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

838 Accesses

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

Full Text

¹⁹F NMR as a tool in chemical biology

Diana Gimenez,
Aoife Phelan,
Cormac D. Murphy and
Steven L. Cobb

Review
Published 28 Jan 2021

800 Accesses

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1. Graphical Abstract
2. Figure 1: Selected examples of ¹⁹F-labelled amino acid analogues used as probes in chemical biology.
  
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3. Figure 2: (a) Sequences of the antimicrobial peptide MSI-78 and pFtBSer-containing analogs and cartoon repres...
  
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4. Figure 3: (a) Chemical structures of a selection of trifluoromethyl tags. (b) Comparative analysis showing th...
  
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5. Figure 4: (a) First bromodomain of Brd4 with all three tryptophan residues displayed in blue and labelled by ...
  
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6. Figure 5: (a) Enzymatic hydroxylation of GBBNF in the presence of hBBOX (b) ¹⁹F NMR spectra showing the conve...
  
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7. Figure 6: (a) In-cell enzymatic hydrolysis of the fluorinated anandamide analogue ARN1203 catalyzed by hFAAH....
  
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8. Figure 7: (a) X-ray crystal structure of CAM highlighting the location the phenylalanine residues replaced by...
  
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9. Figure 8: ¹⁹F PREs of 4-F, 5-F, 6-F, 7-FTrp49 containing MTSL-modified ^S52CCV-N. The ¹⁹F NMR resonances of ox...
  
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10. Figure 9: ¹⁹F NMR as a direct probe of Ud NS1A ED homodimerization. Schematic representation showing the loca...
  
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11. Figure 10: (a) Representative spectrum of a 182 μM sample of Aβ1-40-tfM35 at varying times indicating the majo...
  
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12. Figure 11: Illustration of the conformational switch induced by SDS in 4-tfmF-labelled α-Syn. Also shown are t...
  
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13. Figure 12: (a) Structural models of the Myc‐Max (left), Myc‐Max‐DNA (middle) and Myc‐Max‐BRCA1 complexes (righ...
  
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14. Figure 13: (a) Side (left) and bottom (right) views of the pentameric apo ELIC X-ray structure (PDB ID: 3RQU) ...
  
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15. Figure 14: (a) General structure of a selection of recently developed ¹⁹F-labelled nucleotides for their use a...
  
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16. Figure 15: Monitoring biotransformation of the fluorinated pesticide cyhalothrin by the fungus C. elegans. The...
  
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17. Figure 16: Following the biodegradation of emerging fluorinated pollutants by ¹⁹F NMR. The spectra are from cu...
  
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18. Figure 17: Discovery of new fluorinated natural products by ¹⁹F NMR. The spectrum is of the culture supernatan...
  
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19. Figure 18: Application of ¹⁹F NMR to investigate the biosynthesis of nucleocidin. The spectra are from culture...
  
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20. Figure 19: Detection of new fluorofengycins (indicated by arrows) in culture supernatants of Bacillus sp. CS93...
  
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21. Figure 20: Measurement of β-galactosidase activity in MCF7 cancer cells expressing lacZ using ¹⁹F NMR. The deg...
  
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22. Figure 21: Detection of ions using ¹⁹F NMR. (a) Structure of TF-BAPTA and its ¹⁹F iCEST spectra in the presenc...
  
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23. Figure 22: (a) The ONOO⁻-mediated decarbonylation of 5-fluoroisatin and 6-fluoroisatin. The selectivity of (b)...
  
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Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

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CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

Anthony J. Fernandes,
Armen Panossian,
Bastien Michelet,
Agnès Martin-Mingot,
Frédéric R. Leroux and
Sébastien Thibaudeau

Review
Published 03 Feb 2021

522 Accesses

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1. Graphical Abstract
2. Figure 1: Stabilizing interaction in the CF₃CH₂⁺ carbenium ion (top) and structure of the first observable fl...
  
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3. Scheme 1: Isodesmic equations accounting for the destabilizing effect of the CF₃ group. ΔE in kcal⋅mol⁻¹, cal...
  
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4. Scheme 2: Stabilizing effect of fluorine atoms by resonance electron donation in carbenium ions (δ in ppm).
  
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5. Scheme 3: Direct in situ NMR observation of α-(trifluoromethyl)carbenium ion or protonated alcohols. Δδ = δ₁₉...
  
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6. Scheme 4: Reported ¹³C NMR chemical shifts for the α-(trifluoromethyl)carbenium ion 10c (δ in ppm).
  
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7. Scheme 5: Direct NMR observation of α-(trifluoromethyl)carbenium ions in situ (δ in ppm).
  
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8. Scheme 6: Illustration of the ion pair solvolysis mechanism for sulfonate 13f. YOH = solvent.
  
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9. Figure 2: Solvolysis rate for 13a–i and 17.
  
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10. Figure 3: Structures of allyl triflates 18 and 19 and allyl brosylate 20. Bs = p-BrC₆H₄SO₂.
  
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11. Figure 4: Structure of tosylate derivatives 21.
  
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12. Figure 5: a) Structure of triflate derivatives 22. b) Stereochemistry outcomes of the reaction starting from (...
  
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13. Scheme 7: Solvolysis reaction of naphthalene and anthracenyl derivatives 26 and 29.
  
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14. Figure 6: Structure of bisarylated derivatives 34.
  
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15. Figure 7: Structure of bisarylated derivatives 36.
  
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16. Scheme 8: Reactivity of 9c in the presence of a Brønsted acid.
  
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17. Scheme 9: Cationic electrocyclization of 38a–c under strongly acidic conditions.
  
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18. Scheme 10: Brønsted acid-catalyzed synthesis of indenes 42 and indanes 43.
  
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19. Scheme 11: Reactivity of sulfurane 44 in triflic acid.
  
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20. Scheme 12: Solvolysis of triflate 45f in alcoholic solvents.
  
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21. Scheme 13: Synthesis of labeled ¹⁸O-52.
  
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22. Scheme 14: Reactivity of sulfurane 53 in triflic acid.
  
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23. Figure 8: Structure of tosylates 56 and 21f.
  
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24. Scheme 15: Resonance forms in benzylic carbenium ions.
  
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25. Figure 9: Structure of pyrrole derivatives 58 and 59.
  
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26. Scheme 16: Resonance structure 60↔60’.
  
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27. Scheme 17: Ga(OTf)₃-catalyzed synthesis of 3,3’- and 3,6’-bis(indolyl)methane from trifluoromethylated 3-indol...
  
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28. Scheme 18: Proposed reaction mechanism.
  
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29. Scheme 19: Metal-free 1,2-phosphorylation of 3-indolylmethanols.
  
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30. Scheme 20: Superacid-mediated arylation of thiophene derivatives.
  
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31. Scheme 21: In situ mechanistic NMR investigations.
  
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32. Scheme 22: Proposed mechanisms for the prenyltransferase-catalyzed condensation.
  
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33. Scheme 23: Influence of a CF₃ group on the allylic S_N1- and S_N2-mechanism-based reactions.
  
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34. Scheme 24: Influence of the CF₃ group on the condensation reaction.
  
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35. Scheme 25: Solvolysis of 90 in TFE.
  
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36. Scheme 26: Solvolysis of allyl triflates 94 and 97 and isomerization attempt of 96.
  
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37. Scheme 27: Proposed mechanism for the formation of 95.
  
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38. Scheme 28: Formation of α-(trifluoromethyl)allylcarbenium ion 100 in a superacid.
  
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39. Scheme 29: Lewis acid activation of CF₃-substituted allylic alcohols.
  
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40. Scheme 30: Bimetallic-cluster-stabilized α-(trifluoromethyl)carbenium ions.
  
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41. Scheme 31: Reactivity of cluster-stabilized α-(trifluoromethyl)carbenium ions.
  
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42. Scheme 32: α-(Trifluoromethyl)propargylium ion 122↔122’ generated from silyl ether 120 in a superacid.
  
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43. Scheme 33: Formation of α-(trifluoromethyl)propargylium ions from CF₃-substituted propargyl alcohols.
  
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44. Scheme 34: Direct NMR observation of the protonation of some trifluoromethyl ketones in situ and the correspon...
  
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45. Scheme 35: Selected resonance forms in protonated fluoroketone derivatives.
  
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46. Scheme 36: Acid-catalyzed Friedel–Crafts reactions of trifluoromethyl ketones 143a,b and 147a–c.
  
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47. Scheme 37: Enantioselective hydroarylation of CF₃-substituted ketones.
  
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48. Scheme 38: Acid-catalyzed arylation of ketones 152a–c.
  
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49. Scheme 39: Reactivity of 156 in a superacid.
  
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50. Scheme 40: Reactivity of α-CF₃-substituted heteroaromatic ketones and alcohols as well as 1,3-diketones.
  
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51. Scheme 41: Reactivity of 168 with benzene in the presence of a Lewis or Brønsted acid.
  
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52. Scheme 42: Acid-catalyzed three-component asymmetric reaction.
  
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53. Scheme 43: Anodic oxidation of amines 178a–c and proposed mechanism.
  
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54. Scheme 44: Reactivity of 179b in the presence of a strong Lewis acid.
  
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55. Scheme 45: Trifluoromethylated derivatives as precursors of trifluoromethylated iminium ions.
  
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56. Scheme 46: Mannich reaction with trifluoromethylated hemiaminal 189.
  
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57. Scheme 47: Suitable nucleophiles reacting with 192 after Lewis acid activation.
  
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58. Scheme 48: Strecker reaction involving the trifluoromethylated iminium ion 187.
  
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59. Scheme 49: Reactivity of 199 toward nucleophiles.
  
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60. Scheme 50: Reactivity of 204a with benzene in the presence of a Lewis acid.
  
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61. Scheme 51: Reactivity of α-(trifluoromethyl)-α-chloro sulfides in the presence of strong Lewis acids.
  
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62. Scheme 52: Anodic oxidation of sulfides 213a–h and Pummerer rearrangement.
  
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63. Scheme 53: Mechanism for the electrochemical oxidation of the sulfide 213a.
  
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64. Scheme 54: Reactivity of (trifluoromethyl)diazomethane (217a) in HSO₃F.
  
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65. Figure 10: a) Structure of diazoalkanes 217a–c and b) rate-limiting steps of their decomposition.
  
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66. Scheme 55: Deamination reaction of racemic 221 and enantioenriched (S)-221.
  
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67. Scheme 56: Deamination reaction of labeled 221-d₂. Elimination products were formed in this reaction, the yiel...
  
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68. Scheme 57: Deamination reaction of 225-d₂. Elimination products were also formed in this reaction in undetermi...
  
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69. Scheme 58: Formation of 229 from 228 via 1,2-H-shift.
  
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70. Scheme 59: Deamination reaction of 230. Elimination products were formed in this reaction, the yield of which ...
  
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71. Scheme 60: Deamination of several diazonium ions. Elimination products were formed in these reactions, the yie...
  
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72. Scheme 61: Solvolysis reaction mechanism of alkyl tosylates.
  
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73. Scheme 62: Solvolysis outcome for the tosylates 248 and 249 in HSO₃FSbF₅.
  
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74. Figure 11: Solvolysis rate of 248, 249, 252, and 253 in 91% H₂SO₄.
  
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75. Scheme 63: Illustration of the reaction pathways. TsCl, pyridine, −5 °C (A); 98% H₂SO₄, 30 °C (B); 98% H₂SO₄, ...
  
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76. Scheme 64: Proposed solvolysis mechanism for the aliphatic tosylate 248.
  
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77. Scheme 65: Solvolysis of the derivatives 259 and 260.
  
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78. Scheme 66: Solvolysis of triflate 261. SOH = solvent.
  
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79. Scheme 67: Intramolecular Friedel–Crafts alkylations upon the solvolysis of triflates 264 and 267.
  
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80. Scheme 68: α-CF₃-enhanced γ-silyl elimination of cyclobutyltosylates 270a,b.
  
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81. Scheme 69: γ-Silyl elimination in the synthesis of a large variety of CF₃-substituted cyclopropanes. Pf = pent...
  
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82. Scheme 70: Synthetic pathways to 281. ^aNMR yields.
  
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83. Scheme 71: The cyclopropyl-substituted homoallylcyclobutylcarbenium ion manifold.
  
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84. Scheme 72: Reactivity of CF₃-substituted cyclopropylcarbinyl derivatives 287a–c. LG = leaving group.
  
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85. Scheme 73: Reactivity of CF₃-substituted cyclopropylcarbinyl derivatives 291a–c.
  
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86. Scheme 74: Superacid-promoted dimerization or TFP.
  
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87. Scheme 75: Reactivity of TFP in a superacid.
  
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88. Scheme 76: gem-Difluorination of α-fluoroalkyl styrenes via the formation of a “hidden” α-R_F-substituted carbe...
  
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89. Scheme 77: Solvolysis of CF₃-substituted pentyne 307.
  
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90. Scheme 78: Photochemical rearrangement of 313.
  
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91. Figure 12: Structure of 2-norbornylcarbenium ion 318 and argued model for the stabilization of this cation.
  
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92. Figure 13: Structures and solvolysis rate (TFE, 25 °C) of the sulfonates 319–321. Mos = p-MeOC₆H₄SO₂.
  
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93. Scheme 79: Mechanism for the solvolysis of 323. SOH = solvent.
  
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94. Scheme 80: Products formed by the hydrolysis of 328.
  
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95. Scheme 81: Proposed carbenium ion intermediates in an equilibrium during the solvolysis of tosylates 328, 333,...
  
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Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

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Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

Wilfred J. M. Lewis,
David M. Shaw and
Jeremy Robertson

Full Research Paper
Published 02 Feb 2021

504 Accesses

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1. Graphical Abstract
2. Figure 1: The clazamycins, and selected bacterial pyrrolizidines of the vinylogous urea type. For consistency...
  
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3. Figure 2: Key species in the biosynthesis of legonmycins A (3) and B (4), and the pyrrolizixenamides A–D (9–12...
  
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4. Scheme 1: Preparation of the legonmycin core.
  
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5. Scheme 2: Hypothesis for the oxidative hydrolysis of diacylated pyrrolizidinone 18 (R = iBu).
  
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6. Scheme 3: Preparation of C(7a)-functionalized pyrrolizinone derivatives and synthesis of legonmycins A and B.
  
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Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

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

Yan Sun,
Jing Sun and
Chao-Guo Yan

Full Research Paper
Published 03 Jan 2013

483 Accesses

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

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The preparation and properties of 1,1-difluorocyclopropane derivatives

Kymbat S. Adekenova,
Peter B. Wyatt and
Sergazy M. Adekenov

Review
Published 26 Jan 2021

438 Accesses

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1. Graphical Abstract
2. Scheme 1: Synthesis of 1,1-difluoro-2,3-dimethylcyclopropane (2).
  
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3. Scheme 2: Cyclopropanation via dehydrohalogenation of chlorodifluoromethane.
  
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4. Scheme 3: Difluorocyclopropanation of methylstyrene 7 using dibromodifluoromethane and zinc.
  
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5. Scheme 4: Synthesis of difluorocyclopropanes from the reaction of dibromodifluoromethane and triphenylphosphi...
  
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6. Scheme 5: Generation of difluorocarbene in a catalytic two-phase system and its addition to tetramethylethyle...
  
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7. Scheme 6: The reaction of methylstyrene 7 with chlorodifluoromethane (11) in the presence of a tetraarylarson...
  
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8. Scheme 7: Pyrolysis of sodium chlorodifluoroacetate (12) in refluxing diglyme in the presence of alkene 13.
  
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9. Scheme 8: Synthesis of boron-substituted gem-difluorocyclopropanes 16.
  
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10. Scheme 9: Addition of sodium bromodifluoroacetate (17) to alkenes.
  
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11. Scheme 10: Addition of sodium bromodifluoroacetate (17) to silyloxy-substituted cyclopropanes 20.
  
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12. Scheme 11: Synthesis of difluorinated nucleosides.
  
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13. Scheme 12: Addition of butyl acrylate (26) to difluorocarbene generated from TFDA (25).
  
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14. Scheme 13: Addition of difluorocarbene to propargyl esters 27 and conversion of the difluorocyclopropenes 28 t...
  
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15. Scheme 14: The generation of difluorocyclopropanes using MDFA 30.
  
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16. Scheme 15: gem-Difluorocyclopropanation of styrene (32) using difluorocarbene generated from TMSCF₃ (31) under...
  
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17. Scheme 16: Synthesis of a gem-difluorocyclopropane derivative using HFPO (41) as a source of difluorocarbene.
  
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18. Scheme 17: Cyclopropanation of (Z)-2-butene in the presence of difluorodiazirine (44).
  
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19. Scheme 18: The cyclopropanation of 1-octene (46) using Seyferth's reagent (45) as a source of difluorocarbene.
  
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20. Scheme 19: Alternative approaches for the difluorocarbene synthesis from trimethyl(trifluoromethyl)tin (48).
  
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21. Scheme 20: Difluorocyclopropanation of cyclohexene (49).
  
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22. Scheme 21: Synthesis of difluorocyclopropane derivative 53 using bis(trifluoromethyl)cadmium (51) as the diflu...
  
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23. Scheme 22: Addition of difluorocarbene generated from tris(trifluoromethyl)bismuth (54).
  
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24. Scheme 23: Addition of a stable (trifluoromethyl)zinc reagent to styrenes.
  
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25. Scheme 24: The preparation of 2,2-difluorocyclopropanecarboxylic acids of type 58.
  
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26. Scheme 25: Difluorocyclopropanation via Michael cyclization.
  
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27. Scheme 26: Difluorocyclopropanation using N-acylimidazolidinone 60.
  
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28. Scheme 27: Difluorocyclopropanation through the cyclization of phenylacetonitrile (61) and 1,2-dibromo-1,1-dif...
  
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29. Scheme 28: gem-Difluoroolefins 64 for the synthesis of functionalized cyclopropanes 65.
  
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30. Scheme 29: Preparation of aminocyclopropanes 70.
  
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31. Scheme 30: Synthesis of fluorinated methylenecyclopropane 74 via selenoxide elimination.
  
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32. Scheme 31: Reductive dehalogenation of (1R,3R)-75.
  
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33. Scheme 32: Synthesis of chiral monoacetates by lipase catalysis.
  
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34. Scheme 33: Transformation of (±)-trans-81 using Rhodococcus sp. AJ270.
  
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35. Scheme 34: Transformation of (±)-trans-83 using Rhodococcus sp. AJ270.
  
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36. Scheme 35: Hydrogenation of difluorocyclopropenes through enantioselective hydrocupration.
  
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37. Scheme 36: Enantioselective transfer hydrogenation of difluorocyclopropenes with a Ru-based catalyst.
  
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38. Scheme 37: The thermal transformation of trans-1,2-dichloro-3,3-difluorocyclopropane (84).
  
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39. Scheme 38: cis–trans-Epimerization of 1,1-difluoro-2,3-dimethylcyclopropane.
  
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40. Scheme 39: 2,2-Difluorotrimethylene diradical intermediate.
  
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41. Scheme 40: Ring opening of stereoisomers 88 and 89.
  
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42. Scheme 41: [1,3]-Rearrangement of alkenylcyclopropanes 90–92.
  
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43. Scheme 42: Thermolytic rearrangement of 2,2-difluoro-1-vinylcyclopropane (90).
  
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44. Scheme 43: Thermal rearrangement for ethyl 3-(2,2-difluoro)-3-phenylcyclopropyl)acrylates 93 and 95.
  
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45. Scheme 44: Possible pathways of the ring opening of 1,1-difluoro-2-vinylcyclopropane.
  
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46. Scheme 45: Equilibrium between 1,1-difluoro-2-methylenecyclopropane (96) and (difluoromethylene)cyclopropane 97...
  
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47. Scheme 46: Ring opening of substituted 1,1-difluoro-2,2-dimethyl-3-methylenecyclopropane 98.
  
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48. Scheme 47: 1,1-Difluorospiropentane rearrangement.
  
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49. Scheme 48: Acetolysis of (2,2-difluorocyclopropyl)methyl tosylate (104) and (1,1-difluoro-2-methylcyclopropyl)...
  
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50. Scheme 49: Ring opening of gem-difluorocyclopropyl ketones 106 and 108 by thiolate nucleophiles.
  
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51. Scheme 50: Hydrolysis of gem-difluorocyclopropyl acetals 110.
  
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52. Scheme 51: Ring-opening reaction of 2,2-difluorocyclopropyl ketones 113 in the presence of ionic liquid as a s...
  
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53. Scheme 52: Ring opening of gem-difluorocyclopropyl ketones 113a by MgI₂-initiated reaction with diarylimines 1...
  
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54. Scheme 53: Ring-opening reaction of gem-difluorocyclopropylstannanes 117.
  
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55. Scheme 54: Preparation of 1-fluorovinyl vinyl ketone 123 and the synthesis of 2-fluorocyclopentenone 124. TBAT...
  
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56. Scheme 55: Iodine atom-transfer ring opening of 1,1-difluoro-2-(1-iodoalkyl)cyclopropanes 125a–c.
  
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57. Scheme 56: Ring opening of bromomethyl gem-difluorocyclopropanes 130 and formation of gem-difluoromethylene-co...
  
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58. Scheme 57: Ring-opening aerobic oxidation reaction of gem-difluorocyclopropanes 132.
  
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59. Scheme 58: Dibrominative ring-opening functionalization of gem-difluorocyclopropanes 134.
  
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60. Scheme 59: The selective formation of (E,E)- and (E,Z)-fluorodienals 136 and 137 from difluorocyclopropyl acet...
  
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61. Scheme 60: Proposed mechanism for the reaction of difluoro(methylene)cyclopropane 139 with Br₂.
  
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62. Scheme 61: Thermal rearrangement of F₂MCP 139 and iodine by CuI catalysis.
  
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63. Scheme 62: Synthesis of 2-fluoropyrroles 142.
  
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64. Scheme 63: Ring opening of gem-difluorocyclopropyl ketones 143 mediated by BX₃.
  
  Jump to Scheme 63
65. Scheme 64: Lewis acid-promoted ring-opening reaction of 2,2-difluorocyclopropanecarbonyl chloride (148).
  
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66. Scheme 65: Ring-opening reaction of the gem-difluorocyclopropyl ketone 106 by methanolic KOH.
  
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67. Scheme 66: Hydrogenolysis of 1,1-difluoro-3-methyl-2-phenylcyclopropane (151).
  
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68. Scheme 67: Synthesis of monofluoroalkenes 157.
  
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69. Scheme 68: The stereoselective Ag-catalyzed defluorinative ring-opening diarylation of 1-trimethylsiloxy-2,2-d...
  
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70. Scheme 69: Synthesis of 2-fluorinated allylic compounds 162.
  
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71. Scheme 70: Pd-catalyzed cross-coupling reactions of gem-difluorinated cyclopropanes 161.
  
  Jump to Scheme 70
72. Scheme 71: The (Z)-selective Pd-catalyzed ring-opening sulfonylation of 2-(2,2-difluorocyclopropyl)naphthalene...
  
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73. Figure 1: Structures of zosuquidar hydrochloride and PF-06700841.
  
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74. Scheme 72: Synthesis of methylene-gem-difluorocyclopropane analogs of nucleosides.
  
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75. Figure 2: Anthracene-difluorocyclopropane hybrid derivatives.
  
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76. Figure 3: Further examples of difluorcyclopropanes in modern drug discovery.
  
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Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

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Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

Yamato Fujihira,
Yumeng Liang,
Makoto Ono,
Kazuki Hirano,
Takumi Kagawa and
Norio Shibata

Letter
Published 12 Feb 2021

436 Accesses

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1. Graphical Abstract
2. Scheme 1: Chemistry of the CF₃ anion generated from HCF₃. a) Decomposition of the trifluoromethyl anion to di...
  
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3. Figure 1: Trifluoromethyl ketones. a) Hydrolysis of trifluoromethyl ketones. b) Selected examples of biologic...
  
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4. Scheme 2: Trifluoromethylation of esters by HCF₃ by a) Russell and Roques (1998), b) Prakash and co-workers (...
  
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5. Scheme 3: Substrate scope of esters 1 for trifluoromethylation by HCF₃ under the optimized conditions. ^aDeter...
  
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Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

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Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

Alexander Leslie,
Thomas S. Moody,
Megan Smyth,
Scott Wharry and
Marcus Baumann

Full Research Paper
Published 04 Feb 2021

429 Accesses

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1. Graphical Abstract
2. Scheme 1: The continuous flow set-up used.
  
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3. Figure 1: Scope of Cbz-carbamate products obtained via flow process (*t_Res = 60 min, **T = 80 °C; isolated yi...
  
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4. Scheme 2: Side reaction during formation of product 3m.
  
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5. Scheme 3: Flow set-up for the CALB-mediated impurity tagging approach.
  
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6. Scheme 4: Strategies towards accessing β-amino acid derivatives 8.
  
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7. Scheme 5: Complementary flow approaches towards the β-amino acid derivatives 8.
  
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8. Scheme 6: Batch hydrolysis of the ester group in the presence of the carbamate.
  
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Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

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High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

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

Full Research Paper
Published 08 Mar 2018

401 Accesses

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

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Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

Savva A. Ponomarev,
Roman V. Larkovich,
Alexander S. Aldoshin,
Andrey A. Tabolin,
Sema L. Ioffe,
Jonathan Groß,
Till Opatz and
Valentine G. Nenajdenko

Full Research Paper
Published 27 Jan 2021

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1. Graphical Abstract
2. Scheme 1: Scope of the nitrostyrenes 1 in the Diels–Alder reaction with CPD (dr = exo:endo).
  
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3. Figure 1: The structure assignment of norbornenes 2 by ¹H (a) and NOE (b) NMR spectroscopy.
  
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4. Figure 2: ¹³C NMR spectrum of the mixture of exo- and endo-isomers of norbornene 2l.
  
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5. Figure 3: The predicted reaction pathway for the Diels–Alder reaction of nitrostyrene 1h with CPD is displaye...
  
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6. Scheme 2: The Diels–Alder reaction of nitrostyrene 1h with spiro[2.4]hepta-4,6-diene.
  
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7. Scheme 3: Diels–Alder reaction of nitrostyrenes 1 with CHD (dr = exo:endo). (а) Reaction under microwave acti...
  
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8. Scheme 4: Kinetic study of reactions of 1h with CPD and CHD.
  
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9. Figure 4: Kinetic curves for the reactions of nitrostyrene 1h with CPD (50–130 °C) and CHD at 110 °C.
  
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10. Scheme 5: The Diels–Alder reaction of the nitrostyrene 1h with 1-methoxy-1,3-cyclohexadiene.
  
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11. Scheme 6: Selected chemical transformations of norbornenes 2 (dr = exo:endo).
  
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