1 / 63

The Synthesis of Pyridine; Over a Century of Research

The Synthesis of Pyridine; Over a Century of Research. PRESENTED BY PHILIPPE BOLDUC COLLINS GROUP UNIVERSITÉ DE MONTREAL FEBRUARY 2 ND 2010. History of Pyridine. 1846: FIRST ISOLATION BY ANDERSON 1869 AND 1871: KÖRNER AND DEWAR PROPOSED CORRECT STRUCTURE.

creola
Télécharger la présentation

The Synthesis of Pyridine; Over a Century of Research

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. The Synthesis of Pyridine; Over a Century of Research PRESENTED BY PHILIPPE BOLDUC COLLINS GROUP UNIVERSITÉ DE MONTREAL FEBRUARY 2ND 2010

  2. History of Pyridine • 1846: FIRST ISOLATION BY ANDERSON • 1869 AND 1871: KÖRNER AND DEWAR PROPOSED CORRECT STRUCTURE. • 1876: FIRST SYNTHETIC ROUTE BY RAMSAY. • 1930’S: DECADE WHERE NIACIN WAS RECOGNISED AS IMPORTANT FOR THE PREVENTION OF DERMATITIS AND DEMENTIA. • 1940’S : 2-VINYLPYRIDINE AND 2-PICOLINE WERE NOW A CONSTITUENT OF LATEX AND DEMAND OUTSTRETCHED AVAILABILITY FROM COAL TAR. THIS PUSHED CHEMISTS TO DEVELOP INDUSTRIAL PROCESSES TOWARDS PYRIDINES. • FOR THE LAST 60 YEARS MEDICINAL CHEMISTRY INCREASED THE DEMAND FURTHER WITH THE FINDING OF MANY BIOACTIVE MOLECULES.

  3. Example of Bioactive Pyridines 3 G. D., Henry. Tetrahedron. 60 (2004) 60643-6061

  4. Pyridine Synthesis • Many methods of making pyridine were developed. The methods are usually arranged according to the disconnection; • [2+2+1+1] : ......................... • [3+2+1] : ............................. • [3+3] : ................................. • [2+2+2] : ............................ • [4+2] : ................................. • [5+1] would refer to: .......... • [6+0] : ……………………………

  5. Pyridine Synthesis: [2+2+1+1] approach • The Classic Hantzsch disconnection allows, and is limited, to make symetrical pyridines. • 1,4-Dihydropyridinesare usually isolated prior to oxidation. • Pyridines issued from this route have interesting activity as calcium channel blocker used in heart conditions. • This route sets severe constraints on the substitution patterns of the pyridines. J.-J. Xia, G.-W. Wang. Synthesis 2005, 2379–2383.

  6. Pyridine Synthesis: [2+2+1+1] approach • Research for one pot ‘greener’ approach; Wang’s work on the synthesis of various pyridines using the Hantzsch approach. J.-J. Xia, G.-W. Wang. Synthesis 2005, 2379–2383.

  7. Pyridine Synthesis: [2+2+1+1] approach • In spite of many years of research, the synthesis of 3,5-dicyano pyridines was still defective. Korienko and his team used the Hantzsch approach in order to achieve this pattern N. M. Evdokimov,I. V. Magedov, A. S. Kireev, A. Kornienko Org. Lett.2006 (8), 5, 899-902

  8. Pyridine Synthesis: [2+2+1+1] approach 8 • Although the synthesis of these compounds went very well, never did they obtain a yield over 50% of pyridine. .. N. M. Evdokimov,I. V. Magedov, A. S. Kireev, A. Kornienko Org. Lett.2006 (8), 5, 899-902

  9. Pyridine Synthesis: [2+2+1+1] approach 9 • In an attempt to improve the reaction, they tested various other oxidant than air without any improvement. • Then they got a clue from these results. • The steric hindrance caused by the o-substituents prevented the aromatisation. N. M. Evdokimov,I. V. Magedov, A. S. Kireev, A. Kornienko Org. Lett.2006 (8), 5, 899-902

  10. Pyridine Synthesis: [2+2+1+1] approach 10 • This led to the conclusion that an NADH-like mechanism occurred, where a single-hydride transfer route occurred instead of a regular oxidation. N. M. Evdokimov,I. V. Magedov, A. S. Kireev, A. Kornienko Org. Lett.2006 (8), 5, 899-902

  11. Pyridine Synthesis: [3+2+1] approach 11 • Common method used for the [3+2+1] disconnection approach is the base-promoted Michael addition which forms a 1,5-dicarbonyl intermediate. • When x is a pyridinium, quinolinium or picolinium salt the reaction is called a Kröhnke synthesis.

  12. Pyridine Synthesis: [3+2+1] approach 12 • Katritzky’s synthesis of pyridines via a [3+2+1] approach Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999, 12, 2114.

  13. Pyridine Synthesis: [3+2+1] approach 13 • Katritzky’s synthesis of pyridines via a [3+2+1] approach is not revolutionary. The yields are generally a little lower than Krohnke but the scope is greater. • Krohnke’s review is from 1976. Kröhnke, F. Synthesis 1976, 1. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999, 12, 2114.

  14. Pyridine Synthesis: [3+2+1] approach 14 Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999, 12, 2114.

  15. Pyridine Synthesis: [3+2+1] approach 15 • Another interesting approach to the [3+2+1] route is the acid catalyzed condensation of the ketone onto the alkynone. Bagley and coworker developed these conditions for a 3+3 approach. C. Glover, E. A. Merritt, M. C. BagleySynlett 2007 (16), 2459–2482

  16. Pyridine Synthesis: [3+2+1] approach 16 C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

  17. Pyridine Synthesis: [3+2+1] approach 17 • Reissig and coworker published this approach towards 4-hydroxypyridines. • Few groups focus on the synthesis of chiral pyridines. C. Eidamshaus, H.-A. Reissig. Adv. Synth. Catal. 2009, 351, 1162-1166.

  18. Pyridine Synthesis: [3+2+1] approach 18 • Example showing that it is possible to use chiral nitriles as well. C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

  19. Pyridine Synthesis: [3+3] approach • The [3+3] approach is well known as the Bohlmann-Rahtz pyridine synthesis. C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

  20. Pyridine Synthesis: [3+3] approach 20 • In order to improve the method, Bagley and his team made a number of different experiments. They first investigated the solvent effect. C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

  21. Pyridine Synthesis: [3+3] approach 21 • Maybe an acid could both catalyse the addition step and the isomerisation. C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

  22. Pyridine Synthesis: [3+3] approach 22 • Following this succes in the Brontred acid-catalyzed conditions, they investigated the Lewis acid-catalyzed route. C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

  23. Pyridine Synthesis: [3+3] approach 23 • Zinc(II) and Ytterbium(III) gave the best results. C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

  24. Pyridine Synthesis: [3+3] approach 24 • To conclude their method, they show small table of comparison between Bronstead and Lewis acid-catalized routes and the traditional reaction conditions. C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

  25. Pyridine Synthesis: [3+3] approach 25 • Further innovation with the [3+3] disconnection strategy came from Katritzky and co-workers in 1997, who employed a-benzotriazole nitriles as nucleophiles for Michael addition onto a,b-unsaturated carbonyls, as shown here. S. A. Belyakov, A. E. Sorochinsky, S. A. Henderson, J. Chen, A. R. Katritzky. J. Org. Chem. 1997, 62, 6210-6214

  26. Pyridine Synthesis: [3+3] approach 26 • The last 3+3 shown today was developped by Brandsma and coworkers in 2002. It uses the reaction of lithiated allenes and alkynes with methoxymethyl isocyanate. Very good yield all around 90%, but limited scope N.A. Nedolya, N. I. Schlyakhtina,.L. V. Klyba, I. A. Ushakov, S. V. Fedorova, L. Brandsma Tetrahedron Letters. 2002 (43) 9679–9681

  27. Pyridine Synthesis: [2+2+2] approach • Original laboratory preparation of pyridine by Ramsey in 1876 used this disconnection. • Passing acetylene gas along with hydrogen cyanide thru a red-hot tube afforded some pyridine. • Cobalt-catalysed [2+2+2] replaced this method. G. D., Henry. Tetrahedron. 60 (2004) 60643-6061

  28. Pyridine Synthesis: [2+2+2] approach • Cobalt catalysed [2+2+2] have been extensively studied by Helmut Bonnemann. H. Bonnemann. Angew. Chem. Int. Ed. Engl. 1985 (24) . 248-262

  29. Pyridine Synthesis: [2+2+2] approach • The exchange of 65% of the L ligand for propyne was investigated versus the temperature. Modifying on the left the L ligand and on the right the Y ligand H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24) . 248-262

  30. Pyridine Synthesis: [2+2+2] approach 30 • The alkynes seems to be attaching to the Cobalt faster than the nitrile. H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24) . 248-262

  31. Pyridine Synthesis: [2+2+2] approach • This preference for the alkyne brings the problem of chemoselectivity. • Starting material readily available (two-atom fragment) • Allows for large numbers of differentially substituted pyridines • Atom economy • Hard to separate large number of very similar molecules. • A solution is to take non-substituted alkynes like acetylene. H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24) . 248-262

  32. Pyridine Synthesis: [2+2+2] approach • Addition of a Nitrile to the Three Possible Cobaltacyclopentadiene Intermediates Could Yield Four Pyridine • Regioisomers; Only the 2,4,6- and 2,5,6-Isomers Are Formed • Two Different Terminal Alkynes React with One Nitrile in the Presence of a Cobalt Catalyst To Afford Eight • Different Pyridine Derivatives C. Brandli ,T. R. Ward. J. Comb. Chem. 2000, 2, 42-47

  33. Pyridine Synthesis: [2+2+2] approach • 2-vinylpyridine is an important constituent of latex. • The 2+2+2 cobalt-catalyzed cycloaddition is a very effective route to it. • The 2-vinylpyridine synthesis must be carried out below 130- 140"C, since acrylonitrile and 2-vinylpyridine undergo thermalpolymerisation. H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24) . 248-262

  34. Pyridine Synthesis: [2+2+2] approach 34 • The search for the best catalyst was then important. • The best results to date were obtained with the complex 30. H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24) . 248-262

  35. Pyridine Synthesis: [2+2+2] approach 35 • The outstanding position of this catalyst is apparently due to the fact that the catalytic vinylation reactions (32) and (33) are largely suppressed by it. • All other catalyst systems named in Table 9 cause the reactions of acrylonitrile and 2-vinylpyridine to give appreciable amounts of 55 and 56 or 57. • These activated olefins can compete with acetylene for cobalt coordination sites and they therefore act as catalyst poisons. • Cobalt-catalysed sythesis of pyridine is very sensitive to conditions. • Once optimized, it is extremelly effective. H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24) . 248-262

  36. Pyridine Synthesis: [2+2+2] approach • Medicinal chemistry still uses this method to screen great library of produts. • In this image, Ward explains that 3920 pyridines were synthetized from these 14 alkynes mixed with these 10 nitriles. C. Brandli ,T. R. Ward. J. Comb. Chem. 2000, 2, 42-47

  37. Pyridine Synthesis: [2+2+2] approach • Clearly, to overcome the problem of selectivity, the best approach is to fuse two of the reacting species together. • In this example from Carlos Saa some cyclo-fused pyridines are synthesised with good regio chemistry J. A., Varela, C., Saa. Synlett. 2008(17). 2571-2578.

  38. Pyridine Synthesis: [2+2+2] approach • The team of Heller focuses on making different axially chiral pyridines using enantio-selective catalysts. H.-J. Drexler, A. Spannenberg, B. Sundermann, C. Sundermann, A. Gutnov, B. Heller, C. Fischer.Angew. Chem. Int. Ed. 2004, 43, 3795 –3797

  39. Pyridine Synthesis: [2+2+2] approach • The best catalyst they investigated were the enantiomers 4 and 5 H.-J. Drexler, A. Spannenberg, B. Sundermann, C. Sundermann, A. Gutnov, B. Heller, C. Fischer. Angew. Chem. Int. Ed. 2004, 43, 3795 –3797

  40. Pyridine Synthesis: [2+2+2] approach • They believe that the enantio-selectivity comes from the intermediate cobaltacyclopentadiene shown on the bottom right that will then be attacked by the nitrile to form the pyridine ring. H.-J. Drexler, A. Spannenberg, B. Sundermann, C. Sundermann, A. Gutnov, B. Heller, C. Fischer. Angew. Chem. Int. Ed. 2004, 43, 3795 –3797

  41. Pyridine Synthesis: [4+2] approach • The next disconnection is the [4+2]. • The 4+2 disconnection have evolved greatly in recent years. • It includes Hetero Diels-Alder type of cyclisation

  42. Pyridine Synthesis: [4+2] approach 42 • Boger and coworkers investigated in 1981 the use of 4+2 cycloadditions . • They used triazine as the diene and a ketone transformed into an enamine as the dienophile. Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179.

  43. Pyridine Synthesis: [4+2] approach 43 • The scope of the reaction Boger, D. L.; Panek, J. s. J. Org. Chem. 1981, 46, 2179.

  44. Pyridine Synthesis: [4+2] approach • More recently, Bondock developed a new Diels-alder approach with 2,4-dimethyl-5-methoxyoxazole as the electron rich diene. Bondock, S. Heteroatom Chemistry. 2005 (16), 1, 49-55.

  45. Pyridine Synthesis: [4+2] approach 45 • In this example he shows the Diels-Alder on acyclic dienophiles Bondock, S. Heteroatom Chemistry. 2005 (16), 1, 49-55.

  46. Pyridine Synthesis: [4+2] approach • Other cyclic pyridine derivatives. Bondock, S. Heteroatom Chemistry. 2005 (16), 1, 49-55.

  47. Pyridine Synthesis: [4+2] approach • An other [4+2]; Involving a hetero-Diels-Alder reaction using isotellurazoles with acetylenic dienophiles has been investigated by Thompson. Guo. K, M. J. Thompson, B. Chen. J. Org. Chem. 2009, 74, 6999-7006

  48. Pyridine Synthesis: [4+2] approach • Scope of the reaction Yukichi, T. Yu, O. Akiko, M.-O., Hisashi, K., Maiko, S., Shigenobu, A., Yuji, T., Satoshi, O. Tetrahedron letters 2009 (50), 6651-6653.

  49. Pyridine Synthesis: [4+2] approach • Mohammad Movassaghi published his findings in the synthesis of pyridines in 2007 using also a [4+2] type of disconnection. • ‘The recognition of the unique electrophilic activation of amides with trifluoromethanesulfonic anhydride (Tf2O) in the presence of 2-chloropyridine (2-ClPyr) as the base additive made possible the development of this methodology’ Hill, D. M., Ahmad, O. K. Movassaghi, M. J. Am. Chem. Soc. 2007, 129, 10096-10097.

  50. Pyridine Synthesis: [4+2] approach • Based on mechanistic findings in previous research, they proposed this single step pyridine synthesis mechanism for the alkyne nucephile. • next they examined the direct condensation of enol ethers withv N-vinyl and N-aryl amides Hill, D. M., Ahmad, O. K. Movassaghi, M. J. Am. Chem. Soc. 2007, 129, 10096-10097.

More Related