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

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. 2

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

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] : …………………………… 4

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. 5

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. 6

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 7

8. Pyridine Synthesis: [2+2+1+1] approach 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 8

9. Pyridine Synthesis: [2+2+1+1] approach 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. N. M. Evdokimov,I. V. Magedov, A. S. Kireev, A. Kornienko Org. Lett.2006 (8), 5, 899-902 9 The steric hindrance caused by the o-substituents prevented the aromatisation.

10. Pyridine Synthesis: [2+2+1+1] approach 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 10

11. Pyridine Synthesis: [3+2+1] approach 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. 11

12. Pyridine Synthesis: [3+2+1] approach 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. 12

13. Pyridine Synthesis: [3+2+1] approach Kröhnke, F. Synthesis 1976, 1. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999, 12, 2114. 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.

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

15. Pyridine Synthesis: [3+2+1] approach 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. Bagley Synlett 2007 (16), 2459–2482 15

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

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

18. Pyridine Synthesis: [3+2+1] approach 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 18

19. Pyridine Synthesis: [3+3] approach C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482 The [3+3] approach is well known as the Bohlmann-Rahtz pyridine synthesis. The original Bolmann-Rahtz pyridine synthesis (1957) R1 R2 R3 MeCO 2 EtH77 MeCO 2 EtMe81 MeCOMeH72 MeCOMeMe90 MeCNMe72 MeCNH80 PhCNMe77 MeCO 2 EtPh81 MeCO 2 EtC 7 H 15 87 19

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

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

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

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

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

25. Pyridine Synthesis: [3+3] approach S. A. Belyakov, A. E. Sorochinsky, S. A. Henderson, J. Chen, A. R. Katritzky. J. Org. Chem. 1997, 62, 6210-6214 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 ,  -unsaturated carbonyls, as shown here.

26. Pyridine Synthesis: [3+3] approach N.A. Nedolya, N. I. Schlyakhtina,.L. V. Klyba, I. A. Ushakov, S. V. Fedorova, L. Brandsma Tetrahedron Letters. 2002 (43) 9679– 9681 Very good yield all around 90%, but limited scope 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.

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 27

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

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 29

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

31. Pyridine Synthesis: [2+2+2] approach H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24). 248-262 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. 31

32. Pyridine Synthesis: [2+2+2] approach C. Brandli,T. R. Ward. J. Comb. Chem. 2000, 2, 42-47 32 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

33. Pyridine Synthesis: [2+2+2] approach H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24). 248-262 33 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.

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

35. Pyridine Synthesis: [2+2+2] approach H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24). 248-262 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.

36. Pyridine Synthesis: [2+2+2] approach C. Brandli,T. R. Ward. J. Comb. Chem. 2000, 2, 42-47 36 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.

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. 37

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 38

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 39

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 40

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 41

42. Pyridine Synthesis: [4+2] approach Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179. 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. 42

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

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

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

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

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 47

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. 48

49. Pyridine Synthesis: [4+2] approach Hill, D. M., Ahmad, O. K. Movassaghi, M. J. Am. Chem. Soc. 2007, 129, 10096-10097. 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 (Tf 2 O) in the presence of 2-chloropyridine (2-ClPyr) as the base additive made possible the development of this methodology’ 49

50. Pyridine Synthesis: [4+2] approach Hill, D. M., Ahmad, O. K. Movassaghi, M. J. Am. Chem. Soc. 2007, 129, 10096-10097. 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 50

51. Pyridine Synthesis: [4+2] approach Hill, D. M., Ahmad, O. K. Movassaghi, M. J. Am. Chem. Soc. 2007, 129, 10096-10097. The example shown below highlights the greater efficiency of this chemistry when nucleophilic acetylenes are employed in place of enol derivatives. 51

52. Pyridine Synthesis: [4+2] approach Hill, D. M., Ahmad, O. J. Am. Chem. Soc. 2007, 129, 10096-10097. The scope of the reaction.... 52

53. Pyridine Synthesis: [4+2] approach Hill, D. M., Ahmad, O. J. Am. Chem. Soc. 2007, 129, 10096-10097. The scope of the reaction.... 53

54. Pyridine Synthesis: [4+2] approach This 4+2 approach was developed by Lenoir. Lenoir, I.; Smith, M. L. J. Chem. Soc., Perkin Trans. 1 2000, 641. This disconnection, was Reported By Smith and Lenoir in 2000 and is an innovative radical annulation reaction of vinyl isonitriles and iodoalkynes to give the cyclopenta-fused pyridines 54

55. Pyridine Synthesis: [4+2] approach Lenoir, I.; Smith, M. L. J. Chem. Soc., Perkin Trans. 1 2000, 641. Other types of heterocycles may be achieve. 55

56. Pyridine Synthesis: [5+1] approach Analogous to Hantzsch’s synthesis. Pros The [5+1] approach is a simple and reliable route to 2,6-disubstituted pyridines when the starting material is available. Cons 1,4-dihydropyridine intermediate isolated. Method depends on the availability of 1,5 di-carbonyl compounds 56

57. Pyridine Synthesis: [5+1] approach Chubb, R. W. J.; Bryce, M. R.; Tarbit, B. J. Chem. Soc., Perkin Trans. 1 2001, 16, 1853. 57

58. Pyridine Synthesis: [5+1] approach Katritzky, A. R.; Denisenko, A.; Arend, M. J. Org. Chem. 1999, 64, 6076. 58

59. Pyridine Synthesis: [5+1] approach Katritzky, A. R.; Denisenko, A.; Arend, M. J. Org. Chem. 1999, 64, 6076. 59

60. Pyridine Synthesis: [6+0] approach The next and last method seen today is the new 6+0 disconnection by Beauchemin, last July. T. Rizk, E. J.-F. Bilodeau,A.M. Beauchemin.Angew. Chem. Int. Ed. 2009, 48, 8325 –8327 60

61. Pyridine Synthesis: [6+0] approach Once the optimal conditions established they did a screening to establish a scope T. Rizk, E. J.-F. Bilodeau,A.M. Beauchemin.Angew. Chem. Int. Ed. 2009, 48, 8325 –8327 61

62. Pyridine Synthesis: [6+0] approach Once the optimal conditions established they did a screening to establish a scope T. Rizk, E. J.-F. Bilodeau,A.M. Beauchemin.Angew. Chem. Int. Ed. 2009, 48, 8325 –8327 62

63. Conclusion 63