Recyclable Organomolybdenum Lewis Acid Catalyst and Microwave Assisted Pechmann Condensation Reactions Student : Chia-Pei Chung Supervisor : Prof. Shuchun Joyce Yu 2006 / 07 / 20 Department of Chemistry & Biochemistry Chung Cheng University

Pechmann Condensation The Pechmann condensation is a synthesis of coumarins, starting from a phenol and a ester or carboxylic acid containing a β-carbonyl group. Coumarin synthesis Woodruff, E. H. Organic Syntheses, 1944, 24, 69. Pechmann, H. V.; Duisberg, C. Ber. 1883, 16, 2119.

Coumarins present in seeds, root, and leaves of many plant species As additives to food and cosmetics, optical brightening agents, and dispersed fluorescent and laser dyes has clinical value as the precursor for several anticoagulants, antibacterial, anticancer can be synthesized by one of such methods as the Claisen rearrangement, Perkin reaction, Knoevenagel condensation, Reformatsky reaction, Wittig reactions, as well as the Pechmann Condensation reaction

Acidic Catalysts for Pechmann Condensation Proton Donor Brønsted Acids H2SO4, HCl, TFA (trifluoroacetic acid) Pechmann V. H.; Duisberg C. Chem. Ber. 1884, 17, 929. Woods, L. L.; Sapp, J. J. Org. Chem. 1962, 27, 3703. Traditional Lewis Acid Catalysts InCl3, AlCl3, BiCl3, FeCl3, TiCl4, ZrCl4, P2O5, PCl3, POCl3 Bose, D. S.; Rudradas, A. P.; Babu, M. H. Tetrahedron Lett. 2002, 43, 9195. S. K. De, R. A. Gibbs, Synthesis, 2005, 1231. Simmonis, H.; Remmert, P. Chem. Ber. 1914, 47, 2229. Robertson, A.; Sandrock, W. F.; Henry, C. B. J. Chem. Soc. 1931, 2426.

Acidic Catalysts for Pechmann Condensation -- continued Lanthanide Lewis Acid Catalysts Yb(III), Sm(III) Fillion, E. et. al. J. Org. Chem. 2006, 71, 409. Bahekar, S. S.; Shinde, D. B. Tetrahedron Lett. 2004, 45, 7999. Others graphite / montmorillonite K10 Amberlyst-15, Nafion Heteropoly acid (H6P2W18O62．24H2O) Fre`re, S.; Thie´ry, V.; Besson, T. Tetrahedron Lett. 2001, 42, 2791. Sabou, R.; Hoelderich, W. F.; Ramprasad, D.; Weinand, R. J. Catal. 2005, 232, 34. Laufer, M. C.; Hausmann, H.; Hölderich, W. F. J. Catal. 2003, 218, 315. Autino, J. C. et. al. Tetrahedron Lett. 2004, 45, 8935.

TFA Catalyzed Pechmann Condensation Phenol used: Phloroglucinol, 2-Methylresorcinol, Resorcinol, Orcinol, 4-Chlororesorcinol, Pyrogallol, 3-Hydroxydiphenyl amine β-carbonyl esters used: Ethyl benzoyl acetate Woods, L. L.; Sapp, J. J. Org. Chem. 1962, 27, 3703.

Indium(III) Chloride Catalyzed Pechmann Condensation Phenol used: Resorcinol, Orcinol, 4-, Pyrogallol, 3-Hydroxydiphenyl amine, 3-methoxyphenol, 1,3,5-trihydroxybenzene, phenol, 1-naphthol Bose, D. S.; Rudradas, A. P.; Babu, M. H. Tetrahedron Lett. 2002, 43, 9195.

POCl3 Catalyzed Pechmann Condensation in Neutral Ionic Liquids Phenol used: Resorcinol, 2-Methylresorcinol, Orcinol, Pyrogallol, 1,3,5-trihydroxybenzene, 2',4'-Dihydroxyacetophenone Potdar, M. K.; Rasalkar, M. S.; Mohile, S. S.; Salunkhe, M. M. J. Mol. Catal. A Chem. 2005, 235, 249.

Yb(OTf)3 Catalyzed Pechmann Condensation Phenol used: 3,5-dimethoxyphenol, 3,4-dimethoxyphenol, sesamol, 3-methoxy-2-methylphenol Fillion, E. et. al. J. Org. Chem. 2006, 71, 409.

Microwave acceleration of the Pechmann reaction on graphite/montmorillonite K10 Experimental conditions Conventional heating Microwave irradiation Reaction time (min) Yield (%) Neat (fusion) 120 36 85 39 Support: graphite 44 50 Support: graphite:K10 (2:1)a, b 66 64 30 a. No modifications were observed when a preliminary activation (2 h at 180°C) of the clay was realized. b. No significant results were observed in the absence of graphite (montmorillonite K10 + phenol + b-ketoester). Fre`re, S.; Thie´ry, V.; Besson, T. Tetrahedron Lett. 2001, 42, 2791.

Wells–Dawson heteropolyacid Catalyzed Pechmann Condensation Phenol used: resorcinol, phloroglucinol, 3-methoxyphenol, pyrogallol, 3,4-dimethylphenol, 3-methylphenol, orcinol, 1-naphthol Romanelli,G. P.; Bennardi, D.; Ruiz, D. M.; Baronetti, G.; Thomas, H. J.; Autino, J. C. Tetrahedron Lett. 2004, 45, 8935.

Synthesis of Coumarins by Grubbs’ Catalyst Van, T. N.; Debenedetti, S.; Kimpe, N. D. Tetrahedron Lett. 2003, 44, 4199.

Disadvantages of Brønsted Acids Proton Donor Brønsted Acids Catalysts have to be used in excess, for example sulfuric acid, 10–12 equiv, trifluoroacetic acid, 3–4 equiv. Longer reaction time and very often temperatures to be excess 150 oC and above. 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 Traditional and Lanthanide Lewis Acid 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.

Motivation Low Oxidation State Transition Metals Green Chemistry Relatively high moisture – and oxygen – stability Inexpensive Tunable electronic and steric environments around metal center Green Chemistry Greener solvents R.T. ionic liquids, [Bmim]PF6 Energy saving Catalysis under microwave flash heating replace thermal heating Recyclable catalyst

Preparation of Organomolybdenum Catalyst Thermal conditions

Crotonaldehyde-Lewis Acid Adduct 1H chemical shift H1 H2 H3 H4 crotonaldehyde crotonaldehyde + Cat. 9.41 6.08 7.01 2.03 9.89 6.71 8.14 2.32 Chemical shift diff. 0.48 0.63 1.13 0.29 Childs, R. F. et. al. Can. J. Chem. 1982, 60, 801.

Lewis acid △δ on H3 (ppm) BBr3 1.49 AlCl3 1.23 [OP(2-Py)3W(CO)(NO)2](SbF6)2 [OP(2-Py)3W(CO)(NO)2](BF4)2 1.22 [P(2-Py)3W(CO)(NO)2](SbF6)2 1.21 [HOC(2-Py)3W(CO)(NO)2](SbF6)2 1.19 [P(2-Py)3W(CO)(NO)2](BF4)2 1.18 BF3 1.17 AlEtCl2 1.15 [OP(2-Py)3Mo(CO)(NO)2](BF4)2 1.13 [HC(2-Py)3Mo(CO)(NO)2](SbF6)2 1.05 TiCl4 1.03 [P(2-Py)3Mo(CO)(NO)2](BF4)2 0.99 [Me3P(CO)3(NO)W]+ 0.93 SnCl4 0.87 [CpMo(CO)2]+(PF6) 0.70 Et3Al 0.63 [CpFe(CO)2]+BF4 0.54

Spectral Data of CO Coordinated Catalysts Organometallic compound chemical shift (13C NMR) IR absorption band [OP(2-py)3W(CO)(NO)2](BF4)2 190.5 ppm 2156 cm-1/ nujol [P(2-py)3W(CO)(NO)2](SbF6)2 192.0 ppm 2143 cm-1/ nujol [P(2-py)3W(CO)(NO)2](BF4)2 192.2 ppm 2148 cm-1/KBr Vapor CO 2143 cm-1 Mo(CO)6 202.3 ppm 2115,1983 cm-1/nujol W(CO)6 192.1 ppm 2110,1980 cm-1/KBr [OP(2-py)3Mo(CO)(NO)2](BF4)2 223.0 ppm 2060 cm-1/KBr [P(2-py)3Mo(CO)(NO)2](BF4)2 222.0 ppm 2046cm-1/KBr OP(2-py)3Mo(CO)3 227.5 ppm 1910,1806 cm-1/nujol P(2-py)3Mo(CO)3 227.3 ppm 1908,1797cm-1/CD3Cl OP(2-py)3W(CO)3 222.1 ppm 1890 cm-1/ nujol P(2-py)3W(CO)3 222.9 ppm 1880,1762 cm-1/KBr

Organomolybdenum Lewis Acid Catalyzed Pechmann Condensation Thermal conditions Solvent system: [bmim]PF6 or CH3CN or DMF or CH3NO2 or THF

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

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

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.

Entry Phenol Yield (%) 1 n. d. 6 11 2 7 12 3 8 13 4 9 5 10

Entry Phenol Time Yield (%) (h) 1 1 h 98 8 10 h 82 2 25 min 80 9 4 h 84 3 15 75 10 24 h 81 4 69 11 n. d. 5 12 6 93 13 7 5 h 91

Entry Phenol Time Yield (%) [Bmim]PF6 CH3NO2 THF CH3CN DMF 1 1 h 91 64 32 9 n. d. 2 24 h -- 86 54 24 3 25 min 84 (20 min) 12 5 4 7 h 82 42 (68)* 40 (69)* (5)* 15 (10 min) 19 13 6 2 h 83 81 (79)* *After reacting 24 h, the products’ yield

Entry Phenol Time Yield (%) [Bmim]PF6 CH3NO2 THF CH3CN DMF 7 15 min 84 21 18 16 n. d. 8 2 h -- 82 80 (5)* 9 4 h (20 min) 22 10 24 h 60 26 5 *After reacting 24 h, the products’ yield

Entry Phenol Time Yield (%) [Bmim]PF6 CH3NO2 THF CH3CN DMF 11 10 h 92 (6 h) 31 21 6 n. d. 12 24 h -- 54 40 13 5 h 93 (1 h) 43 14 82 68 52 15 88 (5 h) 18 10 16 34 24 28

Entry Phenol Time Yield (%) [Bmim]PF6 CH3NO2 THF CH3CN DMF 17 4 h 92 (2 h) 75 64 65 61 18 6 h -- 88 90 77 19 8 h 82 20 10 h 16 10 5 n. d. 21 24 h 38 23 14

Entry Phenol Time Yield (%) [Bmim]PF6 CH3NO2 THF CH3CN DMF 22 24 h n. d. 23 24

1 8 2 9 3 10 4 11 5 12 6 13 7 Entry Phenol Yield (%) neat [Bmim]PF6 98 69 (20 min) 8 82 (10 h) 88 (5 h) 2 80 (25 min) 84 (20 min) 9 (4 h) 92 (2 h) 3 75 (15 min) (10 min) 10 81 (24h) 4 69 11 n. d. (24 h) 5 12 6 93 (6 h) 13 7 91 93 (1 h) 71 (20 min)

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

Mechanism of Microwave Heating Dipole Rotation

Ionic Conduction

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

Microwave Flash Heating Microwave energy Digestion bottle Liquid raises temperature quickly

Preparation of Organomolybdenum Catalyst Microwave Flash Heating Conditions

Organomolybdenum Lewis Acid Catalyzed Pechmann Condensation Microwave Flash Heating Conditions

1 8 2 9 3 10 4 11 5 12 6 13 7 Entry Phenol Yield (%) neat [Bmim]PF6 93 (7 min) 86 8 80 (15 min) 46 (17 min) 2 92 (5 min) 83 (3 min) 9 (10 min) 69 3 89 91 (1 min) 10 66 17 4 (6 min) 90 (2 min) 11 n. d. 5 73 84 12 6 51 13 7 68

Microwave Flash Heating and Power Supply Curve

Entry Phenol Thermal / Yield (%) MW / Yield (%) neat [Bmim]PF6 1 98 (1 h) 91 (1 h) 69 (20 min) 93 (7 min) 86 (7 min) 94 (8 min) 2 80 (25 min) 84 (20 min) 92 (5 min) 83 (3 min) 3 75 (15 min) 82 (10 min) 89 91 (1 min) 4 69 86 (4 min) 90 (2 min) 5 (4 h) 73

Entry Phenol Thermal / Yield (%) MW / Yield (%) neat [Bmim]PF6 6 93 (10 h) 92 (6 h) (17 min) 51 7 91 (5 h) 93 (1 h) 71 (20 min) (15 min) 68 8 82 88 80 46 9 84 (4 h) 92 (2 h) 86 (10 min) 69 10 81 (24 h) 66 17

Recyclability of Organomolybdenum Lewis Acid Catalyst Substrate Adduct Added Extraction CHCl3 Catalyst Solution Ionic Liquid [Bmim]PF6

Recyclability of Organomolybdenum Lewis Acid Catalyst in [bmim]PF6

Proposed Mechanism

Proposed Mechanism

Catalytic Reactivity of [A(2-py)3M(CO)(NO)2]2+ on Pechmann Condensation Catalysts Yield (%) A(2-py)3 M O=P(2-py)3 Mo 98 P(2-py)3 82 W 74 71

Catalytic Reactivity of [A(2-py)3M(CO)(NO)2]2+ on Mukaiyama Aldol Reaction Catalysts Yield (%) A(2-py)3 M O=P(2-py)3 Mo 93 P(2-py)3 85 W 56 45 李婉甄碩士論文 ‘有機鉬金屬路易士酸在微波中對於Mukaiyama Aldol反應催化活性之探討’ 中正大學化學研究所, 2005.

Catalytic Reactivity of [A(2-py)3M(CO)(NO)2]2+ on Diels Alder Reaction Catalysts Concentration (M) /Time (min) Yield (%) (endo: exo) A(2-py)3 M O=P(2-py)3a W 0.67 / 45 97 (90:10) O=P(2-py)3b Mo 85 (90:10) P(2-py)3c 0.022 / 30 87 (94:6) 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. b:李婉甄碩士論文 ‘有機鉬金屬路易士酸在微波中對於Mukaiyama Aldol反應催化活性之探討’ 中正大學化學研究所, 2005. c: 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

Conclusions We have successfully demonstrated the catalytic activity of [O=P(2-py)3Mo(CO)(NO)2](BF4)2 for the synthesis of a variety of coumarins under solvent-free and ionic liquid system ([Bmim]PF6) conditions. This practical and simple method led to good yields of the coumarin derivatives under mild conditions and within short times. The time economy, along with the conservation of the organomolybdenum Lewis acid catalyst activity and the high recovery of the Lewis acid catalyst, play for both low environmental impact and low cost. Other green advantages of the procedure are the low formation of wastes, easy purification; and principally, the replacement of corrosive and environmental unfriendly acids.

Conclusions The successful use of microwave irradiation in providing this rapid and direct route to coumarins in comparison to classical procedures contributes to confirming the participation of specific effects in some microwave-assisted organic synthesis. Because the [O=P(2-py)3Mo(CO)(NO)2](BF4)2 catalyst is relatively high moisture – and oxygen – stability, we use neutral ionic liquids, [Bmim]PF6, for Pechmann condensation as a recyclable media, and still have good yield for several times.

Entry Phenol Thermal / Yield (%) MW / Yield (%) neat [Bmim]PF6 11 n. d. (24 h) (17 min) 12 13