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 Mukaiyama Reaction Silyl enol etherKetone or Aldehyde Mukaiyama, T. et. al. Chem. Lett. 1973,

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, Loh, T. P. et. al. Chem. Commun. 1996, Saigo, K. et. al. Chem. Lett. 1974, Kobayashi, S. et. al. Tetrahedron Lett. 1997, 26, methyl imidazole Mukaiyama, T. et. al. Chem. Lett. 1973, Sasidharan, M. et. al. Chem. Lett. 2003, 32, Takeshi, O. et. al. Tetrahedron Lett. 2002, 43,

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

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, Kobayashi, S. et. al. Tetrahedron Lett. 1997, 26,

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, Chen, S. L.; Ji, S. J.; Loh, T. P. Tetrahedron Lett. 2004, Li, G. L.; Zhao, G. J. Org. Chem. 2005, 70, Mukaiyama, T.; Kawano, Y.; Fujisawa, H. Chem. Lett. 2005, 34, 88-89

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

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

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

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

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

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

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

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

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 Preparation of Organomolybdenum Catalyst  Thermal Conditions

18  Microwave Flash Heating Conditions

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

20 chemical shift diff. Lewis acid △ δ on H 3 (ppm) BBr AlCl [OP(2-Py) 3 W(CO)(NO) 2 ](SbF 6 ) [OP(2-Py) 3 W(CO)(NO) 2 ](BF 4 ) [OP(2-Py) 3 W(CO)(NO) 2 ](SbF 6 ) [HOC(2-Py) 3 W(CO)(NO) 2 ](SbF 6 ) [P(2-Py) 3 W(CO)(NO) 2 ](BF 4 ) BF AlEtCl [HC(2-Py) 3 Mo(CO)(NO) 2 ](SbF 6 ) TiCl [P(2-Py) 3 Mo(CO)(NO) 2 ](BF 4 ) [OP(2-Py) 3 Mo(CO)(NO) 2 ](BF 4 ) [Me 3 P(CO) 3 (NO)W] SnCl [CpMo(CO) 2 ] + (PF 6 )0.70 Et 3 Al0.63 [CpFe(CO) 2 ] + BF

21 Organomolybdenum Lewis Acid Catalyzed Mukaiyama Aldol Reactions under Thermal Conditions

22 Entry R R' Yield (%) CH 3 CN DMF >

23 Entry R R' Yield (%) CH 3 CN DMF <

24 EntryRR'Yield (%) CH 3 CN DMF EntryRR'Yield (%) CH 3 CN DMF >≈ > DMF : 3.82 ; 36.7 CH 3 CN : 3.92 ; 37.5

25 Entry R R' Yield (%) > CH 3 CNDMFCH 3 NO 2

26 Entry R R' Yield (%) > CH 3 CNDMF CH 3 NO 2

27 EntryRR'Yield (%)EntryRR'Yield (%) > > DMF : 3.82 ; 36.7 CH 3 CN : 3.92 ; 37.5 CH 3 NO 2 : 3.46 ; ≈ CH 3 CN DMFCH 3 NO 2 CH 3 CN DMF CH 3 NO 2

28 Entry R R' Yield (%) > CH 3 CN DMF

29 Entry R R' Yield (%) > < <1075 CH 3 CN DMF

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

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

32 Mechanism of Microwave Heating Dipole Rotation

33 Ionic Conduction

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

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

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

37 Entry R R' Time Yield (%) (min) CH 3 CN DMF BmimPF > < <10

38 Entry R R' Time Yield (%) (min) CH 3 CN DMF BmimPF < <10

39 EntryRR'Yield(%) Thermal mw (5hr) (10mim) EntryRR'Yield (%) Thermal mw (5hr) (10mim) > <

40 EntryRR'Yield (%) Thermal mw (5hr) (10mim) EntryRR'Yield (%) Thermal mw (5hr) (10mim)

41 SolventDipole momentDielectric constant CH 3 NO CH 3 CN DMF BmimPF ~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 Proposed Mechanism σ -donation

43

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 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 / (90:10) O=P(2-py) 3 Mo 0.67 / (90:10) P(2-py) 3 b W / (94:6) HO-C(2-py) 3 c W 2.256*10 -3 / (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 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。