fluorination of cyclopropanols with Selectfluor.
  
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28. Scheme 27: Na₂S₂O₈-promoted ring-opening/alkynylation of cyclopropanols with EBX.
  
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29. Scheme 28: Ag(I)-catalyzed ring-opening and chlorination of cyclopropanols with aldehydes.
  
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30. Scheme 29: Ag(I)-catalyzed ring-opening/alkynylation of cyclopropanols with EBX.
  
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31. Scheme 30: Na₂S₂O₈-promoted ring-opening/alkylation of cyclopropanols with acrylamides.
  
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32. Scheme 31: Cyclopropanol ring-opening initiated tandem cyclization with acrylamides or 2-isocyanobiphenyls.
  
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33. Scheme 32: Ag(II)-mediated oxidative ring-opening/fluorination of cyclopropanols with AgF₂.
  
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34. Scheme 33: Cu(II)-catalyzed ring-opening/fluoromethylation of cyclopropanols with sulfinate salts.
  
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35. Scheme 34: Cu(II)-catalyzed ring-opening/sulfonylation of cyclopropanols with sulfinate salts.
  
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36. Scheme 35: Na₂S₂O₈-promoted ring-opening/arylation of cyclopropanols with propiolamides.
  
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37. Scheme 36: The ring-opening and [3 + 2]-annulation of cyclopropanols with α,β-unsaturated aldehydes.
  
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38. Scheme 37: Cu(II)-catalyzed ring-opening/arylation of cyclopropanols with aromatic nitrogen heterocyles.
  
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39. Scheme 38: Ag(I)-catalyzed ring-opening and difluoromethylthiolation of cyclopropanols with PhSO₂SCF₂H.
  
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40. Scheme 39: Ag(I)-catalyzed ring-opening and acylation of cyclopropanols with aldehydes.
  
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41. Scheme 40: Aerobic oxidation ring-opening of cyclopropanols for the synthesis of 2-oxyranyl ketones.
  
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42. Scheme 41: Aerobic oxidation ring-opening of cyclopropanols for the synthesis of linear enones.
  
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43. Scheme 42: Aerobic oxidation ring-opening of cyclopropanols for the synthesis of metabolite.
  
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Beilstein J. Org. Chem. 2019, 15, 256–278, doi:10.3762/bjoc.15.23

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First synthesis of cryptands with sucrose scaffold

Patrycja Sokołowska,
Michał Kowalski and
Sławomir Jarosz

Full Research Paper
Published 23 Jan 2019

354 Accesses

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1. Graphical Abstract
2. Figure 1: Macrocyclic derivatives with sucrose scaffold.
  
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3. Figure 2: Strategy to sucrose cryptands with additional macrocyclic unit.
  
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4. Scheme 1: a) 50% NaOH, Bu₄NHSO₄, 74%; b) NaI, acetone, 95%; c) Na₂CO₃, ACN, 80 °C, 24 h, 33%.
  
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5. Figure 3: A concept for synthesis of a cryptand from penta-O-benzylsucrose (2).
  
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6. Scheme 2: a) MsCl, Et₃N, DMAP, DCM, −78 °C to rt.; b) Na₂CO₃, KI, ACN, reflux.
  
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7. Scheme 3: a) AllBr, TBAB, PhMe, 50% NaOH, 50 °C, 18 h, 94%; b) i. O₃, DCM, −78 °C; ii. NaBH₄, DCM, MeOH, rt, ...
  
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8. Scheme 4: a) 50% NaOH, Bu₄NHSO₄, 58%; b) NaI, acetone, 95%; c) Na₂CO₃, ACN, 80 °C, 24 h, 45.5%.
  
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Beilstein J. Org. Chem. 2019, 15, 210–217, doi:10.3762/bjoc.15.20

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Tandem copper and photoredox catalysis in photocatalytic alkene difunctionalization reactions

Nicholas L. Reed,
Madeline I. Herman,
Vladimir P. Miltchev and
Tehshik P. Yoon

Letter
Published 05 Feb 2019

339 Accesses

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1. Graphical Abstract
2. Figure 1: a) Photocatalytic oxyamination, b) photocatalytic diamination, and c) proposed mechanism for photoc...
  
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3. Figure 2: Scope studies for dual-catalytic alkene difunctionalization using 2.5 mol % 3, 30 mol % Cu(TFA)₂, a...
  
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Beilstein J. Org. Chem. 2019, 15, 351–356, doi:10.3762/bjoc.15.30

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A novel and efficient synthesis of phenanthrene derivatives via palladium/norbornadiene-catalyzed domino one-pot reaction

Yue Zhong,
Wen-Yu Wu,
Shao-Peng Yu,
Tian-Yuan Fan,
Hai-Tao Yu,
Nian-Guang Li,
Zhi-Hao Shi,
Yu-Ping Tang and
Jin-Ao Duan

Full Research Paper
Published 31 Jan 2019

323 Accesses

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1. Graphical Abstract
2. Figure 1: Representative natural products containing a phenanthrene moiety.
  
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3. Scheme 1: Different methods for the synthesis of phenanthrene derivatives.
  
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4. Scheme 2: Substrate scope with various aryl iodides. Reaction conditions: 1 (0.3 mmol, 1.0 equiv), 2a (0.36 m...
  
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5. Scheme 3: Scope of the reaction in terms of ortho-bromobenzoyl chlorides. Reaction conditions: 1a (0.3 mmol, ...
  
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6. Scheme 4: Gram scale synthesis of z-6.
  
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7. Scheme 5: Proposed mechanism for the formation of phenanthrene derivatives.
  
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Beilstein J. Org. Chem. 2019, 15, 291–298, doi:10.3762/bjoc.15.26

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