Part 1: COMBINATORIAL SYNTHESIS OF NITROGENCONTAINING HETEROCYCLES Part 2A: DEVELOPMENT AND APPLICATION OF HANTZSCH ESTER Part 2B: DEVELOPMENT AND APPLICATION OF A HYPERVALENT IODINE REAGENT CHE JUN NATIONAL UNIVERSITY OF SINGAPORE 2011 i Part 1: COMBINATORIAL SYNTHESIS OF NITROGENCONTAINING HETEROCYCLES Part 2A: DEVELOPMENT AND APPLICATION OF HANTZSCH ESTER Part 2B: DEVELOPMENT AND APPLICATION OF A HYPERVALENT IODINE REAGENT CHE JUN (B.Sc., Soochow University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2011 ii Acknowledgements I would like to express my greatest gratitude to my supervisor, Associate Professor Lam Yulin, for her patient guidance, continuous flow of ideas, encouragement and invaluable advice throughout my studies. I would like to express my appreciation to my group members, Ching Shi Min, Fang Zhanxiong, Fu Han, Gao Yaojun, Gao Yongnian, He Rongjun, Kong Kah Hoe, Makam Shantha Kumar Raghavendra, Sanjay Samanta, William Lin Xijie, Woen Susanto, and Wong Lingkai for their help and encouragement during my research. I would also like to thank staff from the NMR, MS, Chromatography laboratories and chemical supplies for their patience to help me greatly in analyzing compounds and purchasing of chemicals. I am also greatful to the National University of Singapore for awarding me the research scholarship. Finally, I would like to thank my family for their support. i Table of Contents Acknowledgements i Table of Contents ii Summary vii List of Tables ix List of Figures xi List of Schemes xii List of Abbreviations xiii List of Publications xvi Part Chapter 1: Introduction 1.1 Combinatorial Solid-Phase Synthesis 1.1.1 Introduction 1.1.2 Solid-Phase Synthesis 1.1.3 Advantages and Disadvantages 1.2 Solid Supports 1.2.1 Polystyrene Resins 1.2.2 Polyethylene Glycol-Containg Polymers 1.2.3 Polyacrylamide Polymers. 1.3 Linkers 1.3.1 Acid-labile Linkers 1.3.2 Nucleophile- and Base-labile Linkers 1.3.2.1 Nucleophile-labile Linkers ii 1.3.2.2 Base-labile Linkers 1.3.3 Photo-labile Linkers 11 1.3.4 Safety-catch Linkers 11 1.3.5 Traceless Linkers 12 1.4 Analytical Methods for Solid-Phase Synthesis 14 1.4.1 FTIR Methods 15 1.4.2 Gel Phase NMR 15 1.4.3 High-Resolution Magic Angle Spinning (HR-MAS) NMR 16 1.4.4 Spectrophotometric Methods 16 1.5 Objectives of Our Studies 16 1.6 References 17 Chapter Combinatorial Solid-phase Synthesis of Hetero-annulated 1,3-Oxazin6-ones 2.1 Introduction 22 2.1.1 Importance of Fused 1,3-oxazin-6-ones 22 2.1.2 Synthetic Strategy 23 2.2 Results and Discussion 24 2.2.1 Synthesis of Polymer-supported Five-membered Heterocycle Amine 24 2.2.1.1 Synthesis of Polymer-supported 5-Amino-3-disubstituted-3Himidazole 2-1-4 24 2.2.1.2 Synthesis of Polymer-supported 5-Amino-2,3-disubstituted-3Himidazole 2-1-5 25 2.2.1.3 Synthesis of Polymer-supported 5-Amino-1,3-trisubstituted-1Hpyrazole 2-1-8 27 iii 2.2.1.4 Synthesis of Polymer-supported 2-Amino-1,4,5-dimethyl-1H-pyrrole 2-1-9 28 2.2.1.5 Synthesis of Polymer-supported 5-Amino-2,3-disubstituted thiophene 2-1-10 28 2.2.2 Solid-Phase Synthesis of the 1,3-Oxazin-6-one Ring Formation 28 2.2.2.1 Solution-Phase Synthesis of 2-1-17 28 2.2.2.2 Solid-Phase Synthesis of 2-1-17 31 2.2.2.3 Solid-Phase Synthesis of 2-1-16, 2-1-18, 2-1-19 and 2-1-20 33 2.3 Conclusion 33 2.4 Experimental Section 33 2.4.1 Materials 33 2.4.2 General Procedure and Compound Characterization Data 34 2.5 References 54 Part 2A Chapter Reduction of Ketimines and Electron-Withdrawing Group Conjugated Olefins by Polymer-Supported Hantzsch 1,4-dihydropyridine Ester 3.1 Introduction 57 3.2 Results and Discussion 59 3.2.1 Reduction of Active Alkenes 59 3.2.2 Reduction of Ketimines 64 3.2.3 Reduction of (Z)-α-cyano-β-bromomethylcinnamates and Its Analogs 66 3.3 Conclusion 67 3.4 Experiment Section 67 3.4.1 Materials 67 iv 68 3.4.2 General Procedure and Compound Characterization Data 3.5 References 75 Chapter TiCl4 Catalyzed Hydrogenation of α,β-Unsaturated Ketones and Alkylidene Malonic Diesters by Hantzsch 1,4-Dihydropyridine Ester 4.1 Introduction 78 4.2 Results and Discussion 78 4.3 Conclusion 84 4.4 Experiment Section 84 4.4.1 Materials 84 4.4.2 General Procedure and Compound Characterization Data 84 4.4.2.1 General Procedure for the Synthesis α,β-Unsaturated Ketones 84 4.4.2.2 General Procedure for the Reduction of α,β-Unsaturated Ketones 87 4.4.2.3 General Procedure for the Synthesis of Alkylidene Malonic Diesters 91 4.4.2.4 General Procedure for the Reduction of Alkylidene Malonic Diesters 92 4.5 References 94 Part 2B Chapter Applications of o-Iodosophenylphosphoric Acid in Oxidation, Chlorination and Alkoxylation Reactions 5.1 Introduction 97 5.2 Results and Discussion 97 v 5.2.1 Synthesis of the o-Iodosophenylphosphoric Acid 98 5.2.2 Oxidation of Phosphines 98 5.2.3 Oxidation of Sulfides 100 5.2.4 Oxiadation of Alcohols 103 5.2.5 α-Chlorination of Ketones 105 5.2.6 α-Alkoxylation and α-Hydroxylation of Ketones 107 5.3 Conclusion 109 5.4 Experiment Section 109 5.4.1 Materials 109 5.4.2 General Procedure and Compound Characterization Data 109 5.4.2.1 Procedure for the Synthesis of 5-4e 109 5.4.2.2 Procedure for the Synthesis of 5-8f 110 5.4.2.3 Procedure for the Synthesis of 5-8g 111 5.4.2.4 Procedure for the Synthesis of 5-10c 111 5.4.2.5 General Procedure for the Phosphine Oxidation by 5-1 112 5.4.2.6 General Procedure for the Sulfide Oxidation by 5-1 112 5.4.2.7 General Procedure for the Alcohol Oxidation by 5-1 112 5.4.2.8 General Procedure for α-Chlorination of the Ketones with 5-1 113 5.4.2.9 General Procedure for α-Alkoxylation of the Ketones with 5-1 113 5.5 References 114 vi Summary This thesis is composed by two parts: Combinatorial Synthesis of N-Containing Heterocycles (Part 1). Development and Application of Hantzsch Ester (Part 2a); Development and Application of Hypervalent Iodine Compounds (Part 2b); Part of this thesis focuses on combinatorial synthesis of N-containing heterocycles. In this project, a microwave-assisted Solid-Phase Synthesis of hetero-annulated 1,3-oxazin-6-ones has been developed. Significant rate enhancement was observed for all steps carried out under microwave irradiation and the overall reaction time was dramatically shortened when compared to the conventional procedures. A representative set of 20 bi- and tricyclic heteroannulated 1,3-oxazin-6-ones was prepared. Part 2a comprises two projects. (i) Reduction of Ketimines and Electron-Withdrawing Group Conjugated Olefins by Polymer-Supported Hantzsch 1,4-dihydropyridine Ester; (ii) TiCl4 Catalyzed Hydrogenation of α,β-Unsaturated Ketones and Alkylidene Malonic Diesters by Hantzsch 1,4-Dihydropyridine Ester. In the first project, we have demonstrated that the reductions of (i) active alkenes, (ii) ketimines and (iii) (Z)-α-cyano-β- bromomethylcinnamates and its analogs could be achieved with the polymer supported Hantzsch ester in high yields and chemoselectivity. In the second project, we have shown that the TiCl4-catalyzed Hantzsch 1,4-Dihydropyridine Ester reduction of α,β-unsaturated ketones and alkylidene malonic diesters is a rapid and experimentally simple procedure for the preparation of saturated ketones and alkyl malonic diesters. vii Part 2b is Development and Applications of a Hypervalent Iodine Reagent. In this project, we have demonstrated that the hypervalent iodine compound can be used for the oxiadation of phosphines, sulphur ethers and alcohols. In addition, we have demonstrated α-chlorination, α-alkoxylation and α-hydroxylation of ketones with the hypervalent iodine compounds. All the reactions can be performed efficiency with good yields. viii Sulfoxides have fascinated organic chemist worldwide for a long time owing to their varied reactivity as a functional group for transformations into a variety of organo sulfur compounds. These transformations are useful for the synthesis of drugs and sulfur-substituted natural products.9 Sulfoxides are usually obtained by the oxidation of sulfides and the use of hypervalent iodine compounds for such an oxidation has already been studied by several groups.10 Krishnacharya10a reported the sulfoxidation with IBX while John10a reported the sulfoxidation with iodosylarene. However with IBX and iodosylarene, the reactions proceeded very slowly without an acid catalyst. To address this problem, Kalyan10b reported the sulfoxidation of diphenylsulfide with Me-IBX. However when Me-IBX was applied to other sulfide substrates, the yield of the desired product obtained was less satisfactory. Table 5-4 Microwave-assisted oxidation of dibenzyl sulfide 5-4a a) Entry Solvent Temp. Time Yielda) THF MW, 60 °C 20 88% THF MW, 70 °C 10 90% THF MW, 80 °C 95% Yield of isolated product With reagent 5-1 in hand, we proceeded to examine its applicability in the sulfide oxidation. Dibenzyl sulfide 5-4a was initially treated with 5-1 in CH3CN at room temperature for 60 min. This gave 5-5a in 76% yield. To optimize the reaction, various solvents were screened and we found that the reaction proceeded well in THF (Entry 2, Table 5-3). To perform the reaction more expeditiously, we explored the reactions under microwave conditions. A systematic variation of the reaction time and temperature was carried out using 5-4a and 5-1 in THF (Table 5-4). We discovered that when the reaction was carried out at 80 oC, the 101 reaction was completed within and provided the desired product 5-5a in 95% yield (Entry 3, Table 5-4). Table 5-5 Oxidation of various sulfides a) Yield of isolated product Encouraged by this result, we examined the oxidation with other sulfides using the optimized reaction condition and obtained generally good yields for all the substrates (Table 5-5). 102 Table 5-6 Optimization of the reaction condition for oxidation of 5-6a to 5-7a a) b) Entry Equivalent of Bu4NBr Reaction Condition Yielda) 0.5 equiv DCM, rt, h 82% 0.5 equiv THF, rt, h 63% 0.5 equiv CH3CN, rt, h 72% 0.5 equiv DMF, rt, h 81% 0.5 equiv DCM, MW, 60 oC, 10 NRb 0.5 equiv DCM, MW, 70 oC, 10 NRb 0.5 equiv DCM, MW, 85 oC, 82% 0.2 equiv DCM, MW, 85 oC, 70% 1.2 equiv DCM, MW, 85 oC, 90% Isolated yield The reaction is not completed according to the TLC 5.2.4 Oxiadation of Alcohols The oxidation of alcohols to carbonyl compounds by hypervalent iodine compounds such as IBX11a, (diacetoxyiodo) benzene11b, and Me-IBX11b have already been reported. In this chapter, we have employed 5-1 to the oxidation of alcohols. Reaction optimization using diphenylmethanol 5-6a showed that the reaction proceeded well with reagent 5-1 in the present of a catalyst Bu4NBr in DCM to give benzophenone in good yield (Entry 9, Table 56). To demonstrate the general applicability of 5-1 to the oxidation of alcohols, a number of 103 other alcohols were examined and generally good results were obtained for all the substrates (Table 5-7). Table 5-7 Oxidation of various alcohols to carbonyl compounds a) Isolated yield 5.2.5 α-Chlorination of Ketones Table 5-8 Optimization of the reaction condition for the α-chlorination of ketones 104 a) Entry Solvent Reaction Condition Yielda) THF rt, h 5% THF reflux, o/n 22% THF MW, 90 oC, 30 10% THF MW, 100 oC, 30 18% THF MW, 110 oC, 30 22% THF MW, 120 oC, 30 33% CH3CN rt, h 100% CH3CN MW, 60 oC, 100% CH3CN MW, 70 oC, 100% Isolated yield α-Haloketones are important intermediates in organic synthesis and their high reactivities with large number of nucleophiles provide a variety of useful compounds.12 They can be made by the α-halogenation of ketones using halide sources (X-) in combination with various hypervalent iodine compounds.12 However, the yield of the halogenations is usually not good and at times even over-halogenation was found.12b Here, we have demonstrated that reagent51 can also be used to carry out the chlorination of the ketones with lewis acid AlCl3. Reaction optimization using propiophenone 5-8a showed that the reaction works very well with reagent 5-1 under a catalyst AlCl3 in CH3CN to give the 5-9a in quantitative yield (Table 58). When the reaction was performed in THF, the yield was very poor. Even raising the temperature to reflux condition or carrying out the reaction under microwave condition did not significantly improve the yield (Entries and 3, Table 5-8). Using the optimized 105 condition (Entry 8, Table 5-8), seven α-chloroketones were oxidized with reagent 5-1 in good yields (Table 5-9). Table 5-9 α-Chlorination of various ketones a) Isolated yield 106 5.2.6 α-Alkoxylation and α-Hydroxylation of Ketones Scheme 5-2 α-Alkoxylation of 5-10b Scheme 5-3 α-hydroxylation of 5-10b Earlier works have demonstrated that α-alkoxylation of the ketones can be achieved by some hypervalent iodine compounds, such as HNIB14a, HTIB14b and diacetoxyiodo styrene12c. To explore the application of 5-1 in the α-alkoxylation of ketones, we proceeded to prepare 511b using a procedure previously reported by Justik14. However, when the procedure was applied to other substrates, 5-11bb was found as a side product (Scheme 5-2). Attempts to avoid the formation of 5-11bb by changing the solvent from MeOH to CH3CN resulted in the formation of the α-hydroxylation product 5-11cc (Scheme 5-3). We hypothesized that the formation of 5-11bb may be attributed to the use of trimethylorthoformate (TMOF) because when 2.3 eguiv. of TMOF was used, 5-11b and 5-11bb were obtained in 23% and 62% yield respectively. Furthermore, when TMOF was used as the solvent, no 5-11b was found. To our delight, when TMOF was removed from the reaction, only 5-11b was found in 85% yield. To explore the effects of microwave on the reaction, we carried out the reaction under microwave-assisted condition (Table 5-10) which increased the yield of 5-11b to 88%. Similar α-alkoxylation reactions were applied to five other ketones and the yields obtained are shown in Table 5-10. 107 Table 5-10 α-Alkoxylation of various ketones to α-alkoxylated compounds a) Isolated yield b) Reaction was performed under MW 60 oC for c) Reaction was performed under MW 90 oC for 10 108 5.3 Conclusion In summary, we have demonstrated that 5-1 can be used for the oxidation of phosphines, sulfides and alcohols. In addition, we have demonstrated the α-chlorination, α-alkoxylation and α-hydroxylation of ketones with 5-1. All the reactions proceeded efficiently and with good yields. 5.4 Experiment Section 5.4.1 Materials All chemical reagents were obtained from Aldrich, Merck, Lancaster or Fluka and used without further purification. Analytical TLC was carried out on pre-coated plates (Merck silica gel 60, F254) and visualized with UV light or stained with ninhydrin. 1H NMR and 13C NMR spectra were measured at 298 K on a Bruker AMX 500 Fourier Transform spectrometer. Chemical shifts were reported in  (ppm), relative to the internal standard of TMS. The signals observed were described as: s, d, t, q, m. The number of protons (n) for a given resonance was indicated as nH. Mass spectrometry was performed on a Finnigan MAT 95/XL-T spectrometer under electron impact (EI) ionization and electrospray ionization (ESI) techniques. Microwave reactions were performed in sealed tube conditions on a Biotage InitiatorTM microwave synthesizer. 5.4.2 General Procedure and Compound Characterization Data 109 5.4.2.1 Procedure for the Synthesis of 5-4e To a solution of 2-(phenylthio)ethanol (0.1540 g, mmol) in DCM (5 mL) was added benzoyl chloride (0.1680 g, 1.2 mmol), TEA (0.1214 g, 1.2 mmol) and DMAP (0.0241 g, 0.2 mmol). The reaction mixture was stirred at rt for h. Thereafter, it was concentrated and purified by column chromatography (Merck silica gel 60, F254) to give compound 5-4e. Compound 5-4e: 1H NMR (CDCl3, 500 MHz): δ 3.30-3.33 (t, H, J = 7.0 Hz, PhSCH2CH2), 4.51-4.54 (t, H, J = 7.4 Hz, PhSCH2CH2), 7.24-7.58 (m, H, ArH), 8.01-8.02 (d, H, J = 7.6 Hz, ArH). 13 C NMR (CDCl3, 75 MHz): δ 32.6, 63.6, 126.7, 128.4, 129.1, 129.7, 129.9, 130.0, 133.1, 135.2, 166.4. HRMS (EI, C15H14O2S): Calcd: 258.0715; found: 258.0717. 5.4.2.2 Procedure for the Synthesis of 5-8f To a solution of 4-hydroxylacetophenone (0.1361 g, mmol) in DCM (5 mL) was added 4-toluenesulfonyl chloride (0.2288 g, 1.2 mmol), TEA (0.1214 g, 1.2 mmol) and DMAP (0.0241 g, 0.2 mmol). The reaction mixture was stirred at rt for h. Thereafter, it was concentrated and purified by column chromatography (Merck silica gel 60, F254) to give compound 5-8f. Compound 5-8f: 1H NMR (CDCl3, 500 MHz): δ 2.39 (s, H, PhCH3), 2.51 (s, H, PhCOCH3), 7.02-7.04 (d, H, J = 8.9 Hz, ArH), 7.27-7.29 (d, H, J = 8.2 Hz, ArH), 7.647.66 (d, H, J = 8.2 Hz, ArH), 7.84-7.85 (t, H, J = 4.4 Hz, ArH). 13C NMR (CDCl3, 125 MHz): δ 21.6, 26.6, 122.4, 128.4, 130.0, 130.0, 132.0, 135.6, 145.9, 152.9, 196.6. HRMS (EI, C15H14O4S): Calcd: 290.0613; found: 290.0617. 110 5.4.2.3 Procedure for the Synthesis of 5-8g To a solution of 4-hydroxylacetophenone (0.1361 g, mmol) in DCM (5 mL) was added 1-naphthalene sulfonyl chloride (0.2718 g, 1.2 mmol), TEA (0.1214 g, 1.2 mmol) and DMAP (0.0241 g, 0.2 mmol). The reaction mixture was stirred at rt for h. Thereafter, it was concentrated and purified by column chromatography (Merck silica gel 60, F254) to give compound 5-8g. Compound 5-8g: 1H NMR (CDCl3, 500 MHz): δ 2.47 (s, H, PhCOCH3), 6.95-6.97 (d, H, J = 8.2 Hz, ArH), 7.41-8.11 (m, H, ArH), 8.79-8.81 (d, H, J = 8.8 Hz, ArH). 13C NMR (CDCl3, 125 MHz): δ 26.3, 121.8, 123.8, 124.5, 127.3, 128.1, 128.9, 129.0, 129.8, 130.2, 131.1, 133.8, 135.4, 135.9, 152.7, 196.3. HRMS (EI, C18H14O4S): Calcd: 326.0613; found: 326.0615. 5.4.2.4 Procedure for the Synthesis of 5-10c To a solution of 4-hydroxyl propiophenone (0.1501 g, mmol) in DCM (5 mL) was added 1-naphthalene sulfonyl chloride (0.2718 g, 1.2 mmol), TEA (0.1214 g, 1.2 mmol) and DMAP (0.0241 g, 0.2 mmol). The reaction mixture was stirred at rt for h. Thereafter, it was concentrated and purified by column chromatography (Merck silica gel 60, F254) to give the target compound 5-10c. Compound 5-10c: 1H NMR (CDCl3, 500 MHz): δ 1.12-1.15 (t, H, J = 7.3 Hz, PhCOCH2CH3), 2.84-2.89 (q, H, PhCOCH2CH3), 6.95-6.97 (q, H, ArH), 7.42-8.12 (m, H, ArH), 8.80-8.81 (d, H, J = 8.9 Hz, ArH). 13 C NMR (CDCl3, 125 MHz): δ 8.04, 31.8, 111 122.1, 124.0, 124.8, 127.5, 128.4, 129.2, 129.2, 129.7, 130.5, 131.3, 134.1, 135.5, 136.1, 152.8, 199.2. HRMS (EI, C19H16O4S): Calcd: 340.0769; found: 340.0771. 5.4.2.5 General Procedure for the Phosphine Oxidation by 5-1 To a solution of the respective phosphine 5-2 (0.2 mmol) in dry CH3CN (2 mL) was added 5-1 (0.3 mmol). The reaction was irradiated under MW at 60 oC for min. When the reaction was completed, the reaction mixture was concentrated and filtered through a small pad of silica to give compound 5-3. 5.4.2.6 General Procedure for the Sulfide Oxidation by 5-1 To a solution of the respective sulfide 5-4 (0.2 mmol) in dry THF (2 mL) was added 5-1 (0.3 mmol). The reaction was irradiated under MW at 80 oC for min. When the reaction was completed, the reaction mixture was concentrated and filtered through a small pad of silica to give compound 5-5. Compound 5-5e: 1H NMR (CDCl3, 300 MHz): δ 3.19-3.25 (m, H, PhCOOCH2CH2), 4.644.68 (m, H, PhCOOCH2CH2), 7.36-7.66 (m, H, ArH), 7.91-7.93 (d, H, J = 7.5 Hz, ArH). 13 C NMR (CDCl3, 75 MHz): δ 56.1, 57.5, 123.9, 128.4, 129.4, 129.7, 131.2, 133.3, 143.3, 166.0. HRMS (EI, C15H14O3S): Calcd: 274.0664; found: 274.0668. 5.4.2.7 General Procedure for the Alcohol Oxidation by 5-1 To a solution of the respective alcohol 5-6 (0.2 mmol) and Bu4NBr (0.24 mmol) in dry DCM (2 mL) was added 5-1 (0.3 mmol). The reaction was irradiated under MW at 85 oC for 112 min. When the reaction was completed, the reaction mixture was concentrated and purified by a column chromatography (Merck silica gel 60, F254) to give compound 5-7. 5.4.2.8 General Procedure for α-Chlorination of the Ketones with 5-1 To a solution of the respective ketone 5-8 (0.2 mmol) and 5-1 (0.3 mmol) in dry CH3CN (2 mL) was added AlCl3 (0.3 mmol). The reaction was irradiated under MW at 60 oC for min. When the reaction was completed, the reaction mixture was concentrated and filtered through a small pad of silica to give compound 5-9. Compound 5-9f: 1H NMR (CDCl3, 500 MHz): δ 2.45 (s, H, PhCH3), 4.64 (s, H, PhCOCH2Cl), 7.11-7.13 (q, H, ArH), 7.32-7.33 (d, H, J = 8.2 Hz, ArH), 7.70-7.72 (d, H, J = 8.2 Hz, ArH), 7.89-7.91 (q, H, ArH). 13 C NMR (CDCl3, 125 MHz): δ 21.7, 45.7, 122.8, 128.5, 130.0, 130.4, 132.1, 132.8, 146.0, 153.6, 189.9. HRMS (EI, C15H13O4S35Cl): Calcd: 324.0223; found: 324.0230. Compound 5-9g: 1H NMR (CDCl3, 500 MHz): δ 4.58 (s, H, PhCOCH2Cl), 7.02-7.03 (q, H, ArH), 7.47-8.17 (m, H, ArH), 8.79-8.81 (d, H, J = 8.9 Hz, ArH). 13 C NMR (CDCl3, 125 MHz): δ 45.5, 122.1, 122.5, 124.0, 124.8, 127.5, 128.4, 129.1, 129.2, 130.3, 131.3, 132.7, 134.1, 136.1, 153.5, 189.7. HRMS (EI, C18H13O4S35Cl): Calcd: 360.0223; found: 360.0212. 5.4.2.9 General Procedure for α-Alkoxylation of the Ketones with 5-1 To a solution of the respective ketone 5-10 (0.2 mmol) and 5-1 (0.3 mmol) in dry MeOH (2 mL) was added concentrated H2SO4 (0.6 mmol). The reaction was irradiated under MW at 113 90 oC for 10 min. When the reaction was completed, the reaction mixture was concentrated and filtered through a small pad of silica to give compound 5-11. Compound 5-11c: 1H NMR (CDCl3, 500 MHz): δ 1.40-1.42 (d, H, J = 6.9 Hz, PhCOCHCH3), 3.31 (s, H, OCH3), 4.43-4.47 (q, H, PhCOCHCH3), 6.98-7.00 (m, H, ArH), 7.47-8.16 (m, H, ArH), 8.79-8.81 (d, H, J = 8.9 Hz, ArH). 13C NMR (CDCl3, 125 MHz): δ 18.1, 57.2, 80.6, 122.1, 124.0, 124.9, 127.5, 128.5, 129.1, 129.1, 130.6, 130.7, 131.3, 133.3, 134.1, 136.0, 153.1, 199.2. HRMS (EI, C20H18O5S): Calcd: 370.0875; found: 370.0872. 5.5 References 1. Kevin, W. K.; Barry, I. P.; George, Just. Bioorg. Med. Chem. Lett. 1999, 9, 353-356. 2. (a) Koser, G. F. Adv. Heterocycl. Chem. 2004, 86, 225–292. (b) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893–2903. (c) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 3759–3772. (d) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 467–495. (e) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358. (f) Uyanik, M.; Ishihara, K. Chem. Commun. 2009, 2086–2099. (g) Yusubov, M. S.; Zhdankin, V. V. 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General nucleophile- and base-labile linkers and their cleavage reagents 8 Figure 1- 6 General representation of a nucleophile-labile linker 9 Figure 1- 7 Generic representative of base-labile cleavage process 10 Figure 1- 8 Safety-catch Linkers 12 Figure 2 -1 Library of 2 -1- 16, 2 -1- 17, 2 -1- 18, 2 -1- 19, 2 -1- 20 31 Figure 3 -1 Polymer-supported Hantzsch ester 56 Figure 3-2 Reduction of Ketimines and Electron-Withdrawing... with 3 -1 57 xi List of Schemes Scheme 1- 1 Nucleophile promoted cleavage 9 Scheme 1- 2 Base promoted cleavage 10 Scheme 1- 3 Cleavage of a Photo-labile linker in SPS 11 Scheme 1- 4 Cleavage of Kenner’s Safety-catch linker in SPS 12 Scheme 1- 5 Aryl silyl system linker and its cleavage condition 13 Scheme 1- 6 Germanium traceless linker and its cleavage condition 13 Scheme 1- 7 Sulfur-based linker example 14 Scheme... Scheme 1- 8 Selenium-based linker example 14 Scheme 2 -1 SPS of Hetero-annulated 1, 3-Oxazin-6-ones 22 Scheme 2-2 Solution phase synthesis of 2-2-5 24 Scheme 2-3 Solution phase synthesis of 2-2-7 25 Scheme 2-4 Solution phase synthesis of 2 -1- 17a 28 Scheme 5 -1 Synthesis of o-iodosophenylphosphoric acid 5 -1 97 Scheme 5-2 α-Alkoxylation of 5 -10 b 10 6 Scheme 5-3 α-Hydroxylation of 5 -10 b 10 6 xii List of Abbreviations... L J.; Sheppard, R C J Chem Soc Perkin Trans 1 19 81, 529-538 13 (a) Small, P W.; Sherrington, D C J Chem Soc Chem Commun 19 89, 15 89 -15 91 (b) Raillard, S P.; Ji, G.; Mann, A D.; Baer, A Org Process Res Dev 19 99, 3, 17 7 -18 3 14 Beaver, K A.; Siegmund, A C.; Speak, K L Tetrahedron Lett 19 96, 37, 3 213 -3 214 15 Barany, G.; Merrifield, R B Peptides, 19 79, 2, 1- 8 16 Hirao, A.; Itsuno, S.; Hattori, I.; Yamaguchi,... Chem 19 71, 246, 19 22 -19 41 4 (a) Tuek, C.; Gold, L Science, 19 90, 249, 505- 510 (b) Andrew, D E.; Jack, W S Nature, 19 90, 346, 818 -822 (c) Fassina, G.; Verdoliva, A.; Ruvo, M.; Cassani, G J Mol Recogn 19 96, 9, 564-570 5 Cironi, P.; Alvarez, M.; Albericio, F Mini Reviews in Medcinal Chemistry 2006, 6, 11 -25 6 Verlander, M International Journal of Peptide Research and Therapeutics, 2007, 13 , 7582 17 7... the oxidations and C-C coupling reactions under mild reaction conditions and with a broad tolerance of other functional groups Thus, the third objective of our study is to investigate the development and applications of a hypervalent iodine compounds 1. 6 References 1 Merrifield, R B J Am Chem Soc 19 63, 85, 214 9-54 2 Merrifield, R B.; Stewart, J M.; Jernberg, N Anal Chem 19 66, 38, 19 05 -19 14 3 Gutte, B.;... Optimization of the reaction condition for α-chlorination of ketones 10 4 Table 5-9 α-Chlorination of various ketones 10 5 Table 5 -10 α-Alkoxylation of various ketones to α-alkoxylated compounds 10 7 x List of Figures Figure 1- 1 Solid-Phase Synthesis 2 Figure 1- 2 The internal molecular structure of polystyrene 3 Figure 1- 3 TantaGel resin 4 Figure 1- 4 Acid-labile linkers and their cleavage acids 6 Figure 1- 5 General... reduction of 3-4a to 3-5a 63 Table 3-7 Reduction of ketimines by 3 -1 64 Table 3-8 Cyclization of (Z)-α-cyano-β-bromomethyl cinnamates and its analogs by 3 -1 65 Table 4 -1 Catalyst screening for reduction of 4-1a 78 Table 4-2 Solvent screening for reduction of 4-1a 79 Table 4-3 Reduction of α,β-unsaturated ketone anologs 81 Table 4-4 Reduction of alkylidene malonic diester anologs 83 Table 5 -1 Optimization of. .. Nucleosides, nucleotides and Nucleic Acids 2005, 24, 777-7 81 8 Letsinger, R L.; Mahadevan, V J Am Chem Soc 19 65, 87, 3526-3527 9 (a) Bayer, E Angew Chem Int Ed 19 91, 30, 11 3 -12 9 (b) Bayer, E.; Rapp, W Chem Peptides Protein 19 86, 3, 3-8 10 Rademann, J.; Grotli, M.; Meldal, M.; Bock, K J Am Chem Soc .19 99, 12 1, 5459-5466 11 Atherton, E.; Clive, D L J.; Sheppard, R C J Am Chem Soc 19 75, 97, 6584-6585 12 (a) Arshady,... Polymer-Supported Hantzsch 1, 4-Dihydropyridine Ester: an Efficient Biomimetic Hydrogen Source for the Reduction of Ketimines and ElectronWithdrawing Group Conjugated Olefins Adv Synth Catal 2 010 , 352, 17 52 -17 58 3 Che Jun, Lam Yulin Rapid and Regioselective Hydrogenation of α,β-Unsaturated Ketones and Alkylidene Malonic Diesters Using Hantzsch Ester Catalyzed by Titanium Tetrachloride Synlett, 2 010 , 16 , 2 415 -2420 . Figure 1- 7 Generic representative of base-labile cleavage process 10 Figure 1- 8 Safety-catch Linkers 12 Figure 2 -1 Library of 2 -1- 16, 2 -1- 17, 2 -1- 18, 2 -1- 19, 2 -1- 20 31 Figure 3 -1 Polymer-supported. xvi Part 1 Chapter 1: Introduction 1. 1 Combinatorial Solid-Phase Synthesis 1 1. 1 .1 Introduction 1 1. 1.2 Solid-Phase Synthesis 1 1. 1.3 Advantages and Disadvantages 2 1. 2 Solid. Part 1: COMBINATORIAL SYNTHESIS OF NITROGEN- CONTAINING HETEROCYCLES Part 2A: DEVELOPMENT AND APPLICATION OF HANTZSCH ESTER Part 2B: DEVELOPMENT AND APPLICATION OF A HYPERVALENT IODINE