Copper(II)-Mediated 2-Quinoxalinol Salens in Alcohol Oxidation and C-H Activation: A Greener Approach by Weerasiri Arachchige Kushan Chandana Weerasiri A dissertation submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Auburn, Alabama August 2, 2014 Keywords: 2-Quinoxalinol, Copper, Oxidation, Alcohols, C-H Activation Copyright 2014 by Weerasiri Arachchige Kushan Chandana Weerasiri Approved by Anne E. V. Gorden, Chair, Associate Professor of Chemistry and Biochemistry Stewart Schneller, Professor of Chemistry and Biochemistry Orlando Acevedo, Associate Professor of Chemistry and Biochemistry Edward Parish, Professor of Chemistry and Biochemistry ii Abstract Reduction of waste production in chemical processes is the idea of greener chemistry by using less toxic or benign methods and eliminating purification steps. Because of this, using a catalytic rather than stoichiometric method is much preferred. In this dissertation, 2-quinoxalinol salen (salqu) copper(II) complexes are used in selective oxidation of alcohols and in C-H functionalization. The oxidation of propargylic alcohols was investigated using tert-butyl hydroperoxide (TBHP) as the oxidant. This catalytic system produced excellent yields (up to 99 %) of ?,?-acetylenic carbonyl compounds from a wide variety of substrates within a short reaction time (1 h). This catalytic protocol can also be used with propargylic alcohols that contain alkyl groups in the ?-position, which can be difficult to oxidize selectively using other available oxidation methods. Excellent selectivity was achieved for the oxidation of propargylic alcohols over that of isolated hydroxy groups, triple bonds or propargylic methylene groups. The work continued using a water-soluble version of salqu copper(II) complex considering the principles of green and sustainable chemistry. First, the water-soluble salqu copper(II) complex was designed and then synthesized in multistep organic synthesis. It was found that this catalytic system is capable of performing selective oxidation of propargylic, benzylic and allylic alcohols in water effectively. This reaction constitutes of a rare example of propargylic alcohol oxidation in water, and this process is iii considered greener through the elimination of the use of hazardous organic solvents, toxic metals, and high catalyst loading. The oxidation occurs in good yields (up to 99 %) with excellent selectivity for propargylic, benzylic and allylic alcohols, and the reaction is thought to go through a radical pathway. It was also found that the water-soluble salqu copper(II) complex is an efficient catalyst for the selective functionalization of benzylic and allylic C-H bonds to the corresponding carbonyl compounds in the presence of oxidant TBHP. The reactions proceed with very low catalyst loading (1 mol %) in water and good yields (up to 96 %) can be achieved for a wide variety of substrates. Excellent selectivity was also achieved with this catalytic protocol for the activation of benzylic and allylic C(sp3)-H bonds. Allylic C-H activations catalyzed by 2-quinoxalinol salen copper(II) complex was also investigated under molecular oxygen to see the potential of possible replacement of TBHP with molecular oxygen. It was found that TBHP can not be substituted completely by dioxygen, but it is possible to reduce the amount of TBHP by introducing high pressures of oxygen. iv Acknowledgments First, I would like to thank my advisor Dr. Anne Gorden for all the advices and support given throughout my doctoral studies at Auburn University. I would also like to thank my committee members, Dr. Stewart Schneller, Dr. Orlando Acevedo, Dr. Edward Parish and Dr. Robert ?Rusty? Arnold for their help and suggestions given in preparing my dissertation. I appreciate the help and support given by Dr. John Gorden. I thank Dr. Christian Goldsmith and his group for the support given in GC analysis. I also appreciate the help given by Dr. Yonnie Wu in LC-MS and GC-MS analysis, Dr. Michael Meadows in NMR analysis and Dr. Eduardus Duin in EPR analysis. I appreciate the help given by my lab-mates Dr. Yuancheng Li, Branson Maynard, Michael Devore, Nicholas Klann, Charmaine Tutson, Chasity Ward, Emily Hardy, Maya West and undergraduates, faculty members, staff, colleagues and department of chemistry and biochemistry. Last but not least, I would like to thank my family and my friends for their help, support and love. v Adapted with permission from Weerasiri, Kushan C.; Gorden, Anne. E. V. Eur. J. Org. Chem., 2013, 1546-1550. Copyright (2013) Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. vi Table of Contents Abstract ............................................................................................................................... ii Acknowledgments.............................................................................................................. iv List of Tables ..................................................................................................................... vi List of Figures ................................................................................................................... vii List of Schemes ................................................................................................................ viii Chapter 1 Introduction .........................................................................................................1 Chapter 2 Propargylic Alcohol Oxidation .........................................................................14 Chapter 3 Alcohol Oxidation in Water ..............................................................................27 Chapter 4 C-H Activation in Water ...................................................................................39 Chapter 5 C-H Activation using Salqu Copper(II) and Molecular Oxygen ......................47 Chapter 6 Conclusion and Future Work ............................................................................56 Chapter 7 Experimental Section ........................................................................................66 References ..........................................................................................................................83 vii List of Tables Table 2.1 Oxidation of 1-phenyl-2-propyn-1-ol ...............................................................17 Table 2.2 Effects of solvent ..............................................................................................19 Table 2.3 Oxidation of propargylic alcohols with 1 mol % catalyst .................................22 Table 3.1 Effect of reaction condition ..............................................................................33 Table 3.2 Substrate scope ..................................................................................................34 Table 4.1 Time profile of the reaction ..............................................................................41 Table 4.2 Substrate scope .................................................................................................43 Table 5.1 Effect of dioxygen .............................................................................................50 Table 5.2 Effect of TBHP equivalent ................................................................................51 Table 5.3 Yields of 3-acetyl-2-cyclohexen-1-one under different reaction conditions .....53 Table 5.4 Time profile .......................................................................................................54 viii List of Figures Figure 1.1 Examples of copper complexes with O-, N-, N, O- and Schiff base systems ....5 Figure 1.2 Basic structure of salen ligands ..........................................................................7 Figure 1.3 Solid supported copper complexes ...................................................................10 Figure 1.4 Structures of quinoxaline, 2-quinoxalinol and 2-quinoxalinol salen (salqu) ...11 Figure 1.5 Structures of 2-quinoxalinol salen (salqu) copper(II) complexes ....................12 Figure 2.1 GC yields and conversions with the oxidant ratio ............................................18 Figure 2.2 Time profile of oxidation of 1-phenyl-2-propyn-1-ol ......................................20 Figure 2.3 Correlation between log (kX/kH) and para-position Hammett constants ..........25 Figure 3.1 Basic structure of 2-quinoxalinol salen copper(II) complex ............................28 Figure 3.2 Time profile of the reaction ..............................................................................30 Figure 3.3 Effect of Oxidant ..............................................................................................31 Figure 3.4 Effect of TBHP ratio ........................................................................................32 Figure 4.1 Effect of TBHP ratio ........................................................................................42 Figure 5.1 Effect of TBHP equivalent ...............................................................................52 Figure 6.1 Structures of 2-quinoxalinol salen copper(II) complexes ................................56 Figure 6.2 Examples for modified salqu ligands ...............................................................61 Figure 6.3 Salqu ligand with a flexible arm .......................................................................62 Figure 6.4 Examples for solid supported salqu copper(II) complexes ..............................64 ix List of Schemes Scheme 2.1 Oxidation of Propargylic Alcohols ................................................................14 Scheme 2.2 Synthesis of 2-quinoxalinol salen copper(II) complex ..................................16 Scheme 3.1 Synthesis of sulfonated 2-quinoxalinol salen copper(II) complex .................29 Scheme 3.2 Oxidation of 1-phenyl-2-propyn-1-ol.............................................................30 Scheme 3.3 Decomposition of the catalyst-substrate intermediate ...................................37 Scheme 4.1 Synthesis of sulfonated 2-quinoxalinol salen copper(II) complex .................40 Scheme 4.2 Oxidation of diphenylmethane .......................................................................41 Scheme 5.1 Allylic oxidation catalyzed by Cu(II) salqu ...................................................48 Scheme 5.2 Proposed catalytic cycle for allylic oxidation catalyzed by Cu(II) salqu .......49 Scheme 5.3 Oxidation of 1-acetyl-1-cyclohexene catalyzed by Cu(II) salqu ...................50 Scheme 6.1 Retrosynthetic analysis ...................................................................................63 1 Chapter 1 Introduction Because of increasing environmental issues associated with chemical reactions, chemists have to rethink finding ways to make catalytic reactions environmentally more benign. A perfect case for a chemical process would be conversion of neat reactants into 100 % products at room temperature and pressure without involvement of any toxic chemicals, but as we all know, this is not possible in reality. Thus, necessary steps need to be taken to reduce or eliminate the use or generation of hazardous chemical substances in designing chemical products and processes. In this regard, Paul Anastas and John Warner developed the 12 principles of green chemistry in 1998.1 These principles can be summarized as: 1. Prevention 2. Atom economy 3. Less hazardous chemical syntheses 4. Designing safer chemicals 5. Safer solvents and auxiliaries 6. Design for energy efficiency 2 7. Use of renewable feedstocks 8. Reduce derivatives 9. Catalysis 10. Design for degradation 11. Real-time analysis for pollution prevention 12. Inherently safer chemistry for accident1 Scientists have made great strides towards realizing these goals as green chemistry has emerged as an important aspect of all chemistry.2 One example is the development of the field of catalysis in recent years. This is a good approach towards advancing green chemistry as catalytic reagents are superior to stoichiometric reagents helping to reduce energy, cost and waste production.3 A catalyst is a compound that increases the rate of a reaction by lowering the activation energy, but that is not consumed during the reaction.4 Thus, catalysts can be used in small quantities and recycled. Nature uses its own catalysts called enzymes to catalyze reactions with high selectivity in biological systems. Catalysts can be categorized into two major classes: homogeneous and heterogeneous.4 In organic chemistry, catalysts can be found as metal based catalysts and metal free catalysts.5 Metal based catalysts consist of metal/metal salts or organometallic compounds and metal free catalysts are known as organocatalyts consisting of carbon, hydrogen, nitrogen, oxygen and other non metal elements.5 Among those, transition metal catalysts play an important role in organic chemistry.6 Oxidation of organic compounds is an important class of reaction in organic chemistry as it can convert chemically less reactive organic substrates into more reactive 3 chemical compounds of a high oxidation state such as alcohols and carbonyl compounds. Traditional methods for the oxidation of organic compounds involve high-valent metal compounds such as MnO2 and CrO3.7 These compounds are required in stoichiometric amounts and generate lots of toxic waste causing heavy burden to the environment and becoming less popular. Thus, catalytic oxidation of organic substrates has attracted much attention in recent years. In particular, different catalytic methods using transition metals have been developed for the oxidation of organic compounds. Notably, these transition metal catalysts involve metals such as V,8 Cr,9 Mn,6 Fe,10 Co,11 Cu,12 Ru,13 Rh,14 Pd,15 and Ir.16 Among numerous types of transition metal catalyzed oxidations, copper- mediated reactions are of great interest due to their low toxicity, environmental abundance and effectiveness as a catalyst. Different oxidation states of copper (Cu0, CuI, CuII, CuIII) contributes to its chemistry and that makes it easier for copper to be involved in both one-electron and two-electron pathways via organocopper intermediates in oxidation reactions. This allows copper to be an effective catalyst in a broad range of oxidation reactions including reactions in living organisms.17 Copper enzymes have been observed in catalyzing oxidation reactions in biological systems.18 These enzymes can function as oxygenases and oxidases. Oxygenases act as a source of oxygen atoms that are installed into the product and oxidases act as electron acceptors to oxidize the substrates.19,20 Oxygenases are categorized as monooxygenases and dioxygenases depending on whether they incorporate one or two oxygen atoms into their products. For instance, phenylalanine monooxygenase and dopamine ??monooxygenase are two mammalian copper enzymes, 4 which are responsible for the synthesis of neurotransmitters. Phenylalanine monooxygenase converts phenylalanine into tyrosine, which is an essential precursor for the synthesis of dopamine.19 Dopamine ??monooxygenase catalyzes the oxidation of dopamine into noradrenaline. Both dopamine and noradrinaline are important neurotransmitters required for the proper brain function.21 Methane monooxygenase and ammonia monooxygenase are two oxygenases found in micro-organisms. The former is found in methanotrophic bacteria as an integral membrane protein, which is responsible for the C-H activation of methane to methanol.18 The latter is also a membrane-bound protein, which catalyzes the oxidation of ammonia to hydroxylamine.22 These ammonia- oxidizing bacteria are important micro-organisms involved in the nitrogen cycle.22 Copper containing dioxygenases such as quercetinase and indole dioxygenase play a key role in the degradation of aromatic compounds in organisms.23,24 Meanwhile, oxidases catalyze the reduction of O2 to water or hydrogenperoxide and the oxidation of organic substrates. Galactose oxidase is a copper containing metalloenzyme, which catalyzes the oxidation of primary amines to aldehydes.20 Copper amine oxidases convert primary amines into aldehydes in plants, animals and micro-organisms.25 It is challenging to mimic the chemistry of copper oxidation reactions in nature; however, copper salts and copper complexes have been used widely as effective catalysts in oxidation reactions such as epoxidation,26-28 oxidation of alkanes,29-31 alkenes32,33 and alkynes,34-37 benzyllic oxidation,38-40 arene oxidation,41-44 alcohol oxidation,45-48 reaction of carbonyls,49 sulfoxidation,50 reactions of phenols,51 reactions of amines,52 reactions of enamines53 and reactions of anilines.54 These reactions are conducted in the presence of various oxidizing agents such as peroxides,55 peroxyesters,56 m-CPBA57 (meta- 5 chloroperoxybenzoic acid), Oxone58 (potassium peroxymonosulfate) and DDQ59 (2,3- dichloro-5,6-dicyanobenzoquinone); however benign oxidants like tert-butyl hydroperoxide (TBHP), hydrogen peroxide and molecular oxygen have taken much attention in recent years.60 Figure 1.1. Examples of copper complexes with O-donor systems,61 N-donor systems,62 N, O-donor systems47 and Schiff base systems63 6 The copper based catalytic oxidation systems have been studied using various copper salts such as CuCl,45 CuBr,35 CuCl2,32 CuBr2,64 Cu(OH)2,65 Cu(ClO4)2,66 Cu(OAc)2,67 Cu(OTf)233 and Cu(NO3)2.68 These ligand free copper systems are always handy as they are commercially available and cheap; however, copper-ligand systems are of great interest as they help to enhance overall efficiency of the reaction by increased solubility, selectivity and reduced catalyst loading. For this purpose, different ligand systems have been incorporated with copper: O-donor systems,61 N-donor systems,62 N, O-donor systems47 and Schiff base systems63 (Figure 1.1). O-donor systems can derive from ligands containing carboxylates, alkoxides or N-oxides. Ligands bearing N- containing groups such as pyridine, pyrole, pyrazole, imidazole, triazole and indole can act as N-donor systems. Meanwhile, ligands with both of these oxygen and nitrogen moieties can serve as N, O-donor systems. Schiff bases are another type of ligand systems incorporated into copper complexes. Schiff base, named after German chemist Hugo Schiff, is a compound containing carbon-nitrogen double bond where N-atom is attached to an aryl or alkyl group except hydrogen. These compounds are easy to synthesize and capable of making stable complexes with metal ions.69 One type of Schiff base which has attracted much attention is the salen ligand (Figure 1.2). Salen ligands are a fundamental class of organic compounds known since 1933.70 The name salen stems from the two precursors used to synthesize the ligand: salicylaldehyde and ethylene diamine. Salen ligands contain two Schiff bases resulting in a tetradentate chelating ligand with O, N, N, O type donor system. Two O- units derive from the salicylaldehyde and the two N- units derive from the ethylene diamine, which is involved in the Schiff base. 7 Figure 1.2. Basic structure of salen ligand Salen ligands make very stable complexes with copper and most of the other transitions metals including Ti, V, Cr, Mn, Fe, Co, Ni, Zn, Zr, Ru and Pd.71 Group 13 metals such as Al also make stable complexes with salen ligands.69 Tetradentate chelating sites of the salen ligand favors the formation of distorted square planar complexes; however, distorted square pyramidal and distorted octahedral geometries are also formed depending on the coordination around the metal centre.72 These salen-metal complexes have been applied extensively in a wide range of fields such as medicine and catalysis. For instance, palladium-salen complexes have shown high in vitro anti-proliferative effects against human hepatoma cancer.73 Iron-salen complexes have been studied against human cancer cell lines including lung carcinoma, cervix epithelial carcinoma, malignant melanoma, osteosarcoma, breast adenocarcinoma, ovarian carcinoma and cisplatin- resistant ovarian carcinoma.74 Salen complexes of manganese,75 titanium,76 copper77 and cobalt78 have also been investigated as anti-cancer agents. Salen-metal complexes have been applied widely as catalysts in organic reactions including asymmetric catalysis, as the production of optically pure compounds is important in pharmaceutical and fine chemical industries. In 1990, Jacobsen79 and Katsuki80 reported the use of chiral Mn-salen complexes for the enantioselective 8 epoxidation of unfuctionalized olefins. Since then, a lot of salen-metal complexes have been employed in the synthesis of enantiomerically pure compounds. For example, Ti- salen complexes catalyze the asymmetric addition of ethyl cyanoformate to aldehydes.81 This reaction produces chiral cyanohydrins that are useful starting materials in the synthesis of natural products81 and pharmaceutical intermediates.82 Cyanohydrins can also be synthesized by V-salen catalyzed asymmetric cyanation of aldehydes, which is also known as Meerwein-Ponndorf-Verley cyanation.83 Salen complexes of Ti have been reported to catalyze asymmetric sulfoxidation84 and enantioselective oxidation of cyclic dithioacetals85 as well. Chromium is another first raw transition metal, which makes strong complexes with salen ligands and catalyzes a wide range of asymmetric transformations such as epoxide ring opening,86 allylation of alkyl glyoxilates,87 hetero-Diels-Alder reaction88 and aminolysis of epoxides.89 Asymmetric epoxide ring opening90 and hetero-Diels-Alder reaction91 can also be catalyzed by chiral Co-salen complexes. In addition, Co-salen complexes are capable of catalyzing a variety of other reactions including hydrolytic kinetic resolution of terminal epoxides,92 asymmetric Diels-Alder reaction,93 enantioselective cyclopropanation,94 oxidation of alcohols to corresponding carboxylic acid analogs and ketones95 and arylation of azole heteroarenes.96 Copper and zinc salen complexes have also been reported in asymmetric catalysis. Enantioselective alkene aziridination97 is an example for such reaction catalyzed by Cu-salen. Meanwhile, Zn- salen complexes are known to catalyze addition of diethylzinc to aldehydes98 and enantioselective alkynylation of ketones.99 9 In addition to first row transition metals, second row transition metals such as Zr and Ru are capable of asymmetric transformations when coordinated with salen ligands. For instance, enantioselective Baeyer-Villiger oxidation100 can be catalyzed by Zr-salen complexes. Likewise, Ru-salen complexes can catalyze asymmetric aziridination of alkenes,101 sulfimidation102 and cyclopropanation of olefins.103 Not only transition metal complexes, but also main group salen complexes such as Al-salen complex have been reported in enantioselctive catalysis. Some of those reactions include asymmetric catalysis of Michael addition reaction,104 conjugate addition of cyanide to ?,?? unsaturated imides105 and addition of hydrogen cyanide to imines.106 These ligand systems featuring O-donor systems, N-donor systems, N, O-donor systems and Schiff base systems can also be found attached to solid supports in order to increase the recovery and the reusability of the catalyst. This helps to increase the turn over numbers (TON) of the reaction and, therefore, making it viable industrial process.107 The solid support can be either polymers or inorganic oxides where active metal complexes interact with the solid support through covalent bonding or weak Coulombic forces. Most of the recently reported solid supports include polystyrene frame works108 and mesoporous silica such as MCM-41109 (Mobil Crystalline Materials) and SBA-1536 (Santa Barbara Amorphous type materials) (Figure 1.3). 10 Figure 1.3. Solid supported copper complexes We have developed ligands incorporating a 2-quinoxalinol into a salen backbone (Figure 1.4). Quinoxaline is a conjugated heterocyclic compound containing two nitrogen atoms (Figure 1.4). Quinoxaline derivatives are key intermediates as bioactive agents,110,111 dyes,112 and have been key pharmaceutical or medicinal intermediates.113,114 The addition of 2-quinioxalinol makes the salen ligand a highly conjugated system by delocalizing the ?-electrons of 2-quinoxalinol and phenolic moieties through Schiff bases. This makes the 2-quinoxalinol incorporated salen or salqu ligand fluorescence active and alters the coordination site. So these salqu ligands with different electronic 11 properties are expected to be of use in the development of new catalysts, sensors and pharmaceutical agents. Figure 1.4. Structures of quinoxaline, 2-quinoxalinol and 2-quinoxalinol salen (salqu) Salqu ligands are synthesized from 6,7-diamino-2-quinoxalinol and salicylaldehyde. We have coordinated salqu ligands with copper as a novel catalytic sytems for the selective oxidation of organic compounds (Figure 1.5). Previously, it was shown that 2-quinoxalinol salen copper(II) complex can work effectively as a catalytic system for the selective oxidation of benzylic methylenes to carbonyl compounds and allylic oxidations to ?,?-unsaturated ketones.115-117 12 Figure 1.5 Structures of 2-quinoxalinol salen (salqu) copper(II) complexes In this dissertation, 2-quinoxalinol salen copper(II) complexes (complex 1 and complex 2) have been used to promote the selective oxidation of alcohols and C-H functionalization (Figure 1.5). Complex 1 was used to oxidize propargylic alcohols to ?,?-acetylinic carbonyl compounds using tert-butyl hydroperoxide (TBHP) as the 13 terminal oxidant. As the principles of green chemistry encourage the use of safer solvents, a water-soluble version of 2-quinoxalinol salen copper(II) complex, complex 2 (Figure 1.5) was synthesized and used with TBHP for the selective oxidation of propargylic, benzylic and allylic alcohols to their corresponding carbonyl compounds in water replacing volatile hazardous organic solvents. This work was further extended for the C-H activations of organic compounds at benzylic and allylic positions in water, still using the water soluble 2-quinoxalinol salen copper(II) catalyst. Moreover, allylic C-H activations catalyzed by complex 1 were also studied under molecular oxygen as a potential substitution for TBHP to further reduce chemical waste production in the process. 14 Chapter 2 Propargylic Alcohol Oxidation The oxidation of propargylic alcohols to carbonyl compounds is of great interest due to their utility as starting materials in a wide range of organic compounds such as heterocyclic compounds,118 aromatic compounds119 and others.120-132 They have also been used in the synthesis of biologically active compounds133 like anti-cancer agents,134 and nucleosides.135 Direct ?-oxidation of alkynes to their corresponding ketones136-138 and some other methods using terminal alkyne as a building block139-147 have also been reported for preparation of ?,?-acetylenic ketones in addition to the oxidation of propargylic alcohols. Scheme 2.1. Oxidation of Propargylic Alcohols Uemura and co-workers have demonstrated the ability of an oxovanadium complex (vanadium oxyacetylacetonate)148 and calcium phosphate-vanadate apatite149 as catalytic systems for oxidation of propargylic alcohols under aerobic conditions. Both 15 these systems show good results, but produce poor to moderate yields with propargylic alcohols derived from alkyl alkynes.148,149 Pedro and co-workers have described a cobolt(III) complex in the catalyzed aerobic oxidation of propargylic alcohols derived from aryl alkynes.150 Meanwhile, Hanson and co-workers reported isolated examples of oxidation of propargylic alcohols using an 8-quinolinate vanadium complex with air,151 but this system was not effective with propargylic alcohols with aryl groups at ? position. In addition, the toxicity of metal involved is a major issue in both of these methodologies.150,151 Copper has also been used in recently reported methods, as a catalyst for propargylic alcohol oxidation. For instance, ligand promoted, copper nanoparticles with tert-butyl hydroperoxide (TBHP) or air as the oxidant152 and CuCl under aerobic conditions have been described.153 These methods demonstrate the potential of copper as a catalyst in similar oxidations, but each method requires 10-20 mol % of catalyst loadings. Thus, most of these available methods require high catalyst loading (5-6 mol %,150,153 10-20 mol %,152,154 and 30 mol %149) and long reaction times.149-151,154 Furthermore, limitations still remain as these systems are incompatible with propargylic alcohols derived from alkyl alkynes.149 Therefore, in the view of green and sustainable chemistry, the development of a fast, efficient and less toxic method is desirable. Here, we describe the use of a 2-quinoxalinol salen copper(II) complex with tert- butyl hydroperoxide (TBHP) as the oxidant in the catalytic oxidation of propargylic alcohols to the corresponding ?,?-acetylenic ketones. The 2-quinoxalinol salen copper(II) complex was synthesized following a modified reported procedure in our laboratory (Scheme 2.2).155 16 Scheme 2.2. Synthesis of 2-quinoxalinol salen copper(II) complex Synthesis of 2-quinoxalinol began by reacting 1 equiv. of 1,5-difluoro-2,4- dinitrobenzene with 1 equiv. of leucine methyl ester hydrochloride in THF. Then the remaining fluorine group was substituted with an amino group by reacting with ammonium hydroxide solution. Once the resulting product was reduced with Pd/C and HCOONH4, it cyclized and oxidized to afford 2-quinoxalinol.155 The crude mixture of 2- quinoxalinol was purified by silica gel column chromatography with ethyl acetate:hexane:ethanol (8:2:1) as the eluent. 17 Reaction of 2-quinoxalinol with 3,5-diterbutyl-2-hydroxybenzaldehyde in the presence of 1 drop of trifluroacetic acid (TFA) formed the tetradentate salqu ligand. Finally, the coordination of the salqu ligand to copper acetate produced the 2- quinoxalinol salen copper(II) complex. With a 2-quinoxalinol salen copper(II) complex in hand, we began our investigation of propargylic alcohol oxidation by oxidizing commercially available 1- phenyl-2-propyn-1-ol (0.5 mmol) with TBHP (10 eq) and copper(II) catalyst (1 mol %) in CH3CN (1.5 mL) under stirring at 70 ?C for 24 h as a model system. The yield of 1- phenyl-2-propyn-1-one was low under these conditions, however, it was found to improve significantly when the reaction time was reduced (Table 2.1, entries 1-3). The yield had no considerable change when the reaction time reduced from 3 h to 1 h (Table 1, entries 1 and 2), thus the reaction time was set to 1 h to optimize the other conditions of the reaction. Table 2.1. Oxidation of 1-phenyl-2-propyn-1-ol Entry TBHP portions Time/h Conversion of 1a (%) GC yield of 2a (%) 1 1 1 88 56 2 1 3 90 55 3 4 24 85 41 18 Next, the required ratio of TBHP was determined (Figure 2.1). An increasing trend of both yield and conversion of 1-phenyl-2-propyn-1-ol was observed when the amount of oxidant was increased from 1 eq to 2.5 eq. The conversion of the starting propargylic alcohol remained the same with further increases, but the yield was found to be reduced when the TBHP was increased beyond 2.5 eq, perhaps due to the over oxidation of 1-phenyl-2-propyn-1-one. Hence, both the maximum yield and the maximum conversion of 1-phenyl-2-propyn-1-ol were observed at 2.5 eq of TBHP. Figure 2.1. GC yields and conversions with the oxidant ratio A solvent effect for this reaction was characterized by characterizing the reactions using different solvents (Table 2.2). The reaction in methylene chloride gave both low yield and low conversion of 1-phenyl-2-propyn-1-ol (Table 2, entry 1). Both chloroform and 1, 2-dichloroethane (DCE) produced moderate yields and good conversion of starting 19 propargylic alcohol (entries 2 and 3). Using acetontrile resulted in very good yields as well as good conversion; however, the use of tert-butanol and benzonitrile resulted in low yields and low conversions of 1-phenyl-2-propyn-1-ol as compared to the other solvents (entries 5 and 6). Table 2.2. Effect of solventa Entry Solvent Conversion of 1a (%) GC yield of 2a (%) 1 CH2Cl2 72 44 2 CHCl3 97 64 3 DCE 96 62 4 CH3CN 98 83 5 tBuOH 53 39 6 PhCN 59 45 aReaction conditions: 1a (0.5 mmol), catalyst (1 mol %), TBHP (2.5 eq), solvent (1.5 mL), 70 ?C, 1 h Finally, a time profile of the oxidation of 1-phenyl-1-propyn-1-ol was examined with TBHP (2.5 eq) and copper(II) catalyst (1 mol %) in CH3CN (1.5 mL) under stirring at 70 ?C (Figure 2.2). The product yield gradually increased and levels off after 1 h of reaction time. Conversion of the 1-phenyl-2-propyn-1-ol increased and reached a maximum after 1 hour. Subsequent extension of the reaction times further reduced yields 20 of the desired product, presumably because of additional oxidation of the resulting carbonyl compound. Figure 2.2. Time profile of oxidation of 1-phenyl-2-propyn-1-ol On the basis of these optimized reaction conditions, a variety of propargylic alcohol substrates were oxidized with TBHP (2.5 eq) and Cu(II) catalyst (1 mol %) in CH3CN (1.5 mL) under stirring at 70 ?C for 1 h (Table 3). First, the oxidation of propargylic alcohols with substituted aryl groups at ? position was examined. Most of the propargylic alcohols with substituted aryl groups at ? position were converted to the corresponding carbonyl compound in high yields (Table 2.3, entries 1, and 3-9). When Cl was substituted at the 2, 3 and 4 positions of the aryl group, increasing yields of the corresponding carbonyl compound were observed and turn over numbers were 39, 71 and 21 78 respectively (entries 2-4). This could be the results of steric hindrance at the ortho position. When the 4 position of the aryl group of the propargylic alcohol was instead substituted with Br or I, the yield also increased (entries 4-6). These results reflect an electronic effect of the substituent on the aromatic ring. Electron donating groups such as methyl and tert-butyl groups produced good yields under these conditions (entries 7-8), however, a strong electron donating methoxy group produced slightly lower yield as compared to that of tert-butyl group, possibly due to over oxidation of the resulting ketone (entry 9). When an electron withdrawing nitro group was introduced at the para position, the yield was comparatively low (entry 10). Propargylic alcohols having 1- naphthyl and 2-naphthyl groups also produced good yields of corresponding carbonyl compound (entries 11 and 12), but again, the alcohol with 2-naphthyl group produced higher yield compared to that of 1-naphthyl group reflecting the importance of the effects of steric hindrance. Thus, a wide range of functional groups such as Cl, Br, I, Me, t-Bu, OMe, NO2 are tolerated. 22 Table 2.3. Oxidation of propargylic alcohols under optimized condition with 1 mol % catalyst Entry Substrate Conversion of substrate (%) Isolated yield of 2 (%) 1 1a R= H 98 83 2 1b R= 2-Cl 86 39 3 1c R= 3-Cl 100 71 4 1d R= 4-Cl 100 78 5 1e R= 4-Br 100 82 6 1f R= 4-I 100 92 7 1g R= 4-Me 99 82 8 1h R= 4-tBu 100 95 9 1i R= 4-OMe 100 89 10 1j R= 4-NO2 99 51 11 1k 93 82 12 1l 100 87 13 1m 100 99 14a 1n 100 90 23 15a 1o 100 86 16a 1p 88 62 17a 1q 90 85b 18a r 15 _b 19a s 7 _b a For 5 h. b GC yield When a propargylic alcohol with aryl groups at both the R1 and R2 positions was oxidized, it produced excellent yield under these conditions (entry 13). The oxidation of propargylic alcohols having alkyl groups at the ? position gave low yields when oxidized for 1 h; however, when the reaction time was increased to 5 h, they produced good yields of corresponding ketone (entries 14, 15 and 17). Even when a primary propargylic alcohol was oxidized (H at the ? position) it gave a good yield of ?,?-acetylenic aldehyde under this reaction condition (entry 16). Finally, the reaction was studied using an alkyne substrate having an isolated hydroxyl group (entry 18). In this case, no oxidized ketone was observed even after 5 h of reaction time. A small percentage of substrate conversion was observed possibly due to the oxidation of the triple bond. As this reaction is expected to go through a radical pathway, a radical formed at ? carbon to a triple bond is supposed to be more stabilized 24 than that of an isolated carbon. Thus, that could possibly be the reason why propargylic alcohols are more reactive over homopropargylic alcohols under this reaction conditions. When an alkyne was oxidized, it resulted no ?,?-acetylenic ketones (entry 19). Again, this demonstrates the selectivity of this catalyst system for propargylic alcohol oxidation and propargylic methylenes are resistant to oxidation under this catalytic protocol. To characterize the effects of the substituent on this reaction, a correlation to Hammett constants were calculated and plotted according to equation 2.1. The correlation between log (kX/kH) and para-position Hammet constants showed a good fit as shown in Figure 2.3. According to these results, the propargylic alcohol oxidation was accelerated by electron-donating substituents and decelerated by electron-withdrawing substituents. The negative slope (?) indicates that the electron-withdrawing substituents decrease the ratio of log (kX/kH) resulting lower oxidized yields and that the oxidation of propargylic alcohol 1 with copper(II) catalyst is likely to be electrophilic in nature under these reaction conditions. Because of this, it stands to reason that the reaction mechanism may go through an electron deficient intermediate and thus, the electron-donating substituents help to stabilize the intermediate resulting high reaction yields. 25 Equation 2.1. log kX/kH = ??p Figure 2.3. Correlation between log (kX/kH) and para-position Hammet constants. The substituent constants ?p were taken from ref 100.156 In summary, we have found that 2-quinoxalinol salen or salqu copper(II) complex is efficient as a catalyst for the oxidation of propargylic alcohols to the corresponding carbonyl compounds under the oxidant TBHP. This catalytic system produced excellent selectivity for oxidation of propargylic alcohols over isolated alcohols, triple bonds, or propargylic methylenes. Excellent yields were achieved within 1 h, a significantly enhanced reaction time compared to the other available methods.149-151,153 Most other reported methods fail the oxidation of propargylic alcohols with alkyl groups at R1 position;149 however, the salqu copper(II) catalyst with TBHP works well and produces 26 high yields. Furthermore, the use of 1 mol % catalyst for the oxidation of all types of propargylic alcohols (turn over numbers up to 99) is another advantage of this method in the view of industrial and environmental chemistry. Elimination of hazardous organic solvents is another way to make chemical reactions environmentally benign. Thus, this work was continued using a water-soluble version of 2-quinoxalinol salen copper(II) complex in the view of green and sustainable chemistry. The synthesis of water-soluble 2-quinoxalinol salen copper(II) complex and its application for the selective alcohol oxidation is discussed in Chapter 3. 27 Chapter 3 Alcohol Oxidation in Water As the use of safer solvents in reactions are encouraged by green chemistry, water based organic reactions have gained increasing interest in recent years.157-165 Water has reported to have rate acceleration of reactions163 and even when there is no rate acceleration, features like high heat capacity, redox stability, ease of product isolation and most importantly green aspect of it, keep scientists interested in water as a solvent over hazardous volatile organic solvents.159,161 In recent years, water has been used as a solvent for transition metal-catalyzed organic reactions including pericyclic reactions,166-168 olefin metathesis,169 carbonylation,170 arylation,171 hydroformylation,172 Suzuki reaction,173 Mizoroki-Heck reaction174 and others;175-178 however, the use of water as solvent for metal catalyzed radical reactions in organic synthesis is rare. Water is less reactive towards free radicals and it is relatively redox inert molecule. Hence, water could be a useful reaction medium for radical reactions as well as redox reactions of organic compounds. Synthesis of carbonyl compounds by oxidation of alcohols is one of the important redox reactions in organic chemistry. These oxidations are typically conducted by using catalysts featuring toxic metals such as V,148,149 Co,150 Mo,179 Ru,180-182 Pd,183,184 and 28 Ir.185,186 To mitigate the harsh conditions associated with these methods, alternative approaches like Cu-catalyzed152,154,187,188 reactions have been developed. Use of pure oxygen149,150,153,189,190 or air151,152,189 as oxidant for these metal-catalyzed alcohol oxidation reactions can also be seen as a greener approach. The use of water as a reaction medium for alcohol oxidation has less reported. Thus, in the view of green and sustainable chemistry, the development of a mild, less toxic and efficient method is desirable. In this chapter, a radical reaction in water is described for the oxidation of propargylic, benzylic, and allylic alcohols to yield corresponding carbonyl compounds using a water-soluble sulfonated 2-quinoxalinol salen (sulfosalqu) copper(II) complex as a catalytic system. Thus, this study commenced by synthesizing a water-soluble 2- quinoxalinol salen copper(II) complex. Salqu copper(II) complex can be made water-soluble by introducing polar or ionic groups at R1, R2 or R3 positions (Figure 3.1). Figure 3.1. Basic structure of 2-quinoxalinol salen copper(II) complex 29 Here, we use a salicylaldehyde derivative with sulfonate groups to make the R1 and R2 groups of the complex ionic. A sulfonated 2-quinoxalinol salen (sulfosalqu) copper(II) complex was synthesized through the reaction sequence shown in scheme 3.1. The approach to sodium 3-methylsalicylaldehyde-5-sulfonate 4 requires protection of 3- methylsalicylaldehyde 1 followed by sulfonation and then deprotection of the resulting compound 3, and this was achieved by following a modified procedure from literature.191 Sodium 3-methylsalicylaldehyde-5-sulfonate 4 was then reacted with 2-quinoxalinol 5, which was prepared according to the reported procedure in our laboratory,155 and copper acetate in one-pot to yield sulfosalqu copper(II) complex 6. Scheme 3.1. Synthesis of sulfonated 2-quinoxalinol salen (sulfosalqu) copper(II) complex 30 Scheme 3.2. Oxidation of 1-phenyl-2-propyn-1-ol Figure 3.2. Time profile of the reaction with 7 (0.5 mmol), sulfosalqu copper(II) complex (1 mol %) and TBHP (3 eq) in H2O at 70 ?C. Yields and conversions were determined by GC with 1,2-dichlorobenzene added as an internal standard. Using the water soluble catalyst we developed, we tested the oxidation of 1- phenyl-2-propyn-1-ol (0.5 mmol) with TBHP (3 eq) and sulfosalqu copper(II) catalyst (1 mol %) in H2O under stirring at 70 ?C for 1 h as a model system (Scheme 3.2). The yields and conversions were determined by extracting the reaction mixture to ether and then analyzing the organic layer by GC with the internal standard method. The yield of 1- phenyl-2-propyn-1-one was low under these conditions; however, it was found to improve when the reaction time was increased (Figure 3.2). Both conversions and 31 reaction yields reached to a maximum after 3 h and no considerable yield change occurred upon further increasing the reaction time from 3 h to 6 h. Therefore, the 3 h mark was best suited to optimize the other conditions of the reaction. Several different oxidants were then screened for the oxidation of 1-phenyl-2- propyn-1-ol using sulfosalqu copper(II) complex (1 mol %) in water. Hydrogen peroxide, peracetic acid, and m-chloroperbenzoic acid were all ineffective oxidants towards this oxidation, affording low yields of corresponding ketone after 3 h at 70 ?C (Figure 3.3). In contrast, TBHP was an excellent oxidant, producing high yields of 1-phenyl-2-propyn-1- one under these reaction conditions. 0 10 20 30 40 50 60 70 80 90 % Yield H 2 O 2 CH 3 CO 3 H MCP B A T B HP Ox id an t Figure 3.3. Effect of Oxidant. Conditions: 7 (0.5 mmol), sulfosalqu copper(II) complex (1 mol %) and oxidant (3 eq) in H2O at 70 ?C. Yields were determined by GC with 1,2- dichlorobenzene added as an internal standard. As TBHP resulted in producing good yields under these conditions, we went on to analyze the effect of TBHP ratio in the reaction. Yield of 1-phenyl-2-propyn-1-one was (8) increased from 44 % to 82 % when the TBHP ratio was changed from 1 eq to 3 eq 32 (Figure 3.4); however, the addition of more TBHP equivalents did not result in a further improvement in the reaction yield. 0 10 20 30 40 50 60 70 80 90 1 2 3 4 5 % Yield T B HP eq u iv . Figure 3.4. Effect of TBHP ratio. Conditions: 7 (0.5 mmol), sulfosalqu copper(II) complex (1 mol %) and TBHP in H2O at 70 ?C. Yields were determined by GC with 1,2- dichlorobenzene added as an internal standard. Encouraged by these results, we studied the factors that control the reaction yield of 1-phenyl-2-propyn-1-ol oxidation. The reactions were performed in water at 70 ?C for 3 h with 1 mol % copper(II) sulfosalqu complex and 3 eq TBHP, with 1 mol % copper(II) sulfosalqu complex alone, without a copper catalyst, and with catalytic amounts of Cu(OAc)2 or CuCl2 and 3 eq TBHP (Table 3.1). When the reaction was run in the absence of the catalyst, it afforded a very small yield of corresponding ketone after 3 h at 70 ?C (entry 2), showing the important role of copper(II) sulfosalqu complex as the catalyst in this alcohol oxidation. It was also observed that the reaction barely happens in the absence of TBHP, suggesting the lack of driving force of the reaction without the oxidant TBHP (entry 3). Reactions run under normal conditions with Cu(OAc)2 and 33 CuCl2, instead of copper(II) sulfosalqu complex as the catalyst occurred in very low yields of 27 % and 30 % respectively (entries 4 and 5). Even when the amount of Cu(OAc)2 was increased form 1 mol % to 5 mol %, it produced only 35 % yield (entry 4). These results suggested that the copper(II) sulfosalqu complex is responsible for the high yields, not just a copper salt alone as a catalyst. Table 3.1. Effect of reaction conditiona Entry Condition Yield of 8 (%)b 1 Sulfosalqu Cu(II) 82 2 No catalyst 7 3 No TBHP 0.5 4 Cu(OAc)2 27 (35) 5 CuCl2 30 aConditions: 7 (0.5 mmol), sulfosalqu copper(II) complex (1 mol %) and TBHP (3 eq) in H2O at 70 ?C for 3 h. bGC yields with 1,2-dichlorobenzene added as an internal standard. The value in parentheses is the yield when 5 mol % of Cu(OAc)2 used. The substrate scope of the alcohol oxidation was investigated using sulfosalqu copper(II) catalyst (1 mol %) and TBHP (3 eq) in H2O under stirring at 70 ?C for 3 h (Table 3.2). The yields were determined by mass calculation of purified product after silica gel column chromatography. First, the oxidation of propargylic alcohol substrates was examined by varying the electronic properties of the arene. Substrate bearing H (entry 1) and methyl (entry 2) occurred in similar yields. However, the substrate possessing more electron-donating methoxy group (entry 3) underwent the oxidation to give much higher yield of corresponding ketone than that of latter. In contrast, moderate 34 yield was observed for the substrate with a nitro substituent, suggesting a significant influence of the electronic properties of the arene (entry 4). Table 3.2. Substrate scopea Entry Substrate Product Yield (%)b 1 81 2 79 3 90 4 52 5 98 (92) 6c 78 7c,d 54 8c 60 35 9e 74 10e 92 11e 99 12e 63 13c,d 41 14 58 aConditions: 7 (0.5 mmol), sulfosalqu copper(II) complex (1 mol %) and TBHP (3 eq) in H2O at 70 ?C for 3 h. bIsolated yields are shown. The value in parentheses is an isolated yield on a 5 mmol scale. c6 h. dsulfosalqu copper(II) complex (2 mol %). e12 h. Meanwhile, 1,3-diphenyl-2-propyn-1-ol was oxidized to corresponding ketone in almost quantitative yield (entry 5). This reaction was also conducted on a 5 mmol scale and it gave 92 % yield of 1,3-diphenyl-propyn-1-one after purification by silica gel column chromatography with hexane:ethyl acetate as eluent (entry 5). Oxidation of propargylic alcohols containing an alkyl substituent at ? position was relatively slow; however, extension of reaction time to 6 h produced high yields of desired product (entry 6). The reaction also occurred with an alcohol having only hydrogens at ? position 36 (primary propargylic alcohol) 3-phenyl-2-propyn-1-ol to provide corresponding aldehyde in moderate yield (entry 7). In this case, over oxidation resulting 3-phenyl-2-propynal to the corresponding carboxylic acid was also observed, as the reaction medium is water. In addition, oxidation of terminal alkyne, 1-octyn-3-ol was compatible with this catalytic system affording a good yield of the corresponding ketone (entry 8). Under these conditions, oxidations of benzylic alcohols were slightly slower compared to that of propargylic alcohols; however, when the reaction time was increased to 12 h, they produced corresponding ketones in good to excellent yields (entries 9,10 and 11). 2-(1-hydroxyethyl)pyridine also underwent the oxidation on water to give a good yield of 2-acetylpyridine (entry 12). Moreover, this catalytic protocol led to the oxidation of allylic alcohols to the corresponding ?,?-unsaturated ketones in moderate yields (entries 13 and 14). In all cases, the oxidation occurred at the propargylic, benzylic and allylic positions. To study the selectivity of oxidation to these positions, a mixture of 1-phenyl- 2-propyn-1-ol (0.5 mmol) and 1-octanol (0.5 mmol) was oxidized using sulfosalqu copper(II) catalyst (1 mol %) and TBHP (3 eq) in H2O under stirring at 70 ?C for 3 h. Only the oxidation of 1-phenyl-2-propyn-1-ol was observed with no formation of 1- octanal, suggesting the selectivity of this system to propargylic, benzylic and allylic positions. To understand the role of the oxidizing agent, TBHP, oxidation of 1-phenyl-2- propyn-1-ol was examined under a nitrogen atmosphere. Treatment of 1-phenyl-2- propyn-1-ol with sulfosalqu copper(II) catalyst (1 mol %) and TBHP (3 eq) in H2O under nitrogen at 70 ?C for 3 h produced similar results as in normal atmosphere of air, 37 suggesting that TBHP is the only oxidant required for this reaction and oxygen from air has no role to play in the formation of active intermediates in this reaction. This was also evidenced by the fact that the reaction barely happened in the absence of TBHP. Scheme 3.3. Decomposition of the catalyst-substrate intermediate under basic conditions The addition of a base promoter has been reported in other similar reactions to accelerate the oxidation of alcohols when catalyzed with metal complexes using oxidants.151,154 This is due to the rapid decomposition of the catalyst-substrate intermediate forms during the reaction under basic conditions (Scheme 3.2); however, in our case, the addition of 2 mol % NEt3 did not affect the reaction rate. The absence of a rate change in the presence of NEt3 suggests that the reaction may not proceed through such a catalyst-substrate intermediate in this sulfosalqu copper(II) catalytic system. Thus, we suggest that the catalytic oxidation may go through a radical intermediate under these reaction conditions and it may occur at propargylic, benzylic and allylic positions. This is supported by the fact that, in the absence of TBHP, with no radical initiator in the reaction medium the reaction had very poor production of products (Table 3.1 entry 3). To further prove this, oxidation of 1-phenyl-2-propyn-1-ol was conducted under 7 mol % of BHT (Butylated hydroxytoluene) and it only produced 5 % yield of the corresponding ketone. This suggests that the reaction barely happens in the presence of a radical inhibitor. The observed selectivity for propargylic, benzylic and/or allylic alcohol oxidation also supports the formation of a radical intermediate. Because of the 38 propargylic, benzylic and allylic radicals are more stable than isolated radicals, the alcohol oxidation is more preferred at those positions. This may be the reason why, a mixture of 1-phenyl-2-propyn-1-ol and 1-octanol only resulted in oxidation of 1-phenyl- 2-propyn-1-ol. Moreover, experimental results showed that a substrate bearing a methoxy group (Table 3.2, entry 3) underwent the oxidation to give much higher yield of corresponding ketone. In contrast, precursor with a nitro substituent produced a low yield (Table 3.2, entries 4). This could be the result of the ability of the strong electron donors to stabilize the radical intermediates, and the consequence of strong electron withdrawing groups destabilizing the radical intermediate. Thus, it is believed that the formation of this carbon-based radical intermediate is facilitated by the sulfosalqu copper(II) complex. In summary, we have developed a sulfonated 2-quinoxalinol salen copper(II) catalyzed, selective oxidation of propargylic, benzylic and allylic alcohols using tert- butyl hydroperoxide as oxidant. This reaction constitutes a rare example of alcohol oxidation in water and it makes this process greener by eliminating the use of hazardous organic solvents, toxic metals and high catalyst loading. These alcohol oxidations occur in good yields with excellent selectivity for propargylic, benzylic and allylic alcohols. Ease of product isolation by extraction is another advantage of this method. This work was further extended for the C-H functionalization of organic compounds at benzylic and allylic positions in water and that work is discussed in Chapter 4. 39 Chapter 4 C-H Activation in Water The functionalization of C-H bonds is of wide interest as it converts chemically less reactive organic substrates into more reactive chemical compounds, which are versatile building blocks in multistep organic syntheses.192-196 These activations can occur at benzylic,197,198 allylic116,117,199 and aliphatic C(sp3)-H200,201 bonds or even at the aromatic C(sp2)-H202-204 bonds. Such functionalizations are typically carried out using transition metal catalyzed reactions, for example Mn,205-207 Fe,208,209 Co,210,211 Ru,195,212,213 Rh,199,214,215 Pd,216,217 and Ir.200,218 Development of environmentally friendly or greener methods is desired for these C-H functionalizations, in the view of green and sustainable chemistry. In this regard, copper-catalyzed C-H activations have been employed to eliminate the toxicity of metals involved in combination with environmentally benign oxidants such as molecular oxygen62,219-221 and tert-butyl hydroperoxide.38,40,115 Solvent-free conditions40 and polymer supported heterogeneous catalytic sytems39,40,220 have also been studied to make the process efficient and ecofriendly in recent years. Another approach is to use green solvents like water instead of hazardous volatile organic solvents for C-H functionalization.222 40 In this chapter, we report the extension of using copper(II) complex of sulfonated 2-quinoxalinol salen as an efficient catalyst in water for the selective functionalization of benzylic and allylic C-H bonds to the corresponding carbonyl compounds in the presence of oxidant tert-butyl hydroperoxide. Sulfonated 2-quinoxalinol salen (sulfosalqu) copper(II) complex was synthesized in the same way as described in the Chapter 3 (Scheme 4.1). The approach to sodium 3- methylsalicylaldehyde-5-sulfonate 4 requires protection of 3-methylsalicylaldehyde 1 followed by sulfonation and then deprotection of the resulting compound 3. Sodium 3- methylsalicylaldehyde-5-sulfonate 4 was then reacted with 2-quinoxalinol 5, and copper acetate in one-pot to yield sulfosalqu copper(II) complex 6. Scheme 4.1. Synthesis of sulfonated 2-quinoxalinol salen (sulfosalqu) copper(II) complex 41 To begin our study, we examined the oxidation of diphenylmethane (0.5 mmol) using a catalytic amount of sulfosalqu copper(II) complex (1 mol %) and TBHP (3 eq) in H2O under stirring at 70 ?C for 3 h (scheme 4.2). The yields and conversions of the reaction were determined by extracting the reaction mixture to dichloromethane and then analyzing the organic layer by GC with the internal standard method. The reaction, however, did not occur efficiently under these conditions to give the corresponding ketone in good yield (Table 4.1, entry 1). Thus, the reaction time was gradually increased to improve the yield of the reaction. Both conversions and reaction yields were found to improve with the reaction time and it resulted in very good yield of benzophenone (8) after 24 h of reaction time (Table 1, entries 2-7). Scheme 4.2. Oxidation of diphenylmethane Table 4.1. Time profile of the reactiona Entry Time/h Conversion of 7 (%) Yield of 8 (%) 1 1 31 26 3 3 56 48 4 6 68 57 5 12 83 70 6 18 90 75 7 24 95 80 aConditions: 7 (0.5 mmol), sulfosalqu copper(II) complex (1 mol %) and TBHP (3 eq) in H2O at 70 ?C. Yields and conversions were determined by GC with 1,2-dichlorobenzene added as internal standard. 42 This reaction was then examined with 3 eq of hydrogen peroxide as the oxidant; however, the yield of benzophenone was very low (3 mol %), under this reaction condition. Even when the amount of H2O2 was increased to 30 mol % it produced only 4 % yield of desired product. Thus, TBHP was continued to be used as the oxidant for the C-H functionalization. The required amount of TBHP for the reaction was studied by oxidizing diphenylmethane (0.5 mmol) using sulfosalqu copper(II) complex (1 mol %) in H2O under stirring at 70 ?C for 24 h (Figure 4.1). The yield of benzophenone was increased when TBHP amount was increased from 1 eq to 3 eq. After 3 eq of TBHP, reaction yield reached to a maximum and produced almost similar results. The addition of additional equivalents of TBHP also did not reduce the reaction time. 0 10 20 30 40 50 60 70 80 90 1 2 3 4 5 10 % Y ield TB HP e quiv . Figure 4.1. Effect of TBHP ratio. Conditions: 7 (0.5 mmol), sulfosalqu copper(II) complex (1 mol %) and TBHP in H2O at 70 ?C. Yields were determined by GC with 1,2- dichlorobenzene added as an internal standard. 43 Table 4.2. Substrate scopea Entry Substrate Product Yield (%)b 1 80 2 92 3 92 4 96 5 65 6c 56 7c,d 76 8c 62 9e 60 44 10e 74 11e 70 12e 56 aConditions: Substrate (0.5 mmol), sulfosalqu copper(II) complex (1 mol %) and TBHP (3 eq) in H2O at 70 ?C for 24 h. bGC yields are shown. c6 h. dsulfosalqu copper(II) complex (2 mol %). e12 h. The substrate scope of the C-H functionalization was investigated using sulfosalqu copper(II) catalyst (1 mol %) and TBHP (3 eq) in H2O under stirring at 70 ?C for 24 h (Table 4.2). First, a variety of representative benzylic substrates were oxidized. Substrates bearing electron donating R2 groups such as ?Me and ?OMe produced excellent yields (entries 2 and 3). Oxidation of the ether compound provides a direct method to synthesize methyl benzoate from benzyl methyl ether (entry 3). Electronic properties of the arene were varied and the substrate bearing electron-donating methoxy group (entry 4) underwent the oxidation to give excellent yield of corresponding ketone. In contrast, reaction yields dropped when electron-withdrawing groups were introduced to the arene, indicating the importance of the electronic properties of the arene for the C- H activation. In particular, the substrate with a weak deactivating ?Br group produced 65 % yield and the substrate with a strong deactivating ?NO2 group produced 56 % yield of their corresponding carbonyl compounds (entries 5 and 6). This could be the result of the 45 electron-withdrawing properties of bromo and nitro groups that could destabilize the radical intermediates form during the reaction. When 2-ethylnaphthalene was oxidized, it still produced a good yield of corresponding ketone (entry 7). Surprisingly, 1,1-diphenylpropane was oxidized to benzophenone as the major product instead of the expected 1,1-diphenylpropanol, under this catalytic system (entry 8). This observation indicates the reaction to go through a complicated mechanism. Having successfully functionalized benzylic C-H bonds, we examined the capability of this catalytic protocol for the allylic C-H activation. Cyclohexene was oxidized to 2-cyclohexenone in 60 % yield in water (entry 9). Allylic substrates bearing ? CN groups and ?Ac groups also produced moderate to good yields under this catalytic system (entries 10, 11 and 12). Formation of epoxides have also been reported in copper- catalyzed allylic oxidations.108 No formation of epoxides, however were observed under this salqu copper(II) catalytic system when reaction mixtures were analyzed with GC/MS. To gain more insight into the role of the salqu copper(II) catalyst and the TBHP, the oxidation of diphenylmethane was conducted in the absence of each. Withtout the addition of catalyst, oxidation using 3 eq TBHP in water at 70 ?C for 24 h, resulted in very low yield. In fact 4-5 % of benzophenone was observed. Benzophenone, however did not form, when the reaction was carried out in the absence of TBHP, suggesting the importance of a radical initiator for the reaction. Thus, the reaction is thought to go through a radical mechanism. Addition of NEt3, a base promoter, did not increase the rate 46 of the reaction and this is also an evidence for the possibilty of radical intermediate formation. In conclusion, a copper(II) complex of sulfonated 2-quinoxalinol salen (sulfosalqu) has been characterized as an efficient catalyst for the selective functionalization of benzylic and allylic C-H bonds to the corresponding carbonyl compounds in the presence of oxidant tert-butyl hydroperoxide. The reactions proceed with 1 mol % of catalyst loading at 70 ?C in water and good yields (up to 96 %) can be achieved for a variety of substrates. Use of water as the solvent makes this process environmentally benign by eliminating the volatile organic solvents. Excellent selectivity was also achieved with this catalytic protocol for the activation of benzylic and allylic C(sp3)-H bonds. The reaction is thought to go through a radical pathway. 47 Chapter 5 C-H Activation using Salqu Copper(II) and Molecular Oxygen Copper-catalyzed C-H activations have been established over the years with various oxidizing agents including hydrogen peroxide,223-226 tert-butyl hydroperoxide227 (TBHP) and oxygen.221,228 Among those, molecular oxygen is particularly attractive as it is cheap, environmentally benign and naturally abundant.6 Oxygen has the ability to act as an electron acceptor and/or oxygen donor in these metal-catalyzed reactions.6 The most common byproduct formed during the oxidation with molecular oxygen is water, and this increases the atom economy of the reaction when acts as the oxygen donor. Meanwhile, oxidations with TBHP can leave byproducts like tert-butyl alcohol, butylene or unused TBHP as organic waste.6,229 Thus, introduction of molecular oxygen over tert- butyl hydroperoxide is desired for the 2-quinoxalinol salen (salqu) copper(II) catalyzed oxidations. In our previous studies, we have shown that the 2-quinoxalinol salen copper(II) complex with tert-butyl hydroperoxide works as an efficient catalyst for the allylic C-H activations (Scheme 5.1).117 48 Scheme 5.1. Allylic oxidation catalyzed by Cu(II) salqu The proposed reaction mechanism for the allylic oxidation is thought to involve a Cu(II) tert-butyl peroxo intermediate as shown in scheme 5.2.117 This intermediate undergoes a homolytic cleavage of O-O bond by reacting with the allylic substrate to yield allylic radical, tert-butyl alcohol and LCu(II)-O?. After this point, two possible pathways could result in the formation of enone product: (1) reaction of allylic radical with the molecular oxygen in the medium to form allylic peroxy radical and then conversion of that to enone; (2) reaction of allylic radical with the LCu(II)-O? species to form allylic oxyl radical and then conversion of that to enone. Finally, the oxidation of LCu(I) complex by molecular oxygen regenerates the LCu(II) complex, which can be recycled. 49 Scheme 5.2. Proposed catalytic cycle for allylic oxidation catalyzed by Cu(II) salqu117 According to this reaction mechanism, only one equivalent of TBHP is consumed during the reaction. Meanwhile, dioxygen acts as both an oxygen donor to incorporate oxygen atom into the enone and an electron acceptor to oxidize Cu(I) to Cu(II). As this is a radical reaction, it is challenging to prove that the reaction has only one pathway. Thus, introduction of more molecular oxygen to the reaction mixture may favor the oxidation reaction and would help to reduce the amount of chemical oxidant used in the reaction. On the basis of this assumption, here we describe the introduction of molecular oxygen for the salqu copper(II) catalyzed allylic C-H activation. 50 Scheme 5.3. Oxidation of 1-acetyl-1-cyclohexene catalyzed by Cu(II) salqu We began our investigation by studying the oxidation of 1-acetyl-1-cyclohexene (0.5 mmol) using a catalytic amount of 2-quinoxalinol salen copper(II) complex (1 mol %) and TBHP (3 eq) in acetonitrile under stirring at 70 ?C and 1 atm (air) for 24 h in a pressure vessel (Scheme 5.3). Table 5.1. Effect of dioxygena Entry O2 pressure (atm) Yield (%) 1 atmospheric 67 2 1 84 3 10 90 4 20 90 5 30 90 aConditions: 1-acetyl-1-cyclohexene (0.5 mmol), copper(II) salqu complex (1 mol %) and 3 eq TBHP in acetonitrile at 70 ?C for 24 h in a pressure vessel. Yields were determined by GC with 1,2-dichlorobenzene added as an internal standard. The yield of the reaction was determined by analyzing the reaction mixture using GC with the internal standard method. In this method, the reaction run in the pressure vessel with 1 atm of air resulted in 67 % yield of 3-acetyl-2-cyclohexen-1-one (Table 5.1 entry 1). When the reaction ran at 1 atm of oxygen it produced 84 % yield, suggesting that the molecular oxygen clearly plays a role in the reaction by increasing the reaction yield (entry 2). Encouraged by this result, oxygen pressure was further increased to see 51 more improvement in the reaction yield. As the pressure was increased to 10 atm, the yield reached to 90 % (entry 3); however, the oxygen pressures beyond 10 atm did not result in a further improvement in the reaction yield (entries 4 and 5). To study the effect of TBHP, the reaction was examined at 1 atm and 30 atm of oxygen in the absence of TBHP. Both of these experiments resulted in no reaction and it revealed two general features of the reaction: (1) molecular oxygen alone can not oxidize 1-acetyl-1-cyclohexene under this 2-quinoxalinol salen copper(II) catalytic system; (2) the presence of a radical initiator is required in order to occur the reaction. Thus, TBHP can not be replaced with oxygen as the oxidant under this catalytic protocol; however, we seek to reduce the amount of required TBHP in the reaction by introducing more molecular oxygen into the system. Table 5.2. Effect of TBHP equivalenta Entry TBHP (eq) O2 pressure (atm) Yield (%) 1 3 1 84 2 3 10 90 3 3 20 90 4 2 1 49 5 2 10 61 6 2 20 62 7 1 1 36 8 1 10 37 9 1 20 37 aConditions: 1-acetyl-1-cyclohexene (0.5 mmol), copper(II) salqu complex (1 mol %) and TBHP in acetonitrile at 70 ?C for 24 h in a pressure vessel. Yields were determined by GC with 1,2-dichlorobenzene added as an internal standard. With TBHP as the radical initiator in the reaction, we turned our attention to the primary goal of this work: identifying whether oxygen could act as the main oxidizing 52 agent replacing most of the TBHP used in the oxidation of 1-acetyl-1-cyclohexene. The reaction was conducted with different amounts of TBHP equivalents while varying the pressure of oxygen (Table 5.2). Three equivalents of TBHP produced 84 %, 90 % and 90 % yields of 3-acetyl-2-cyclohexen-1-one at 1 atm, 10 atm and 20 atm pressure of oxygen respectively (entries 1, 2 and 3). Likewise, reactions conducted with 2 equivalent of TBHP occured in 49 % yield at 1 atm and increased to 61 % yield at 10 atm (entry 4 and 5). Again, reaction yield at 20 atm was identical to that at 10 atm (entry 6). In contrast, reactions performed with 1 equivalent of TBHP only produced low yields (~37 %) of desired product at all pressures of oxygen (entries 7, 8 and 9). As the reaction yields were relatively low with 1 equivalent of TBHP, the amount of TBHP was not further reduced in this study. Figure 5.1. Effect of TBHP equivalent These results were plotted in Figure 5.1 and it describes the reaction yield as a function of oxygen pressure at various amount of TBHP. According to these results, both 3 eq and 2 eq of TBHP produced greater yields compared to 1 eq of TBHP. The results 53 obtained at 1 eq was low and closer than expected in various pressures of oxygen in accordance with the trend obsereved at higher amounts of TBHP, and the reason for this behavior is not clear at this point. Meanwhile, 3 eq of TBHP produced 90 % of 3-acetyl- 2-cyclohexen-1-one at 10 atm and 2 eq of TBHP produced 61 % yield at the same pressure of oxygen. Thus, 3 eq of TBHP produce better yields of desired product than 2 eq at the same reactions conditions. Table 5.3. Yields of 3-acetyl-2-cyclohexen-1-one under different reaction conditions Entry TBHP (eq) O2 pressure (atm) Yield (%) 1 3 atmospheric 67 2 2 atmospheric 39 3 2 10 61 As the primary goal of this study to reduce the amount of TBHP used in the oxidation reactions, it is worth looking at the results obtained with the 2 eq of TBHP. With 3 eq of TBHP, 1 atm of air and 24 h reaction time, a 67 % yield of 3-acetyl-2- cyclohexen-1-one was observed (Table 5.3, entry 1). Reactions run under similar conditions with 2 eq of TBHP occured in a 39 % yield (entry 2); however, the same reaction with 10 atm oxygen produced similar results to the former (entry 3). These results suggest that equivalents of TBHP required for the reaction can be reduced from 3 eq to 2 eq in the the oxidation of 1-acetyl-1-cyclohexene, at the expense of 10 atm of oxygen under this catalytic protocol. This is a 33 % less TBHP input compared to the original reaction conditions. Even though this is a higher amount of TBHP than anticipated at this point, it is still a significant amount of prevented waste at a larger scale with regard to industrial and environmental chemistry. 54 Table 5.4. Time profilea Entry Time (h) Yield (%) 1 6 51 2 12 61 3 18 65 4 24 62 aConditions: 1-acetyl-1-cyclohexene (0.5 mmol), copper(II) salqu complex (1 mol %) and 2 eq TBHP in acetonitrile at 70 ?C and 10 atm of oxygen for 24 h in a pressure vessel. Yields were determined by GC with 1,2-dichlorobenzene added as an internal standard. Having identified 2 eq of TBHP and 10 atm of oxygen as a better reaction condition, we established the relationship between the time of reaction and the yield (Table 5.4). Reactions were conducted with 1-acetyl-1-cyclohexene (0.5 mmol) using a catalytic amount of 2-quinoxalinol salen copper(II) complex (1 mol %) and TBHP (2 eq) in acetonitrile under stirring at 70 ?C and 10 atm of oxygen for 6 h, 12 h, 18 h and 24 h in a pressure vessel. After 6 h, the yield of 3-acetyl-2-cyclohexen-1-one is 53 % and it incresed to 61 % at 12 h. Longer reaction times beyond 12 hours did not result in a further increase in the yield. Based on these results, a greener method for allylic oxidation can be achieved by using salqu copper(II) catalyst and 2 eq of TBHP at 10 atm of oxygen for 12 h. From these results, we can conclude that molecular oxygen can not completely replace TBHP in the 2-quinoxalinol salen copper(II) catalyzed allylic oxidation; however, it is possible to reduce the amount of TBHP by using high pressures of oxygen. If the reaction happens only according to the above described reaction pathway, it should be 55 still possible to reduce the required amount of TBHP to 1 eq. The decomposition of TBHP during the reaction could be a reason for the need of excess amount of it. These results also seem to suggest that TBHP can not only function as the radical initiator of the reaction while oxygen perfoming the role of oxygen insertion into the enones. Thus, TBHP seems to play a bigger role in allylic oxidation than molecular oxygen under this catalytic system. 56 Chapter 6 Conclusions and Future Work In this dissertation, 2-quinoxalinol salen (salqu) copper(II) complexes were used as catalysts for the selective oxidation of alcohols and C-H functionalizations in the presence of tert-butyl hydroperoxide as the oxidant. Two different salqu copper(II) complexes were studied for these oxidation reactions (Figure 6.1). Figure 6.1. Structures of 2-quinoxalinol salen copper(II) complexes A salqu copper(II) complex was synthesized by reacting 3,5-ditertbutyl-2- hydroxybenzaldehyde with 6,7-diamino-2-quinoxalinol and then coordinating the ligand with Cu(OAc)2. This complex was used for the reactions conducted in organic solvents. 57 To make the salqu copper(II) complex water soluble, sulfonate groups were introduced to the ligand by reacting sulfonated salicylaldehydes with 6,7-diamino-2-quinoxalinol. The oxidation of propargylic alcohols to the corresponding carbonyl compounds was studied with the salqu copper(II) complex. Propargylic alcohol oxidation is complicated as the triple bond can also get easily oxidized. Reaction conditions were optimized using commercially available 1-phenyl-2-propyn-1-ol and it was found that 2- quinoxalinol salen or salqu copper(II) complex is efficient as a catalyst for the oxidation of 1-phenyl-2-propyn-1-ol to 1-phenyl-2-propyn-1-one under the oxidant TBHP. Several solvents were also screened and acetonitrile produced the better results for the oxidation. Time profile of the reaction showed that the maximum yield of 1-phenyl-2-propyn-1-one can be achieved at 1 h of reaction time but, it could further react and reduce the yield if the reaction was kept running. Thus, oxidation reactions were carried out in acetonitrile with 1 mol % catalyst, 3 eq TBHP at 70 ?C for 1 h. Having identified the optimum reaction conditions, the substrate scope of propargylic alcohol oxidation was investigated and a variety of substrates were converted to corresponding carbonyl compounds in good to excellent yields (up to 99 %). A wide range of functional groups such as Cl, Br, I, Me, t-Bu, OMe and NO2 were tolerated under this catalytic protocol. This catalytic system also produced excellent selectivity for oxidation of propargylic alcohols over isolated alcohols, triple bonds, or propargylic methylenes. Substituents on the arene ring of the propargylic substrates also played a part in the reaction. The propargylic alcohol oxidation was accelerated by electron-donating substituents and decelerated by electron-withdrawing substituents. The correlation 58 between log (kX/kH) and para-position Hammett constants showed a negative slope (?) indicating that the oxidation of propargylic alcohols with salqu copper(II) catalyst is likely to be electrophilic in nature under these reaction conditions.187 A water soluble version of 2-quinoxalinol salen copper(II) complex was successfully synthesized to carry out oxidation reactions in water. First, the oxidation of alcohols were studied using sulfosalqu copper(II) complex. Reaction conditions were optimized using commercially available 1-phenyl-2-propyn-1-ol and it was found that sulfosalqu copper(II) complex is efficient as a catalyst in water, for the oxidation of 1- phenyl-2-propyn-1-ol to 1-phenyl-2-propyn-1-one under the oxidant TBHP. The time profile of the reaction showed that the yields up to 83 % could be achieved within 3 h of reaction time. Several different oxidants including hydrogen peroxide, peracetic acid and m-chlroperbenzoic acid were screened for the oxidation; however, TBHP produced the better results for the alcohol dehydrogenation. Reactions carried out in the absence of saulfosalqu copper(II) complex or TBHP produced very small yields of desired product, suggesting their important role in the reaction. Also reactions ran under similar conditions with Cu(OAc)2, instead of saulfosalqu copper(II) complex, produced very low yields (27-35 %) even when 5 mol % of the catalyst used. This clearly indicates that the saulfosalqu copper(II) complex works as an excellent catalyst for the alcohol oxidation, in water. Having identified the optimum conditions for the alcohol oxidation, a wide variety of propargylic, benzylic and allylic alcohols were successfully oxidized to their corresponding carbonyl compounds in good yields (up to 99 %). This is also a rare example of propargylic alcohol oxidation in water. Electron-donor groups on the arene 59 helped to increase the reaction yield. In contrast, electron-withdrawing groups reduced the yield of carbonyl compounds. Under these conditions, oxidation of benzylic alcohols was little slower compared to that of propargylic alcohols. Oxidation of a mixture of 1- phenyl-2-propyn-1-ol and 1-octanol showed only the oxidation of 1-phenyl-2-propyn-1- ol with no formation of 1-octanal, suggesting the selectivity of sulfosalqu copper(II) catalytic system to propargylic, benzylic and allylic positions. Very little alcohol oxidation occurred when the reaction was carried out in the absence of TBHP. Addition of NEt3, a base promoter, did not increase the rate of the reaction and it helps to eliminate the possibility of the reaction to go through an ionic pathway. Thus, the alcohol oxidation is more likely to go through a radical mechanism; however, it has been a challenge to isolate radical intermediates. Sulfosalqu copper(II) complex was also found to be a good catalyst for C-H functionalization in water. Again, better results were obtained when the catalyst was in combination with TBHP. Reaction conditions were optimized using commercially available diphenylmethane and good yields of benzophenone was obtained with 3 eq of TBHP and 24 h of reaction time. Under optimized conditions, a wide variety of benzylic and allylic substrates were converted to corresponding carbonyl compounds in good to excellent yields (up to 96 %). The reaction mechanism is thought to involve radical intermediates. To further reduce the waste production in the oxidation process, molecular oxygen was tested as a potential substituent for the oxidant TBHP in the allylic oxidations. High pressure oxygen reactions suggested that molecular oxygen cannot completely replace TBHP in the 2-quinoxalinol salen copper(II) catalyzed allylic 60 oxidation; however, it was showed that 33 % of the amount of TBHP can be reduced from the original reaction by introducing 10 atm of oxygen. All these results showed that the 2-quinoxalinol salen (salqu) copper(II) complex have been an efficient catalyst for alcohol oxidations and C-H functionalizations. This catalytic system can be further improved to achieve better results including higher yields and selectivity. It is necessary to isolate and characterize radical intermediates of oxidation reactions to better understand the reaction pathway and to fine-tune the reaction conditions to achieve better selectivity. The salqu ligand can be further modified to change the properties of the ligand and to further improve yields and selectivity. For instance, conjugation of the ligand can be increased to see whether it could help to enhance the reaction rates and yields by further stabilizing the radical intermediates formed during the oxidations. This could be achieved by 3 different ways: (1) using salicylaldehyde derivatives with higher conjugation; (2) using higher conjugated diamines instead of 2-quinoxalinol; (3) using both higher conjugated salicylaldehyde and diamine. A few possible examples are shown in figure 6.2. Ligands A, B and C can be synthesized by reaction of 2-hydroxy-1- naphthaldehyde with 2-quinoxalinol, by reaction of 3,5-ditertbutylsalicylaldehyde with 2,3-diaminophenazine and by reaction of 2-hydroxy-1-naphthaldehyde with 2,3- diaminophenazine respectively. These ligands with different electronic properties can be coordinated with copper and then tested for catalytic activity. In addition, these highly conjugated salqu ligands could serve as selective metal coordination systems for use in sensors and extraction applications. These studies would broaden our understanding of the salqu ligand and help us designing more efficient catalytic systems. 61 Figure 6.2. Examples for modified salqu ligands 62 It is also interesting to alter the coordination site of the salqu ligand by introducing a flexible chelating arm. This would allow the salqu ligand to have a less rigid pocket and change the properties of the catalytic site. Hence, it can facilitate the different geometries around the ligand rather than forcing it to be square planar at the metal center. In addition, salqu ligands with altered coordination sites could test for the selective metal extractions or in sensor applications. One possible way to incorporate a flexible arm to a salqu ligand is to replace one phenolic moiety with a non rigid coordinating moiety like ethanol (Figure 6.3). In the case of ligand D, flexible arm could be incorporated in two different ways: (1) reacting 2-quinoxalinol with 2-iodoethanol or 2-bromoethanol; (2) synthesizing N-sustituted 2-quinoxalinol from DFDNB (1,5- difluoro-2,4-dinitrobenzene). Retrosynthetic analysis of ligand D is shown in scheme 6.1. Figure 6.3. Salqu ligand with a flexible arm 63 Scheme 6.1. Retrosynthetic analysis of ligand D Another future effort is to seak to improve the reusability of the catalyst. It was found that the catalyst decomposes to some extent as the reaction proceeds. Again, a 64 reaction mechanism study would help to answer this problem properly. Introduction of a solid support to the salqu copper(II) catalyst is one-way to improve the reusability of the catalyst. This would help the catalyst to be easily recovered and recycled to increase the turnover numbers with regard to industrial and environmental chemistry. According to the basic structure of the salqu ligand, a solid support can be introduced at two different positions: (1) at the hydroxyl group of the 2-quinoxalinol moiety; (2) at the phenolic moiety. Two such structures are shown in figure 6.4. For this purpose, solid supports such as polystyrene frame works and mesoporous silica can be used. Figure 6.4. Examples for solid supported salqu copper(II) complexes 65 In summary, 2-quinoxalinol salen (salqu) copper(II) complexes have been efficient catalysts for alcohol oxidations and C-H functionalizations. Oxidations can be conducted both in organic solvents and in water. Experimental results suggested that the reactions undergo a radical pathway. This catalytic system has been successful in making the oxidation process greener by increasing yields and selectivity, reducing catalytic loading and reaction time and minimizing the waste production. In future efforts, isolation of radical intermediates, alteration of coordination site and enhancement of the reusability of the catalyst are of great interest. 66 Chapter 7 Experimental Section General All reagents were obtained commercially and used without purifications. Amino acid methyl esters, DFDNB, HCl (37 %), aldehydes, ammonium hydroxide (5.0 N), tert- butyl hydroperoxide in decane, palladium on carbon (wet, 5 %) were purchased from Aldrich. Starting materials for oxidation were purchased from Alfa Easer. All organic solvents were purchased from Fisher Scientific and were directly used for synthesis. 1H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 at 400 MHz instrument; chemical shifts (?) were reported in ppm relative to Me4Si. Chromatographic purifications were performed using Fisher (60 ?, 70-230 mesh) silica gel. HRMS data were collected with electrospray ionization or chemical ionization. IR spectroscopic data were collected using SHIMADZU Inc. IR, Prestige-21 Fourier Transfer Infrared Spectrophotometer with the use of KBr solid samples and NaCl windows. GC analysis was performed on a Thermo sciencetific Trace GC Ultra instrument with flame ionization detector (FID). 67 General Procedure Synthesis of 6,7-diamino-2-quinoxalinol (Scheme 2.2) 1,5-difluoro-2,4-dinitrobenzene (5 mmol) was charged in a 100-mL round-bottom flask containing leucine methyl ester (5 mmol) and 2.2 equivalent of diisopropylethylamine (11 mmol) in THF and the reaction mixture was stirred at room temperature for 12 h. Then, 6 equivalents of ammonium hydroxide (30 mmol) was added to the same reaction mixture and stirred at room temperature for an additional 5 h. The reaction solvent was removed under reduced pressure to obtain an orange color oil. This oil was dissolved in ethanol (50 mL), and HCOONH4 (100 mmol) and 5 % wet Pd-C (1.6 g) were added. The reaction mixture was refluxed for 2 h and it was vacuum filtered and washed with ethanol. Then the filtrate was concentrated and the crude product was purified by silica column chromatography (ethyl acetate/hexane/ethanol, 8:2:1) to afford the yellow color 6,7-diamino-2-quinoxalinol; yield: 70 %. Synthesis of 2-quinoxalinol salen (salqu) ligand (Scheme 2.2) Diamino-2-quinoxalinol (2.00 mmol) was charged in a 100-mL round-bottom flask containing 3,5-di-tert-butyl-2-hydroxybenzaldehyde (2.5 mmol), methanol (40 mL) and trifluoroacetic acid (5 mol %). The reaction mixture was stirred at refluxing temperature for 18 h and salqu ligand precipitated in the solution. The solid was vacuum filtered and dried under vacuum. A yellow solid was obtained as the product (60 %). 68 Synthesis of 2-quinoxalinol salen copper(II) complex (Scheme 2.2) 2-Quinoxalinol salen ligand (0.5 mmol) dissolved in 50 mL DCM, Cu(OAc)2.H2O (0.6 mmol) dissolved in 50 mL methanol and 3 mmol of triethylamine were mixed and stirred at refluxing temperature for 2 h. After the solvent was removed, the resulting dark red solid was washed with water and cold ether 3 times each. The solid was obtained in 86 % yield. General procedure for synthesis of propargylic alcohols (Table 2.3, entries 2-12) 2-Chlorobenzaldehyde (2 mmol) was charged in a 100-mL round-bottom flask in a N2 atmosphere and it was slowly treated with ethynylmagnesium bromide (2 mmol) at -20 ?C. The reaction mixture was then stirred at -20 ?C for 2 h. After 2 h, saturated NH4Cl was added to the reaction mixture and the products were extracted to ether. Organic layer was concentrated and the products were purified by column chromatography with hexane/ethyl acetate. General procedure for oxidation of propargylic alcohols (Table 2.3) Propargylic alcohol (0.5 mmol), Cu(II) catalyst (1 mol %) and TBHP in decane (5.0 M, 0.25 mL) were stirred in acetonitrile (1.5 mL) at 70 ?C for 1 h. The reaction was monitored with TLC. After 1 h is completed, it was cooled to room temperature, the solvent was removed with a rotary evaporator, and the products were purified by column chromatography with hexane/ethyl acetate. Yields were determined by isolation of the product or by GC analysis. 69 Synthesis of sodium 3-methylsalicylaldehyde-5-sulfonate (Scheme 3.1) 3-methylsalicylaldehyde (10 mmol) was charged in a 50-mL round-bottom flask containing aniline (10 mmol) in methanol (10 mL) and the reaction mixture was stirred at reflux temperature for 18 h. Then, solvent was removed under reduced pressure to obtain an orange color oil of protected salicylaldehyde; yield: 97 %. To this compound was added five times its weight of concentrated sulfuric acid, and the mixture was heated at 110 ?C for 2 h. After cooling, it was poured into ice-pieces to induce crystallization of N- phenyl-3-methylsalicylaldimine-5-sulfonic acid. A yellow precipitate formed and it was then filtered and washed with ice-water and dried under vacuum to afford the sulfonated salicylaldehyde product; yield: 65 %. N-phenyl-3-methylsalicylaldimine-5-sulfonic acid was dissolved in boiling distilled water, and then anhydrous Na2CO3 was added until the evolution of carbon dioxide ceased. Then the mixture was boiled vigorously for 2 h. After cooling the mixture to 0 ?C, it was filtered and washed with ethanol to give 3- methylsalicylaldehyde-5-sulfonate as a pale yellow solid; yield: 65 %. Synthesis of sulfonated 2-quinoxalinol salen copper(II) complex (Scheme 3.1) 2-quinoxalinol (1 mmol) was charged in a 100-mL round-bottom flask containing 3-methylsalicylaldehyde-5-sulfonate (2.5 mmol), Cu(OAc)2?H2O (1.1 mmol) and a drop of trifluoroacetic acid in ethanol (40 mL), and the reaction mixture was stirred at reflux temperature for 4 h. Then the reaction mixture was filtered and the precipitate was washed with cold ethanol and dichlromethane. Thereafter the solid was collected and dried under vacuum to afford the sulfosalqu copper(II) complex; yield: 60 %. 70 General procedure for the oxidation of alcohols (Table 3.2) Alcohol (0.5 mmol), the Cu(II) catalyst (1 mol %), and TBHP (1.5 mmol) were stirred in water (1.5 mL) at 70 ?C for 3 h. The reaction was monitored by TLC. After 3 h, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The product was purified by column chromatography (hexane/ethyl acetate). Yields were determined by isolating the product or by using GC analysis, and the isolated products were characterized by 1H and 13C NMR spectroscopy. General procedure for the C-H activations (Table 4.2) Diphenylmethane (0.5 mmol), the Cu(II) catalyst (1 mol %), and TBHP (1.5 mmol) were stirred in water (1.5 mL) at 70 ?C for 24 h. The reaction was monitored by TLC. After 24 h, the reaction mixture was cooled to room temperature, and the products were extracted to dichloromethane. The yields were determined by GC analysis of the organic layer with the internal standard method. General procedure for the allylic C-H activations with oxygen (Scheme 5.3) 1-acetyl-1-cyclohexene (0.5 mmol), the Cu(II) catalyst (1 mol %), and TBHP (1.5 mmol) were stirred in acetonitrile (1.5 mL) at 70 ?C and 1-20 atm (oxygen) for 24 h in a pressure vessel. After 24 h, the reaction mixture was cooled to room temperature, and the yields were determined by GC analysis of the reaction mixture with the internal standard method. 71 Data Section 6,7-Diamino-2-quinoxalinol (Scheme 2.2). 1H NMR (400MHz, DMSO): ? 11.74 (s, 1 H), 6.78 (s, 1 H), 6.34 (s, 1 H), 5.37 (bs, 2 H), 4.60 (bs, 2 H), 2.52 (d, 2H), 2.13 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H). 13C NMR (400 MHz, DMSO): ? 155.3, 153.1, 140.1, 132.7, 126.0, 125.7, 111.1, 96.8, 41.7, 26.8, 23.0. 2-Quinoxalinol salen (salqu) ligand (Scheme 2.2). 1H NMR (400 MHz, CDCl3): ? 13.23 (s, 1H), 13.14 (s, 1H), 12.04 (bs, 1H), 8.58 (s,1H), 8.48 (s, 1H), 7.47 (s, 1H), 7.22 (d, 2H), 7.22 (d, 2H), 7.06 (m, 2H), 6.89 (s, 1H),2.57 (d, J = 7.1 Hz, 2H), 2.12 (m, 1H), 1.22 (s, 9H), 1.19 (s, 9H), 1.12 (s, 9H), 1.11 (s,9H), 0.83 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3): ? 166.6, 164.1, 161.4, 158.4,158.1, 155.6, 144.4, 140.4, 138.7, 136.9, 136.8, 131.3, 128.5, 128.0, 127.0, 126.8, 118.2,118.0, 117.8, 105.4, 42.0, 34.9, 34.0, 31.3, 29.3, 26.5, 22.6. 2-Quinoxalinol salen copper(II) complex (Scheme 2.2). IR (solid): 3429, 2955, 2909, 2868, 1661, 1556, 1524, 1495, 1462, 1423, 1385, 1202 cm-1. UV-Vis (CHCl3): 327 (? = 20 000 M-1 cm-1), 450 nm (? = 13 000 M-1 cm-1). Formula (M + H): C42H55N4O3Cu. HRMS: (M + H) calcd. 726.3570, found 726.3575. 3-Methylsalicylaldehyde-5-sulfonate (Scheme 3.1). 1H NMR (400MHz, D2O): ? 9.91 (s, 1 H), 7.94 (dd, J = 2.4, 0.8 Hz, 1 H), 7.80 (dd, J = 2.4, 0.8 Hz, 1 H), 2.24 (s, 3 H). 13C NMR (400 MHz, D2O): ? 197.6, 162.5, 134.0, 133.0, 128.7, 128.6, 119.4, 14.6. HRMS (EI-negative) m/z: [(M ? Na]- calcd. 215.0014, found 215.0015. 72 Sulfonated 2-quinoxalinol salen copper(II) complex (Scheme 3.1). 1H NMR spectrum was featureless due to its paramagnetism. IR (cm-1) 3430 (br), 2957, 2925, 2869, 1668, 1607, 1538, 1441, 1383, 1176, 1119, 1041, 470, 402. HRMS (EI-negative) m/z: [(M + H) ? 2 Na]- calcd. 688.0359, found 688.0361, [M ? 2 Na]2- calcd. 343.5140, found 343.5119. 1-(2-Chlorophenyl)-2-propyn-1-ol (1b, Entry 2, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.77 (dd, J = 7.2, 1.6 Hz, 1 H), 7.26-7.40 (m, 3 H), 5.83 (dd, J = 5.6, 2.4 Hz, 1 H), 3.01 (d, J = 5.6 Hz, 1 H), 2.66 (d, J = 2.4 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 137.3, 132.6, 129.8, 129.7, 128.2, 127.3, 82.4, 74.9, 61.6. IR (cm-1) 3372 (br), 3297, 3069, 2910, 1472, 1440, 1274, 1190, 1031, 952, 816, 755, 644. HRMS (EI) m/z, calcd. 166.0185, found 166.0185. 1-(3-Chlorophenyl)-2-propyn-1-ol (1c, Entry 3, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.55 (s, 1 H), 7.40-7.43 (m, 1 H), 7.31-7.32 (m, 2 H), 5.42 (dd, J = 6.0, 2.4 Hz, 1 H), 3.02 (d, J = 6.0 Hz, 1 H), 2.70 (d, J = 2.4 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 141.8, 134.5, 129.9, 128.6, 126.8, 124.8, 82.9, 75.3, 63.6. IR (cm-1) 3373 (br), 3297, 3065, 2884, 1598, 1577, 1474, 1431, 1192, 1023, 786, 689. HRMS (EI) m/z, calcd. 166.0185, found 166.0173. 1-(4-Chlorophenyl)-2-propyn-1-ol (1d, Entry 4, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.44 (dt, J = 8.8, 2.4 Hz, 2 H), 7.34 (dt, J = 8.8, 2.4 Hz, 2 H), 5.39 (s, 1 H), 3.35 (d, J = 3.6 Hz, 1 H), 2.68 (d, J = 2.4 Hz, 1 H). 13C NMR (400 MHz, 73 CDCl3): ? 138.4, 134.3, 128.7, 128.1, 83.1, 75.2, 63.5. IR (cm-1) 3373 (br), 3297, 3069, 2881, 1648, 1588, 1490, 1404, 1255, 1092, 1013, 949, 836, 791, 673. HRMS (EI) m/z, calcd. 166.0185, found 110.0179. 1-(4-Bromophenyl)-2-propyn-1-ol (1e, Entry 5, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.50 (dt, J = 8.4, 2.4 Hz, 2 H), 7.39 (dt, J = 8.4, 2.4 Hz, 2 H), 5.39 (dd, J = 6.0, 2.0 Hz, 1 H), 3.02 (d, J = 6.0 Hz, 1 H), 2.68 (d, J = 2.0 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 138.9, 131.7, 128.3, 122.5, 83.0, 75.2, 63.6. IR (cm-1) 3374 (br), 3294, 3094, 2880, 1645, 1591, 1486, 1403, 1256, 1010, 949, 831, 786, 666. HRMS (EI) m/z, calcd. 209.9680, found 209.9626. 1-(4-Iodophenyl)-2-propyn-1-ol (1f, Entry 6, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.73 (dt, J = 8.4, 2.4 Hz, 2 H), 7.31 (dt, J = 8.4, 2.4 Hz, 2 H), 5.42 (dd, J = 6.4, 2.0 Hz, 1 H), 2.69 (d, J = 2.0, Hz, 1 H), 2.37 (d, J = 6.4 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 139.6, 137.7, 128.5, 94.3, 82.9, 75.2, 63.8. IR (cm-1) 3362 (br), 3284, 3087, 2889, 1481, 1393, 1021, 1006, 945, 850, 783, 670. HRMS (EI) m/z, calcd. 257.9542, found 257.9600. 1-(p-Tolyl)-2-propyn-1-ol (1g, Entry 7, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.45 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 5.42 (s, 1 H), 2.98 (d, J = 5.6 Hz, 1 H), 2.68 (d, J = 2.0 Hz, 1 H), 2.40 (s, 3 H). 13C NMR (400 MHz, CDCl3): ? 138.3, 137.3, 129.3, 126.6, 83.8, 74.6, 64.1, 21.2. IR (cm-1) 3375 (br), 3291, 3095, 3027, 2922, 1513, 74 1414, 1275, 1179, 1016, 948, 816, 761, 651. HRMS (EI) m/z, calcd. 146.0732, found 146.0758. 1-(4-Tertbutylphenyl)-2-propyn-1-ol (1h, Entry 8, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.51 (dt, J = 8.4, 2.0 Hz, 2 H), 7.45 (dt, J = 8.4, 2.0 Hz, 2 H), 5.44 (dd, J = 6.0, 2.0 Hz, 1 H), 2.83 (d, J = 6.0 Hz, 1 H), 2.68 (d, J = 2.0 Hz, 1 H), 1.37 (s, 9 H). 13C NMR (400 MHz, CDCl3): ? 151.6, 137.2, 126.4, 125.6, 83.8, 74.6, 64.1, 34.6, 31.3. IR (cm-1) 3505 (br), 3267, 3056, 2957, 1510, 1460, 1415, 1363, 1268, 1012, 942, 843, 804, 698. HRMS (EI) m/z, calcd. 188.1201, found 188.1191. 1-(4-Methoxyphenyl)-2-propyn-1-ol (1i, Entry 9, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.47 (dt, J = 8.8, 2.0 Hz, 2 H), 6.91 (dt, J = 8.8, 2.0 Hz, 2 H), 5.41 (dd, J = 6.0, 2.4 Hz, 1 H), 3.82 (s, 3 H), 2.67 (d, J = 2.4 Hz, 1 H), 2.56 (d, J = 6.0 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 159.7, 132.4, 128.1, 114.0, 83.7, 74.6, 63.9, 55.3. IR (cm-1) 3403 (br), 3287, 3072, 2958, 2838, 1610, 1512, 1463, 1250, 1175, 1031, 948, 834, 766, 650. HRMS (EI) m/z, calcd. 162.0681, found 162.0664. 1-(4-Nitrophenyl)-2-propyn-1-ol (1j, Entry 10, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.23 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.4 Hz, 2 H), 5.74 (dd, J = 6.0, 2.0 Hz, 1 H), 2.82 (d, J = 6.0 Hz, 1 H), 2.74 (d, J = 2.0 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 147.8, 146.7, 127.4, 123.8, 82.3, 75.9, 63.3. IR (cm-1) 3502 (br), 3295, 3110, 2898, 1600, 1505, 1348, 1184, 1054, 942, 856, 743, 704, 675, 638. HRMS (EI) m/z, calcd. 177.0426, found 177.0419. 75 1-(1-Naphthyl)-2-propyn-1-ol (1k, Entry 11, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.30 (d, J = 8.4, Hz, 1 H), 7.87-7.92 (m, 3 H), 7.48-7.62 (m, 3 H), 5.65 (dd, J = 6.0, 2.4 Hz, 1 H), 2.76 (d, J = 2.4 Hz, 1 H), 2.41 (d, J = 6.0 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 135.1, 134.0, 130.4, 129.5, 128.8, 126.5, 125.9, 125.2, 124.6, 123.8, 83.2, 75.5, 62.7. IR (cm-1) 3295 (br), 3173, 3046, 2865, 1597, 1510, 1470, 1259, 1062, 1000, 940, 777, 643, 685. HRMS (EI) m/z, calcd. 182.0732, found 182.0737. 1-(2-Naphthyl)-2-propyn-1-ol (1l, Entry 12, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.02 (s, 1 H), 7.85-7.90 (m, 3 H), 7.67 (dd, J = 8.4, 1.6 Hz, 1 H), 7.50-7.54 (m, 2 H), 5.65 (dd, J = 6.4, 2.4 Hz, 1 H), 2.75 (d, J = 6.4 Hz, 1 H), 2.47 (d, J = 2.4 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 137.3, 133.3, 133.1, 128.6, 128.2, 127.7, 126.4, 126.4, 125.5, 124.4, 83.4, 75.1, 64.5. IR (cm-1) 3364 (br), 3277, 3051, 1653, 1599, 1418, 1368, 1275, 1019, 975, 864, 824, 742, 644. HRMS (EI) m/z, calcd. 182.0732, found 182.0733. 1-Phenyl-2-propyn-1-one (2a, Entry 1, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.17-8.20 (m, 2 H), 7.63-7.68 (m, 1 H), 7.50-7.54 (m, 2 H), 3.45 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 177.4, 136.1, 134.5, 129.7, 128.7, 80.7, 80.2. IR (cm-1) 3234, 3061, 2094, 1646, 1596, 1578, 1451, 1314, 1264, 1174, 1006, 698. HRMS (EI) m/z, calcd. 130.0419, found 130.0414. 1-(2-Chlorophenyl)-2-propyn-1-one (2b, Entry 2, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.11-8.13 (m, 1 H), 7.39-7.51 (m, 3 H), 3.49 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 175.9, 134.5, 133.9, 133.8, 133.3, 131.7, 126.8, 81.3, 81.1. IR (cm- 76 1) 3231, 3068, 2961, 2089, 1655, 1586, 1465, 1435, 1235, 999, 732. HRMS (EI) m/z, calcd. 164.0029, found 164.0060. 1-(3-Chlorophenyl)-2-propyn-1-one (2c, Entry 3, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.13-8.14 (m, 1 H), 8.04-8.07 (m, 1 H), 7.60-7.63 (m, 1 H), 7.45- 7.49 (m, 1 H), 3.50 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 176.0, 137.6, 135.0, 134.4, 130.0, 129.5, 127.7, 81.5, 79.8. IR (cm-1) 3251, 3070, 2930, 2097, 1652, 1537, 1426, 1242, 1035, 898, 781, 736. HRMS (EI) m/z, calcd. 164.0029, found 163.9994. 1-(4-Chlorophenyl)-2-propyn-1-one (2d, Entry 4, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.12 (dt, J = 8.8, 2.4 Hz, 2 H), 7.50 (dt, J = 8.8, 2.4 Hz, 2 H), 3.47 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 176.0, 141.2, 134.5, 131.0, 129.1, 81.2, 79.9. IR (cm-1) 3221, 2921, 2099, 1636, 1587, 1259, 1092, 1009, 843, 752. HRMS (EI) m/z, calcd. 164.0029, found 164.0015. 1-(4-Bromophenyl)-2-propyn-1-one (2e, Entry 5, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.03 (dt, J = 8.8, 2.0 Hz, 2 H), 7.66 (dt, J = 8.8, 2.4 Hz, 2 H), 3.48 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 176.2, 134.9, 132.1, 131.0, 130.1, 81.2, 79.9. IR (cm-1) 3218, 3089, 2097, 1637, 1581, 1398, 1259, 1173, 1068, 1005, 840, 748, 672. HRMS (EI) m/z, calcd. 207.9524, found 207.9498. 1-(4-Iodophenyl)-2-propyn-1-one (2f, Entry 6, Table 3). 1H NMR (400MHz, CDCl3): ? 7.85-7.90 (m, 4 H), 3.48 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 176.6, 77 138.1, 135.4, 130.0, 103.2, 81.2, 79.9. IR (cm-1) 3219, 3081, 2100, 1632, 1579, 1392, 1260, 1176, 1002, 840, 737, 673. HRMS (EI) m/z, calcd. 255.9385, found 255.9365. 1-(p-Tolyl)-2-propyn-1-one (2g, Entry 7, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.05 (dt, J = 8.4, 2.0 Hz, 2 H), 7.29 (dt, J = 8.4, 2.0 Hz, 2 H), 3.43 (s, 1 H), 2.43 (s, 3 H). 13C NMR (400 MHz, CDCl3): ? 177.0, 145.7, 133.8, 129.8, 129.4, 80.5, 80.4, 21.8. IR (cm-1) 3248, 3035, 2925, 2859, 2096, 1649, 1603, 1410, 1258, 1177, 1008, 835, 743, 684. HRMS (EI) m/z, calcd. 144.0575, found 144.0568. 1-(4-Tertbutylphenyl)-2-propyn-1-one (2h, Entry 8, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.11 (dt, J = 8.8, 2.0 Hz, 2 H), 7.52 (dt, J = 8.8, 2.0 Hz, 2 H), 3.43 (s, 1 H), 1.36 (s, 9 H). 13C NMR (400 MHz, CDCl3): ? 177.0, 158.6, 133.7, 129.7, 125.7, 80.4, 80.3, 35.3, 31.0. IR (cm-1) 3251, 2965, 2870, 2095, 1649, 1605, 1463, 1410, 1262, 1186, 1109, 1002, 851, 767, 699. HRMS (EI) m/z, calcd. 186.1045, found 186.1042. 1-(4-Methoxyphenyl)-2-propyn-1-one (2i, Entry 9, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.15 (dt, J = 8.8, 2.0 Hz, 2 H), 6.98 (dt, J = 8.8, 2.0 Hz, 2 H), 3.91 (s, 3 H), 3.39 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 175.9, 164.8, 132.1, 129.6, 113.9, 80.4, 80.0, 55.6. IR (cm-1) 3264, 3251, 2992, 2093, 1640, 1600, 1511, 1424, 1271, 1171, 1024, 841, 759, 685. HRMS (EI) m/z, calcd. 160.0524, found 160.0536. 1-(4-Nitrophenyl)-2-propyn-1-one (2j, Entry 10, Table 3). 1H NMR (400MHz, CDCl3): ? 8.33-8.39 (m, 4 H), 3.62 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 175.4, 78 151.1, 140.1, 130.6, 123.9, 82.8, 79.6. IR (cm-1) 3282, 3104, 2098, 1660, 1603, 1522, 1346, 1235, 1005, 855, 717, 669. HRMS (EI) m/z, calcd. 175.0269, found 175.0259. 1-(1-Naphthyl)-2-propyn-1-one (2k, Entry 11, Table 2.3). 1H NMR (400MHz, CDCl3): ? 9.23 (dd, J = 8.8, 0.8 Hz, 1 H), 8.64 (dd, J = 7.2, 1.2 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.93 (dt, J = 8.4, 0.8 Hz, 1 H), 7.68-7.72 (m, 1 H), 7.58-7.62 (m, 2 H), 3.46 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 178.8, 135.7, 135.5, 133.8, 131.9, 130.7, 129.2, 128.6, 126.9, 125.9, 124.4, 81.6, 79.4. IR (cm-1) 3215, 2927, 2089, 1638, 1570, 1509, 1434, 1275, 1232, 1184, 1107, 930, 774, 629. HRMS (EI) m/z, calcd. 180.0575, found 180.0581. 1-(2-Naphthyl)-2-propyn-1-one (2l, Entry 12, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.77 (s, 1 H), 8.16 (dd, J = 8.6, 2.0 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 4.4 Hz, 1 H), 7.91 (d, J = 3.6 Hz, 1 H), 7.60-7.68 (m, 2 H), 3.52 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 177.3, 136.3, 133.7, 133.3, 132.3, 129.9, 129.3, 128.6, 127.9, 127.1, 123.6, 80.6, 80.4. IR (cm-1) 3217, 3060, 2091, 1640, 1622, 1465, 1352, 1281, 1186, 1125, 1005, 941, 831, 760, 717. HRMS (EI) m/z, calcd. 180.0575, found 182.0587. 1,3-Diphenyl-2-propyn-1-one (2m, Entry 12, Table 2.3). 1H NMR (400MHz, CDCl3): ? 8.23-8.26 (m, 2 H), 7.61-7.70 (m, 3 H), 7.40-7.54 (m, 5 H). 13C NMR (400 MHz, CDCl3): ? 178.0, 136.8, 134.2, 133.1, 130.8, 129.6, 128.7, 128.6, 120.1, 93.1, 86.9. IR (cm-1) IR (cm-1) 3052, 3027, 2200, 1634, 1596, 1578, 1488, 1445, 1315, 1209, 1012, 761, 689. HRMS (EI) m/z, calcd. 206.0732, found 206.0704. 79 1-Phenyl-1-pentyn-3-one (2n, Entry 12, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.55-7.58 (m, 2 H), 7.35-7.47 (m, 3 H), 2.69 (q, J = 7.2 Hz, 1 H), 1.21 (t, J = 7.2 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 188.5, 133.0, 130.6, 128.6, 120.0, 90.6, 87.6, 38.8, 8.1. IR (cm-1) 3062, 2980, 2938, 2200, 1676, 1489, 1409, 1352, 1258, 1160, 1112, 1046, 958, 759, 689. HRMS (EI) m/z, calcd. 159.0810, found 159.0823. 4-Methyl-1-phenyl-1-pentyn-3-one (2o, Entry 12, Table 2.3). 1H NMR (400MHz, CDCl3): ? 7.48-7.51 (m, 2 H), 7.27-7.39 (m, 3 H), 2.66 (septet, J = 6.4 Hz, 1 H), 1.18 (d, J = 6.4 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 192.2, 133.0, 130.6, 128.6, 120.1, 91.6, 86.8, 43.1, 18.0. IR (cm-1) 3067, 2975, 2934, 2674, 2199, 1691, 1601, 1452, 1323, 1289, 1177, 1060, 935, 759, 710, 689. HRMS (EI) m/z, calcd. 173.0966, found 173.0970. 1-Octyn-3-one (2p, Entry 12, Table 2.3). 1H NMR (400MHz, CDCl3): ? 3.22 (s, 1 H), 2.58 (t, J = 7.6 Hz, 2 H), 1.68 (quint, J = 7.6 Hz, 2 H), 1.31 (m, 4 H), 0.90 (t, J = 7.2 Hz, 3 H). 13C NMR (400 MHz, CDCl3): ? 187.6, 81.4, 78.3, 45.4, 31.0, 23.4, 22.3, 13.8. HRMS (EI) m/z, calcd. 125.0966, found 125.0957. 1-Phenyl-2-propyn-1-one (Entry 1, Table 3.2). 1H NMR (400MHz, CDCl3): ? 8.17-8.20 (m, 2 H), 7.63-7.68 (m, 1 H), 7.50-7.54 (m, 2 H), 3.45 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 177.4, 136.1, 134.5, 129.7, 128.7, 80.7, 80.2. 80 1-(p-Tolyl)-2-propyn-1-one (Entry 2, Table 3.2). 1H NMR (400MHz, CDCl3): ? 8.05 (dt, J = 8.4, 2.0 Hz, 2 H), 7.29 (dt, J = 8.4, 2.0 Hz, 2 H), 3.43 (s, 1 H), 2.43 (s, 3 H). 13C NMR (400 MHz, CDCl3): ? 177.0, 145.7, 133.8, 129.8, 129.4, 80.5, 80.4, 21.8. 1-(4-Methoxyphenyl)-2-propyn-1-one (Entry 3, Table 3.2). 1H NMR (400MHz, CDCl3): ? 8.15 (dt, J = 8.8, 2.0 Hz, 2 H), 6.98 (dt, J = 8.8, 2.0 Hz, 2 H), 3.91 (s, 3 H), 3.39 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 175.9, 164.8, 132.1, 129.6, 113.9, 80.4, 80.0, 55.6. 1-(4-Nitrophenyl)-2-propyn-1-one (Entry 4, Table 3.2). 1H NMR (400MHz, CDCl3): ? 8.33-8.39 (m, 4 H), 3.61 (s, 1 H). 13C NMR (400 MHz, CDCl3): ? 175.4, 151.1, 140.1, 130.6, 123.9, 82.8, 79.6. 1,3-Diphenyl-2-propyn-1-one (Entry 5, Table 3.2). 1H NMR (400MHz, CDCl3): ? 8.24-8.26 (m, 2 H), 7.63-7.73 (m, 3 H), 7.42-7.56 (m, 5 H). 13C NMR (400 MHz, CDCl3): ? 178.0, 136.8, 134.2, 133.1, 130.8, 129.6, 128.7, 128.6, 120.1, 93.1, 86.9. 1-Phenyl-1-pentyn-3-one (Entry 6, Table 3.2). 1H NMR (400MHz, CDCl3): ? 7.58-7.60 (m, 2 H), 7.38-7.49 (m, 3 H), 2.72 (q, J = 7.2 Hz, 1 H), 1.23 (t, J = 7.2 Hz, 1 H). 13C NMR (400 MHz, CDCl3): ? 188.7, 133.0, 130.6, 128.6, 120.0, 90.6, 87.6, 38.8, 8.1. 81 3-Phenyl-2-propyn-1-al (Entry 7, Table 3.2). 1H NMR (400MHz, CDCl3): ? 9.44 (s, 1 H), 7.62 (d, J = 7.2 Hz, 2 H), 7.51 (t, J = 7.2 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 2 H). 13C NMR (400 MHz, CDCl3): ? 176.5, 133.3, 131.3, 128.7, 119.4, 95.1, 88.4. 1-Octyn-3-one (Entry 8, Table 3.2). 1H NMR (400MHz, CDCl3): ? 3.22 (s, 1 H), 2.58 (t, J = 7.6 Hz, 2 H), 1.68 (quint, J = 7.6 Hz, 2 H), 1.31 (m, 4 H), 0.90 (t, J = 7.2 Hz, 3 H). 13C NMR (400 MHz, CDCl3): ? 187.6, 81.4, 78.3, 45.4, 31.0, 23.4, 22.3, 13.8. Acetophenone (Entry 9, Table 3.2). 1H NMR (400MHz, CDCl3): ? 7.96 (d, J = 7.2 Hz, 2 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.46 (t, J = 9.2 Hz, 2 H), 2.61 (s, 3 H). 13C NMR (400 MHz, CDCl3): ? 198.1, 137.1, 133.1, 128.5, 128.3, 26.6. 1-(4-Methoxyphenyl)ethanone (Entry 10, Table 3.2). 1H NMR (400MHz, CDCl3): ? 7.92 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H), 2.54 (s, 3 H). 13C NMR (400 MHz, CDCl3): ? 196.8, 163.4, 130.5, 130.2, 113.6, 55.4, 26.3. Benzophenone (Entry 11, Table 3.2). 1H NMR (400MHz, CDCl3): ? 7.82 (d, J = 7.6 Hz, 4 H), 7.59 (t, J = 7.6 Hz, 2 H), 7.49 (t, J = 7.6 Hz, 4 H). 13C NMR (400 MHz, CDCl3): ? 196.7, 137.6, 132.4, 130.0, 128.3. 2-Acetylpyridine (Entry 12, Table 3.2). 1H NMR (400MHz, CDCl3): ?, 8.68 (d, J = 4.8 Hz, 1 H), 8.04 (d, J = 7.6 Hz, 1 H), 7.83 (t, J = 7.6 Hz, 1 H), 7.46 (m, 1 H), 2.72 (s, 1 H) 13C NMR (400 MHz, CDCl3): ? 200.1, 153.5, 148.9, 136.5, 127.1, 121.6, 25.8. 82 2-Cyclohexenone (Entry 13, Table 3.2). 1H NMR (400MHz, CDCl3): ? 6.99 (m, 1 H), 5.99 (m, 1 H), 2.39 (m, 2 H), 2.32 (m, 2 H), 2.01 (m, 2 H). 13C NMR (400 MHz, CDCl3): ? 199.7, 150.7, 129.8, 38.0, 25.6, 22.7. 2-Methyl-1-phenyl-2-propen-1-one (Entry 14, Table 3.2). 1H NMR (400MHz, CDCl3): ? 7.75 (m, 2 H), 7.54 (m, 1 H), 7.44 (m, 2 H), 5.92 (s, 1 H), 5.64 (s, 1 H), 2.09 (s, 3 H). 13C NMR (400 MHz, CDCl3): ? 198.4, 143.7, 137.7, 132.0, 129.4, 128.1, 127.1, 18.6. 83 References (1) Anastas P. T.; Warner, J. C. 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