1. Syntheses and Structures of Tungsten(0) Complexes of Tris(2-pyridylmethyl)amine and The Catalytic Applications to Biginelli Condensation Reactions Student : Ru-Ni Dai Supervisor : Prof. Shuchun Joyce Yu 2007 / 06 / 04 Department of Chemistry & Biochemistry Chung Cheng University

2. 2 Multicomponent Reactions (MCRs) MCRs is dependent on the reaction conditions :  Solvent  Temperature  Catalyst  Concentration  The kind of starting materials  Functional groups A. Dömling in: Multicomponent Reactions Wiley-VCH, Weinheim 2005

3. 3 Developement of Catalytic Muticomponent Reactions Biginell, P. Gazz. Chim. Ital. 1893, 23, 360 – 413.

4. 4 3,4-Dihydropyrimidin-2(1H)-one (DHPMs)  Antiviral activity  Antibacterial activity  Antitumor  Antiinflammatiry  Analgesic  Blood palette aggregation inhibitor  Cardiovascular activity Janis, R. A.; Vater, W. Med. Res. Rev. 1989, 16, 309. Atwal, K. S. et. al. J. Med. Chem. 1991, 34, 806-811.

5. 5 Acidic Catalysts for Biginelli Condensation Reactions  Proton Donor Brønsted Acids H 2 SO 4 、 HCl  Traditional Lewis Acid Catalysts InBr 3 、 VCl 3 、 ZnI 2 、 FeCl 3 、 ZnCl 2 、 CuCl 2......etc.  Lanthanide Lewis Acid Catalysts La(III) 、 Yb(III) 、 Sm(II) Biginell, P. i, Gazz. Chim. Ital. 1893, 23, 360 – 413. Dandia, A. et. al. J. Fluorine Chem. 1998, 90, 17-21. Peppe, C. et. al. Tetrahedron. 2002, 58, 4801-4807. Sebti, S. et. al. Catal. Commun. 2005, 6, 455. Jenner, G. Tetrahedron Lett. 2004, 45, 6195. Ma, H. et. al. Tetrahedron Lett. 2000, 41, 9075-9078. Massi, A. et. al. Tetrahedron Lett. 2001, 42, 7975-7978. Shen, Q. et. al. Eur. J. Org. Chem. 2005, 1500-1503.

6. 6 Acidic Catalysts for Biginelli Condensation Reactions -- continued  Heteropoly acids (HPAs) H 3 PMo 12 O 40 、 SiO 2 -NaHSO 4  Others montmorillonite 、 GABA urea & Wang resin Sivudub,K. S. et. al. Tetrahedron Lett. 2005, 46, 8221-8224. Moghadam, M. et. al. Appl. Catal., A: General. 2006, 309, 44-51. Rafiee, E.; Jafari, H. Bioorg. Med. Chem. Lett. 2006, 16, 2463-2466. Sartori, G. et. al. Tetrahedron Lett, 1999, 40, 3465-3468. Wipf, P.; Cunningham, A. Tetrahedron Lett, 1995, 36, 43, 7819-7822. Heravi, M. M. et. al. J. Mol. Catal. A: Chem. 2005, 236, 216–219.

7. 7 H 2 SO 4 and HCl Catalyzed Biginelli Condensation Reactions Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1993, 55, 3784-3791. H 2 SO 4 or HCl ： 3-4 equiv

8. 8 BF 3 ·OEt 2 Catalyzed Biginelli Condensation Reactions Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63, 3454-3457. R 1 = Me, Et R 2 = Me, Et, t-Bu, Ph R 3 = H, F, Me R 4 = H, F, Cl, OMe, NO 2 R 5 = H, Me

9. 9 InBr 3 Catalyzed Biginelli Condensation Reactions Peppe, C. et. al. Tetrahedron. 2002, 58, 4801-4807. Peppe, C.; Yuanc, Y.-F. et. al. Tetrahedron Lett. 2004, 45, 8991-8994. EntrySolvent Amount of InBr 3 (mol%) Reaction time (hr) Yield (%) 1Ethanol10795 2Ethanol5774 3Ethanol2.5766

10. 10 SmI 2 Catalyzed Biginelli Condensation Reactions Han, X.; Xu, F.; Luo,Y.; Shen, Q. Eur. J. Org. Chem. 2005, 1500-1503. R 1 = Me, OEt R 2 = Ph, n-Pr, i-Pr, 4-CH 3 Ph, 2-furyl......etc. R 3 = O, S

11. 11 H 3 PW 12 O 40 Catalyzed Biginelli Condensation Reactions Amini, M. M.; Shaabani, A.; Bazgir, A. Catal. Commun. 2006, 7, 843–847. R 1 = Me, Ph R 2 = Me, OMe, OEt, OBn, NHPh R 3 = C 6 H 5, 4-OMe-C 6 H 4, 4-Cl-C 6 H 4, 3-NO 2 -C 6 H 4......etc. R 4 = O, S Heteropoly acids : HPAs, H 8-n [XM 12 O 40 ] X = Si, P...etc., M = Mo, W

12. 12 Natural HEU Type Zeolite Catalyzed Biginelli Condensation Reactions EntryCatalyst Reaction time (hr) Yield (%) 1HZSM-5 a 1221 2HY b 1280 3Montmorillonite KSF1035 4Natural Zeolite Heulandite4-575 Heravi, M. M. et. al. J. Mol. Catal. A: Chem. 2005, 236, 216–219. a The HZSM-5 = Si/Al =15, H 6 (SiO 2 ) 90 (AlO 2 ) 6 b HY = Si/Al = 2.43 zeolite, H 56 (SiO 2 ) 136 (AlO 2 ) 56

13. 13 Organometallic Lewis acid R 1 = Me, OEt R 2 = Ph, n-Pr, i-Pr, 4-CH 3 Ph, 2-furyl......etc. R 3 = O, S Zhu, C. et. al. J. Am. Chem. Soc. 2005, 127, 16386–16387.

14. 14 Proton Donor Brønsted Acids –Catalysts have to be used in excess, for example sulfuric acid and hydrochloric acid, 5–10 equiv. –Longer reaction time. –Their corrosive nature and the formation of several side products make them difficult to handle. –The disposal of acidic waste leads to environmental pollution. Disadvantages of Brønsted Acids

15. 15 Traditional Lewis Acid Catalysts –Many chlorinated derivatives are highly moisture sensitive and hydrolyse rapidly under conventional storage or standard reaction conditions. –The disposal of acidic waste leads to environmental pollution. –Can not control electronic and steric environments around metal Lewis acid center. Lanthanide Lewis Acid Catalysts –Lanthanide metals are relatively rare. Heteropolys Acid Catalysts –High metal content of each catalyst loading. Disadvantages of Traditional and Lanthanide Lewis Acid and Heteropoly Acids

16. 16 Low Oxidation State Transition Metals –Relatively high moisture – and oxygen – stability –Inexpensive –Tunable electronic and steric environments around metal center Green Chemistry –Greener solvents R.T. ionic liquids, [Bmim]PF 6 –Energy saving Catalysis under microwave flash heating to replace thermal heating Motivations

17. 17 [N(CH 2 2-py) 3 W(CO)(NO) 2 ] (BF 4 ) 2 (3) Que, L. et. al. Jr. J. Am. Chem. Soc. 1988, 110, 2026. Kim, C.; Chen, K.; Kim, J.; Que, L. Jr. J. Am. Chem. Soc. 1997, 119, 5964.

18. 18 Preparation of tpa Ligand (1) and Catalyst Precursor (2) Britovsek, G. J. P.; England, J.; WhiteInorg, A. J. P. Inorg. Chem. 2005, 44, 8125-8134.

19. 19 The Structure of N(CH 2 2-py) 3 W(CO) 3 (2) Xu, L.; Sasaki, Y.; Abe, M. Chem. Lett. 1999, 28, 163-164. [N(CH 2 2-py) 3 W(CO) 3 ] inCD 3 NO 2

20. 20 Preparation of Organotungsten Catalyst S = CH 3 CN

21. 21 Possible Bonding Modes for tpa Ligand : η 4 -N(py) 3 W η 3 -N(py) 2 W η 3 -(py) 3 W [N(CH 2 2-py) 3 W(CO)(NO) 2 ](BF 4 ) 2 inCD 3 NO 2 S = CH 3 CN W 1 -N 1 W 1 -N 2 W 1 -N 3 W 1 -N 4 2.1542.1912.1432.203

22. 22 1 H chemical shift H 1 H 2 H 3 H 4 H 1 H 2 H 3 H 4crotonaldehyde crotonaldehyde + Cat. 9.41 6.08 7.00 2.01 9.41 6.08 7.00 2.01 10.06 6.82 8.18 3.07 Chemical shift diff. 0.65 0.74 1.18 1.06 0.65 0.74 1.18 1.06 Childs, R. F. et. al. Can. J. Chem. 1982, 60, 801. Crotonaldehyde-Lewis Acid Adduct

23. 23 Lewis acid △ δ on H 3 (ppm) BBr 3 1.49 AlCl 3 1.23 [OP(2-Py) 3 W(CO)(NO) 2 ](SbF 6 ) 2 1.23 [OP(2-Py) 3 W(CO)(NO) 2 ](BF 4 ) 2 1.22 [P(2-Py) 3 W(CO)(NO) 2 ](SbF 6 ) 2 1.21 [HOC(2-Py) 3 W(CO)(NO) 2 ](SbF 6 ) 2 1.19 [N(CH 2 2-py) 3 W(CO)(NO) 2 ] (BF 4 ) 2 1.18 [P(2-Py) 3 W(CO)(NO) 2 ](BF 4 ) 2 1.18 BF 3 1.17 AlEtCl 2 1.15 [OP(2-Py) 3 Mo(CO)(NO) 2 ](BF 4 ) 2 1.13 [HC(2-Py) 3 Mo(CO)(NO) 2 ](SbF 6 ) 2 1.05 TiCl 4 1.03 [P(2-Py) 3 Mo(CO)(NO) 2 ](BF 4 ) 2 0.99 [Me 3 P(CO) 3 (NO)W] + 0.93 SnCl 4 0.87 [CpMo(CO) 2 ] + (PF 6 )0.70 Et 3 Al0.63 [CpFe(CO) 2 ] + BF 4 0.54

24. 24 Organotungsten Lewis Acid Catalyzed Biginelli Condensation Thermal conditions Solvent system: DMF or CH 3 CH 2 OH or EA or [Bmim]PF 6

25. 25 Seddon, K. R. et. al. Pure Appl. Chem. 2000, 72, 2275. Ionic Liquids

26. 26 Wasserscheid, P., et. al. Angew. Chem. Int. Ed. 2000, 39, 3772. Coordinative Characteristics of Various Anions

27. 27 Room temperature ionic liquids exhibit many properties which make them potentially attractive media for homogeneous catalysis: They have essentially no vapour pressure. They generally have reasonable thermal stability. They are able to dissolve a wide range of organic, inorganic and organometallic compounds. The solubility of gases. They are immiscible with some organic solvents. Ionic liquids have been referred to as ‘designer solvents’ by a suitable choice of cation / anion.

28. 28 Entry substrate a solventmL time (hr) yield (%) R1R1 R2R2 R3R3 1MeFO Ethanol11094 EA10.7522 [Bmim] PF 6 10.252 DMF0.54.596 2CH 2 ClFO Ethanol1196 EA11.599 DMF0.53.591 3MeFS Ethanol22294 DMF0.5757 [Bmim] PF 6 17--- a Reaction conditions: substrate R 1 : R 2 : R 3 = 1 : 1: 1.5

29. 29 Entry substrate a solventmL time (hr) yield (%) R1R1 R2R2 R3R3 4MeHO Ethanol12.597 DMF0.5496 5 CH 2 ClHO Ethanol14.591 DMF0.52.594 6MeHS Ethanol12.870 EA1862 [Bmim] PF 6 12430 DMF0.51577 a Reaction conditions: substrate R 1 : R 2 : R 3 = 1 : 1: 1.5

30. 30 Entry substrate a solventmL time (hr) yield (%) R1R1 R2R2 R3R3 7MeClO Ethanol1188 DMF0.55.596 8CH 2 ClClO Ethanol1193 DMF0.5290 9MeClS Ethanol11164 EA120.565 DMF0.524.572 a Reaction conditions: substrate R 1 : R 2 : R 3 = 1 : 1: 1.5

31. 31 Entry substrate a solventmL time (hr) yield (%) R1R1 R2R2 R3R3 10MeOHO Ethanol149 EA1292 [Bmim] PF 6 1584 DMF0.55.577 11CH 2 ClOHO Ethanol1599 EA12.594 [Bmim] PF 6 1384 DMF0.51.592 12MeOHS EA1541 [Bmim] PF 6 12420 DMF0.5846

32. 32 The Optimized Conditions for Urea/Ethanol Systems Entry substrate solvent time (hr) yield (%) 1 hr yield (%) 2 hr yield (%) 3 hr yield (%) 4 hr yield (%) R1R1 R2R2 R3R3 1MeFOEthanol109418305170 2CH 2 ClFOEthanol196 --- 4MeHOEthanol2.597651--- 5CH 2 ClHOEthanol4.59151758089 7MeClOEthanol188 --- 8CH 2 ClClOEthanol193 --- 10MeOHOEthanol49143566491 11CH 2 ClOHOEthanol599679496--- R 1 = CH 2 Cl > Me R 2 = F > Cl > OH > H

33. 33 The Optimized Conditions in EA & in Ionic Liquid [Bmim]PF 6 Entry substrate solventmL time (hr) yield (%) R1R1 R2R2 R3R3 2CH 2 ClFOEA11.599 6MeHSEA1862 9MeClSEA120.565 10MeOHOEA1292 11CH 2 ClOHOEA12.594 Entry substrate solventmL time (hr) yield (%) R1R1 R2R2 R3R3 10MeOHO[Bmim] PF 6 1584 11CH 2 ClOHO[Bmim] PF 6 1384 R 1 = CH 2 Cl > Me R 2 = F > OH

34. 34 The Optimized Conditions for Urea/DMF Systems Entry substrate solventmL time (hr) yield (%) R1R1 R2R2 R3R3 1MeFO DMF0.54.596 DMF1990 2CH 2 ClFO DMF0.53.591 DMF1789 4MeHO DMF0.5496 DMF1496 5CH 2 ClHO DMF0.52.594 DMF1585 7MeClO DMF0.55.596 DMF11189 8CH 2 ClClO DMF0.5290 DMF14.577 10MeOHO DMF0.55.577 DMF1977 11CH 2 ClOHO DMF0.51.592 DMF1384

35. 35 Entry substrate solventmL time (hr) yield (%) R1R1 R2R2 R3R3 1MeFODMF0.54.596 2CH 2 ClFOEthanol1196 3MeFSEthanol22294 4MeHOEthanol12.597 5CH 2 ClHODMF0.52.594 6MeHSDMF0.51577 7MeClOEthanol1188 8CH 2 ClClOEthanol1193 9MeClSDMF0.524.572 10MeOHOEA1292 11CH 2 ClOHOEA12.594 12MeOHSDMF0.5846 The Optimized Conditions for All Reactions Systems

36. 36 Entry substrate solventmL cat. (mol%) time (hr) yield (%) R1R1 R2R2 R3R3 1MeFODMF0.5 32.598 0.64.596 2CH 2 ClFODMF0.5 3292 0.63.591 3MeFSDMF0.5 3773 0.6757 4MeHODMF0.5 32.591 0.6479 5CH 2 ClHODMF0.5 31.599 0.62.594 6MeHSDMF0.5 3894 0.61577

37. 37 Entry substrate solventmL cat. (mol%) time (hr) yield (%) R1R1 R2R2 R3R3 7MeClODMF0.5 32.596 0.65.596 8CH 2 ClClODMF0.5 3299 0.6290 9MeClSDMF0.5 324.589 0.624.572 10MeOHODMF0.5 32.586 0.65.577 11CH 2 ClOHODMF0.5 31.593 0.61.592 12MeOHODMF0.5 3874 0.6846

38. 38 Convection transition Thermal v.s. Microwave Heating Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250-6284. microwavethermal

39. 39 Dipole Rotation Mechanism of Microwave Heating

40. 40 Ionic Ionic Conduction

41. 41 Interactive Characteristic between Materials and Microwave Conductor (Metal Material) Reflective Insulator (Telflon) Transparent Dielectric Materials (ex : Water) Absorptive

42. 42 Microwave Flash Heating Microwave energy Liquid raises temperature quickly Digestion bottle

43. 43 Organotungsten Lewis Acid Catalyzed Biginelli Condensation Microwave Flash Heating conditions Solvent system: DMF or [Bmim]PF 6

44. 44 Entry substrate solvent time (min) yield (%) R1R1 R2R2 R3R3 1MeFODMF3067 2CH 2 ClFODMF2085 3MeFSDMF3057 4MeHODMF2076 5CH 2 ClHODMF1079 6MeHSDMF4082 7MeClODMF4589 8CH 2 ClClODMF1088 9MeClSDMF5024 10MeOHODMF3569 11CH 2 ClOHODMF 6 45 12MeOHSDMF50 73

45. 45 Entry substrate solventThermal/Yield(%)MW/Yield(%) R1R1 R2R2 R3R3 1MeFODMF 96 (4.5 hr) 67 (30 min) 2CH 2 ClFODMF 96 (3.5 hr) 85 (20 min) 3MeFSDMF 57 (7 hr) 57 (30 min) 4MeHODMF 79 (4 hr) 76 (20 min) 5CH 2 ClHODMF 94 (2.5 hr) 79 (10 min) 6MeHSDMF 77 (15 hr) 82 (40 min)

46. 46 Entry substrate solventThermal/Yield(%)MW/Yield(%) R1R1 R2R2 R3R3 7MeClODMF 79 (5.5 hr) 89 (45 min) 8CH 2 ClClODMF 90 (2 hr) 88 (10 min) 9MeClSDMF 72 (24.5 hr) 50 a (30 min) 10MeOHODMF 77 (5.5 hr) 69 (35 min) 11CH 2 ClOHODMF 92 (1.5 hr) 45 (6 min) 12MeOHSDMF 74 (8 hr) 73 (50 min) a 4ml DMF + 1ml [Bmim] PF 6

47. 47 Entry substrate solvent time (min) yield (%) R1R1 R2R2 R3R3 1MeFO[Bmim] PF 6 2CH 2 ClFO[Bmim] PF 6 3MeFS[Bmim] PF 6 4MeHO[Bmim] PF 6 5CH 2 ClHO[Bmim] PF 6 6MeHS[Bmim] PF 6 7MeClO[Bmim] PF 6 8CH 2 ClClO[Bmim] PF 6 9MeClS[Bmim] PF 6 10MeOHO[Bmim] PF 6 11CH 2 ClOHO[Bmim] PF 6 12MeOHS[Bmim] PF 6

48. 48 Entry substrate solventThermal/Yield(%)MW/Yield(%) R1R1 R2R2 R3R3 1MeFO[Bmim] PF 6 2 (0.25 hr) 2CH 2 ClFO[Bmim] PF 6 --- 3MeFS[Bmim] PF 6 --- 4MeHO[Bmim] PF 6 --- 5CH 2 ClHO[Bmim] PF 6 --- 6MeHS[Bmim] PF 6 77 (15 hr)

49. 49 Entry substrate solventThermal/Yield(%)MW/Yield(%) R1R1 R2R2 R3R3 7MeClO[Bmim] PF 6 --- 8CH 2 ClClO[Bmim] PF 6 --- 9MeClS[Bmim] PF 6 --- 10MeOHO[Bmim] PF 6 84 (5 hr) 83 (30 min) 11CH 2 ClOHO[Bmim] PF 6 84 (3 hr) 54 (20 min) 12MeOHS[Bmim] PF 6 20 (24 hr)

50. 50 Proposed Mechanism

51. 51 Proposed Mechanism ~~ Continue

52. 52 We have successfully synthesized the organotungsten Lewis acid catalyst, [(tpa)W(CO)(NO) 2 ] (BF 4 ) 2. The acidity of [(tpa)W(CO)(NO) 2 ] 2+ falls between those of AlCl 3 and BF 3 (Δδ = 1.18 ppm), where tpa = N(CH 2 -2-py) 3. The complex [N(CH 2 2-py) 3 W(CO)(NO) 2 ] 2+ has very different structures in solid state and in solutions. In solid state, the tpa ligand is in a tetradentate-coordination mode bound to the W center. While in solution state, tpa has various coordination possibilities (  3 - or  4 -interconversion) as suggested by its 1 H NMR spectral data. Because the lability of CO ligand, the resulting 16-e species (the real active catalyst) should be further stabilized by the fast  3 -to-  4 interconversion. The [(tpa)W(CO)(NO) 2 ](BF 4 ) 2 was demonstrated to be a very effective catalyst for the synthesis of 3,4-dihydropyrimidinone derivatives via a three-component Biginelli condensation reactions. The milder and greener protocols of the syntheses of 3,4-dihydropyrimidinone and its derivatives can be obtained by replacing the molecular solvent media by ionic liquid [Bmim]PF 6. Also, further acceleration can be achieved under irradiation conditions. Conclusions

53. 53 Li, M. et. al. J. Mol. Catal. A: Chem. 2006, 258, 133-138. Entry The proportion IL (mmol)solvent Reaction time (hr) Final product (s) Yield (%) 11:1:1.50None6 0 21:1:1.50.1None2190 31:1:1.50.2None2187 41:1:1.50.1Ethanol6181 51:1:1.50.1Water61+228+13 61:1.5:1.50.1None21+260+24

54. 54 Strecker, A. Liebigs Ann. Chem. 1850, 75, 27. Strecker Reaction Hantzsch Reaction Hantzsch, A. Ann. 1882, 215, 1. Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647. Mannich Reaction

55. 55 Ugi Reaction Ugi, I. Angew. Chem. Int. Engl. 1962, 1, 8. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126, 181 Passerini Reaction

56. 56 Kazmaier, U.; Hebach, C. Synlett. 2003, 1591. Miscellaneous Reaction

57. 57 Kappe, C. O. J. Org. Chem. 1997, 62, 7201-7204. The New Mechanism for Biginelli Condensation Reactions

58. 58 The Old Mechanism for Biginelli Condensation Reactions Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55, 2886-2893.

59. 59 Entry substrate solvent Ratio (R 1 :R 2 :R 3 ) time (hr) yield (%) R1R1 R2R2 R3R3 7MeClODMF 1:1:1.55.596 1:1.5:15.554 8CH 2 ClClODMF 1:1:1.5290 1:1.5:1231 1:1:3278 1.5:1:1277 9MeClSDMF 1:1:1.524.572 1:1.5:124.543

60. 60 The Optimized Conditions for Neat Systems Entry substrate solvent time (hr) yield (%) R1R1 R2R2 R3R3 1MeFO--- 2CH 2 ClFO ---194 Ethanol196 3MeFS---2348 4MeHO--- 5CH 2 ClHO--- 6MeHS ---1759 DMF1577

61. 61 The Optimized Conditions for Thiourea/Ethanol System Entry substrate solventmL time (hr) yield (%) R1R1 R2R2 R3R3 3MeFSEthanol1751 6MeHSEthanol1370 9MeClSEthanol11164 12MeOHSEthanol17.535

62. 62 The Optimized Conditions for Thiourea/DMF System EntrysubstratesolventmLtime (hr) yield (%) R1R1 R2R2 R3R3 3MeFSDMF0.5757 6MeHSDMF0.51577 9MeClSDMF0.524.572 12MeOHSDMF0.5874 R 1 = CH 2 Cl > Me Solvent = 0.5 mL >> 1 mL