1. 1 Microwave Assisted Organomolybdenum Lewis Acid Catalyzed Mukaiyama Aldol Reactions Student : Wanchen Lee Supervisor : Prof. Shuchun Joyce Yu 2005 / 07 / 28 Department of Chemistry & Biochemistry Chung Cheng University

2. 2 Mukaiyama Reaction Silyl enol etherKetone or Aldehyde Mukaiyama, T. et. al. Chem. Lett. 1973, 1011-1014

3. 3 Lewis Acid Catalyzed Mukaiyama Reactions I. Traditional Lewis Acids BF 3 O(Et) 2 、 AlCl 3 、 InCl 3 、 SnCl 4 、 TiCl 4 、 FeCl 3 、 ZSM-5 II. Organometallic Lewis Acids a. Early Transition Metals: Sc (III) 、 V(IV) 、 W(0) Chen, C.T. et. al. Synlett. 1999, 816-818 Loh, T. P. et. al. Chem. Commun. 1996, 1819-1820 Saigo, K. et. al. Chem. Lett. 1974, 323-326 Kobayashi, S. et. al. Tetrahedron Lett. 1997, 26, 4559-4562 1-methyl imidazole Mukaiyama, T. et. al. Chem. Lett. 1973, 1011-1014 Sasidharan, M. et. al. Chem. Lett. 2003, 32, 624-625 Takeshi, O. et. al. Tetrahedron Lett. 2002, 43, 8959-8962

4. 4 b. Late Transition Metals: Fe (II) 、 Ru (II) 、 Cu (II) Chem. Commun. 1992, 1634 Bosnich, B. et. al. Tetrahedron Lett. 1992, 39, 5729-5732 Kobayashi, S. et. al. Tetrahedron 1999, 55, 8739-8746 Kobayashi, S. et. al. Green Chem. 1999, 4, 175-177

5. 5 III. Lanthanide Metal Triflate (OTf) Complexes : Yb (III) 、 La (III) 、 Pr (III) 、 Nd (III) 、 Sm (III) 、 Eu (III) 、 Gd (III) 、 Dy (III) 、 Ho (III) 、 Er (III) Kobayashi, S. et. al. J. Org. Chem. 1994, 13, 3590-3596 Kobayashi, S. et. al. Tetrahedron Lett. 1997, 26, 4559-4562

6. 6 IV. Non-Metallic Catalysts a.PS-Formamide b.Ionic liquids c.Brønsted acid ex: citric acid and benzolic acid d. Lewis base ex: lithium acetate 、 potassium acetate and sodium acetate Ogawa, C.; Sugiura, M.; Kobayashi, S. Chem. Commun. 2003, 192-193 Chen, S. L.; Ji, S. J.; Loh, T. P. Tetrahedron Lett. 2004, 375-377 Li, G. L.; Zhao, G. J. Org. Chem. 2005, 70, 4272-4278 Mukaiyama, T.; Kawano, Y.; Fujisawa, H. Chem. Lett. 2005, 34, 88-89

7. 7 Solvent Systems for Mukaiyama Reactions II. Mixed Solvent System EtOH-H 2 O 、 THF-H 2 O I. Molecular Organic Solvents CH 2 Cl 2 、 CH 3 NO 2 、 CH 3 CN 、 DMF III. Green Solvents R.T. Ionic Liquids (BmimPF 6 ) Water

8. 8 Indium Trichloride Catalyzed Mukaiyama Aldol Reaction in Water Loh, T. P. et. al. Chem. Commun. 1996, 1819-1820

9. 9 Sc(OTf) 3 -Catalyzed Aqueous Aldol Reaction in Micellar Systems Kobayashi, S. et. al. Tetrahedron Lett. 1997, 26, 4559-4562

10. 10 Oxovanadium(IV) Biphenolate Catalyzed Mukaiyama Aldol Reaction Chen, C.T. et. al. Synlett. 1999, 816-818 10 mol% L = 1-methyl imidazole

11. 11 [Ru(salen)(NO)H 2 O]SbF 6 Catalyzed Mukaiyama Aldol Reaction Bosnich, B. et. al. Tetrahedron Lett. 1992, 39, 5729-5732

12. 12 Lewis Acid-Surfactant Combined Catalyst Systems Kobayashi, S. et. al. Green Chem. 1999, 4, 175-177 20 mol % (10 mol %)

13. 13 Lanthanide Triflate as Water-Tolerant Lewis Acid Kobayashi, S. et. al. J. Org. Chem. 1994, 13, 3590-3596

14. 14 Polystyrene Supported Formamide Catalyzed Mukaiyama Aldol Reaction Ogawa, C.; Sugiura, M.; Kobayashi, S. Chem. Commun. 2003, 192-193

15. 15 Ionic Liquid Catalyzed Mukaiyama Aldol Reaction Loh, T. P. et. al. Tetrahedron Lett. 2004, 45, 375-377

16. 16 Motivation I. Traditional Lewis acids are difficult to handle II. Lanthanide metals are relatively expensive III. Low Oxidation State Transition Metals a. Relatively high moisture – and oxygen – stability b. Inexpensive c. Tunable electronic and steric environments around metal Lewis acid center IV. Green Chemistry a. Green solvents R.T. ionic liquids (BmimPF 6 ) and H 2 O b. Energy saving Catalysis under microwave irradiation

17. 17 Preparation of Organomolybdenum Catalyst  Thermal Conditions

18. 18  Microwave Flash Heating Conditions

19. 19 Crotonaldehyde-Lewis Acid Adduct Childs, R. F. et. al. Can. J. Chem. 1982, 60, 801

20. 20 chemical shift diff. 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 [OP(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 [P(2-Py) 3 W(CO)(NO) 2 ](BF 4 ) 2 1.18 BF 3 1.17 AlEtCl 2 1.15 [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 1.01 [OP(2-Py) 3 Mo(CO)(NO) 2 ](BF 4 ) 2 0.992 [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

21. 21 Organomolybdenum Lewis Acid Catalyzed Mukaiyama Aldol Reactions under Thermal Conditions

22. 22 Entry R R' Yield (%) CH 3 CN DMF 1 6572 2>9983 36177 47977 55976 65964

23. 23 Entry R R' Yield (%) CH 3 CN DMF 78997 89694 99896 10 45<10 113679 12 7571

24. 24 EntryRR'Yield (%) CH 3 CN DMF EntryRR'Yield (%) CH 3 CN DMF 1 8997 7 7977 2 9694 8 5976 3 9896 9 5964 4 6572 10 4517 5 9983 11 3690 6 6177 12 7571 >≈ > DMF : 3.82 ; 36.7 CH 3 CN : 3.92 ; 37.5

25. 25 Entry R R' Yield (%) 1437228 2>998562 3778439 4879590 5808468 6898627 CH 3 CNDMFCH 3 NO 2

26. 26 Entry R R' Yield (%) 793 87 8929571 9>999565 10366853 11566550 12607647 CH 3 CNDMF CH 3 NO 2

27. 27 EntryRR'Yield (%)EntryRR'Yield (%) 193 877437228 29295708998562 39995659778439 487959010366853 580846811566550 689862712607647 > > DMF : 3.82 ; 36.7 CH 3 CN : 3.92 ; 37.5 CH 3 NO 2 : 3.46 ; 35.87 ≈ CH 3 CN DMFCH 3 NO 2 CH 3 CN DMF CH 3 NO 2

28. 28 Entry R R' Yield (%) 16188 2>9989 36592 48178 54682 67579 CH 3 CN DMF

29. 29 Entry R R' Yield (%) 78191 8>9993 99285 103362 11<1070 12<1075 CH 3 CN DMF

30. 30 Thermal Heating Convection transition Liquid boiling temperature is always lower than surface temperature of container

31. 31 Interactive Characteristic between Materials and Microwave Conductor (Metal Material) Reflective Insulator (Telflon) Transparent Dielectric Materials (Water) Absorptive

32. 32 Mechanism of Microwave Heating Dipole Rotation

33. 33 Ionic Conduction

34. 34 Microwave Flash Heating Microwave energy Liquid raises temperature quickly Digestion bottle

35. 35 Organomolybdenum Lewis Acid Catalyzed Mukaiyama Aldol Reactions under Microwave Irradiation Conditions

36. 36 Seddon, K. R. et. al. Pure Appl. Chem. 2000, 72, 2275–2287 Ionic Liquids

37. 37 Entry R R' Time Yield (%) (min) CH 3 CN DMF BmimPF 6 110648186 210>996785 310817655 410<106670 51069 84 6107077<10

38. 38 Entry R R' Time Yield (%) (min) CH 3 CN DMF BmimPF 6 710248885 810728578 9103495<10 10 667165 1110738084 12107072<10

39. 39 EntryRR'Yield(%) Thermal mw (5hr) (10mim) EntryRR'Yield (%) Thermal mw (5hr) (10mim) 1 9364 7 4324 2 92>99 8 9972 3 9981 9 7734 4 87<10 10 3666 5 8069 11 5673 6 8970 12 6070

40. 40 EntryRR'Yield (%) Thermal mw (5hr) (10mim) EntryRR'Yield (%) Thermal mw (5hr) (10mim) 1 9381 7 7288 2 9567 8 85 3 9576 9 8495 4 66 10 6871 5 8469 11 6580 6 8677 12 7672

41. 41 SolventDipole momentDielectric constant CH 3 NO 2 3.4635.87 CH 3 CN3.9237.5 DMF3.8236.7 BmimPF 6 1.66~1.68 … Dipolemoment and Dielectric Constant of Catalytic Solvent Systems Reactivity under Thermal Conditions: DMF > CH 3 CN > CH 3 NO 2 Reactivity under Microwave : BmimPF 6 > DMF > CH 3 CN

42. 42 Proposed Mechanism σ -donation

43. 43

44. 44 Catalysts A(2-py) 3 M Yield (%) O=P(2-py) 3 Mo93 P(2-py) 3 Mo85 O=P(2-py) 3 W56 P(2-py) 3 W45 Catalytic Reactivity of [A(2-py) 3 M(CO)(NO) 2 ] 2+ on Mukaiyama Aldol Reaction

45. 45 Catalytic Reactivity of [A(2-py) 3 M(CO)(NO) 2 ] 2+ on Diels Alder Reaction Catalysts A(2-py) 3 M Concentration (M)/Time (min)Yield (%) endo: exo O=P(2-py) 3 a W 0.67 / 45 97 (90:10) O=P(2-py) 3 Mo 0.67 / 45 85 (90:10) P(2-py) 3 b W 0.022 / 30 87 (94:6) HO-C(2-py) 3 c W 2.256*10 -3 / 24 66 (91:9) a: 陳宜宏碩士論文 “ 水溶性有機鎢金屬路易士酸在綠色溶劑及微波中對於 Diels-Alde 反應的影響 ” 中正大學化學研究所, 2003 c: 施子芳碩士論文 “ 有機鎢金屬路易士酸的合成及其催化反應活性之探 中正大學化學研究所, 1998 b: 傅耀賢博士論文 “ 過渡金屬錯合物觸媒的合成、催化活性以及動力學研究 中正大學化學研究所, 2001

46. 46 Conclusions 1. 本實驗成功地合成出有機金屬鉬路易士酸 [O=P(2-py) 3 Mo(CO)(NO) 2 ](BF 4 ) 2 ， 並將催化劑應用於 Mukaiyama 醛醇反應，分別在傳統加熱與微波照射系統反 應條件下，對一系列的 Mukaiyama 醛醇反應具有很好的催化效果。 2. 利用微波系統取代傳統加熱法可有效地縮短反應時間與提升能源效率。 3.Mukaiyama 醛醇反應在不同溶劑系統下，皆有很好的催化效果，且當溶劑系 統為低極性與低介電常數時，催化效果比較好。 4. 本實驗利用綠色溶劑室溫離子液體 (BmimPF 6 ) 取代有機溶劑的使用，可有效 地進行 Mukaiyama 醛醇反應，同時也符合綠色化學的宗旨。 5.Mukaiyama 醛醇反應與 Diels-Alder 加成反應對 [A(2-py) 3 M(CO)(NO) 2 ] 2+ 催化 劑之催化效率，與 A 和 M (A = HO-C 、 P 、 O=P 和 M = Mo 、 W) 有關。對 Mukaiyama 醛醇反應而言，當 M = Mo 時，具較好的催化效果 ; 當 A= P(O) 時， 具較好的催化 效果。對 Diels-Alder 加成反應而言，當 M = W 時，具較好的 催化效果 ; 當 A = P 時，具較好的催化效果。 6. 本實驗合成出具水溶性的催化劑有機金屬鉬路易士酸，且在水中的溶解度可 達 23 g/L ，因此，可進一步將有機金屬鉬路易士酸應用於水相的催化系統。