Application of a TBHP-mediated Wacker-type oxidation to internal alkenes

The Wacker oxidation allows access to methyl ketones from terminal alkenes. This transformation is important for industrial, synthetic, and medicinal chemists, as carbonyls are present in many natural and pharmaceutical products. With the carbonyl, a wide variety of reactions become available, such as the Grignard and the Wittig. Traditional Wacker reaction conditions call for a metal catalyst, typically Pd(II), and an oxidant. These conditions prove challenging for particular substrates such as allylic alcohols and its protected counterparts. The presence of the proximal heteroatom decreases selectivity and can lead to inseparable products. Interested in developing a solution to these challenging substrates, previous members from the Sigman group developed a TBHPmediated Wacker-like oxidation. The proposed key to this method was the quinolineoxazoline (Quinox) ligand. In the reaction, the push-pull nature of the ligand assists Pd in selectively binding the alkene. To further expand the scope of the TBHP-mediated reaction conditions, the system was applied to various internal alkenes with allylic functional groups. For most substrates, the TBHP-mediated conditions selectively produced one product in good yield - a ketone distal from the existing functional group. The method, however, proved to be difficult for cyclic and cis- alkenes generating poor yields. As a whole, the substrate scope for the TBHP-method demonstrated no real need for an electronic bias on internal alkenes and a good tolerance for popularly used protecting groups.

APPLICATION OF A TBHP-MEDIATED WACKER-TYPE OXIDATION TO INTERNAL ALKENES by Jennifer Lynn Edwards A Senior Honors Thesis Submitted to the Faculty of The University of Utah In Partial Fulfillment of the Requirements for the Honors Degree in Bachelor of Science In Chemistry Approved: ____________________ Matthew S. Sigman Supervisor ____________________ Henry S. White Chair, Department of Chemistry ____________________ Thomas G. Richmond Department Honors Advisor ____________________ Dr. Sylvia D. Torti Dean, Honors College May 2013 ! ! ABSTRACT The Wacker oxidation allows access to methyl ketones from terminal alkenes. This transformation is important for industrial, synthetic, and medicinal chemists, as carbonyls are present in many natural and pharmaceutical products. With the carbonyl, a wide variety of reactions become available, such as the Grignard and the Wittig. Traditional Wacker reaction conditions call for a metal catalyst, typically Pd(II), and an oxidant. These conditions prove challenging for particular substrates such as allylic alcohols and its protected counterparts. The presence of the proximal heteroatom decreases selectivity and can lead to inseparable products. Interested in developing a solution to these challenging substrates, previous members from the Sigman group developed a TBHPmediated Wacker-like oxidation. The proposed key to this method was the quinolineoxazoline (Quinox) ligand. In the reaction, the push-pull nature of the ligand assists Pd in selectively binding the alkene. To further expand the scope of the TBHP-mediated reaction conditions, the system was applied to various internal alkenes with allylic functional groups. For most substrates, the TBHP-mediated conditions selectively produced one product in good yield – a ketone distal from the existing functional group. The method, however, proved to be difficult for cyclic and cis- alkenes generating poor yields. As a whole, the substrate scope for the TBHP-method demonstrated no real need for an electronic bias on internal alkenes and a good tolerance for popularly used protecting groups. ! ! ! ii ! LIST OF ABBREVIATIONS Ac acetyl Ac2O acetic anhydride AcOH acetic acid aq. Aqueous β-H beta-hydride Bn benzyl bs broad singlet Bu butyl °C degrees Celsius CH2Cl2 dichloromethane CHCl3 chloroform cm centimeter d doublet Δ heat DCC N,N’-dicyclohexylcarbodiimide DMF dimethylformamide DCM dichloromethane dd doublet of doublets ddd doublet of doublet or doublets DMAP 4-dimethylaminophyidine DMSO dimethyl sulfoxide ! ! ! iii ! equiv. equivalents Et ethyl Et3N triethylamine Et2O diethyl ether EtOAc ethyl actate g gram h hour m multiplet M molar Me methyl MeOH methanol mg milligram min minute mL milliliter mmol millimole mol mole NMR nuclear magnetic resonance OAc acetate Ph phenyl q quartet quinox quinolone oxazoline Rf retention factor rt room temperature ! ! ! iv ! s singlet or second sub substrate t triplet TBHP tert-butyl hydroperoxide TEMPO 2,2,6,6-tetramethylpiperidine TEA triethylamine TLC thin layer chromatography ! ! ! v ! NOTE ON COLLABORATION This work, herein described, was collective effort and continuation of work by Laura Steffens, Ryan DeLuca, Brian Michel and myself from Dr. Matt Sigman’s group at the University of Utah, and Xiaoxiao Qiao and Chunyin Zhu from Dr. Silas Cook’s group at Indiana University. ! ! ! vi ! TABLE OF CONTENTS ABSTRACT ii LIST OF ABBREVIATIONS iii NOTE ON COLLABORATION vi INTRODUCTION 1 METHODS 7 RESULTS 18 DISCUSSION 23 REFERENCES 27 SUPPORTING INFORMATION: NMR SPECTRA S1 ! ! ! vii ! 1 INTRODUCTION The Tsuji-Wacker oxidation directly enables the transformation of an olefin to a carbonyl. The carbonyl is a ubiquitous functional group in chemical space and can be converted into various functional groups through reductions, Wittig olefinations, and aldol condensations, to name a few. Functional group tolerance,4 high yields, predictable regioselectivity, and operational simplicity have led the Wacker oxidation to be used on industrial scale to produce acetaldehyde, amongst other commodity chemicals, and medicinally in the synthesis of various drugs.26 Smidt and co-workers first reported the Pd-catalyzed oxidation of an olefin to a carbonyl, which was further independently optimized by Tsuji and co-workers.2,3 The traditional Wacker oxidation, named for the Wacker Chemie company responsible for developing the reaction, utilizes a palladium catalyst, molecular oxygen as an oxidant, and a copper co-catalyst in a H2O solvent system. Due to poor solubility of the organic substrates in H2O, the Tsuji-Wacker method enhanced the reaction by discovering a new solvent system, comprised of dimethylformamide (DMF) and H2O (Figure 1).25 The reaction occurs as an alkene is formally oxidized adding by H2O causing the alkene to bind to an electrophilic palladium, which helps with the carbonyl formation through a hydride shift (Figure 2). Figure 1. Generic reaction conditions for TsujiWacker oxidation. ! ! ! 2 Figure 2. Mechanism of Tsuji-Wacker oxidation. ! Despite its widespread usage, the reaction’s scope is limited with Lewis basic groups in the allylic position, as the regioselectivity of the reaction dramatically decreases from 90:10 (internal:terminal) to 1:1 (Figure 3).6 The erosion in selectivity is thought to occur because the Lewis basic group can competitively coordinate to the Pd catalyst. With competitive coordination, the H2O molecule can then attack either carbon of the alkene, rather than one selectively (Figure 4). A peroxide-mediated method was developed by the Sigman group in order to overcome the issue of regioselectivity in Wacker-like oxidations of terminal olefins with Lewis basic allylic functional groups.1 Figure 3. Erosion of regioseletivity due to presence of an allylic alcohol. ! Figure 4. Poor selectivity due the presence of the allylic Lewis basic functional group. ! ! ! 3 A broad interest in the Sigman group is the investigation of Pd-catalyzed alkene functionalization reactions and previous studies have led to the development of the tertbutyl hydroperoxide (TBHP)-mediated Wacker-like oxidation.1 The peroxide-mediated variant differs from the traditional Wacker reactions in that the nucleophile and the terminal oxidant are derived from the same molecule, TBHP (Figure 5). The proposed key to this new method is preloading the Pd(Quinox)2Cl2 catalyst with TBHP and leaving only one site for the alkene bind. The quinox ligand is an electronically asymmetric, bidentate ligand (Figure 6) meaning that the quinoline and oxazoline rings, each occupying different coordination sites, having different electronic properties. The nitrogen in the oxazoline ring contains more electron density than the quinoline ring and can be rationalized through a resonance model. The trans effect occurs during substitution reactions with square planar metals, such as Pd. Some of the pre-existing ligands can direct the incoming ligands into the trans position by weakening the bond between the metal and the ligand already across from it, making it more susceptible to substitution. When deprotonated (anionic) TBHP is added to the reaction, it will bind trans to the oxazoline ring in the Pd coordination sphere (Figure 5A, Figure 7) due to the trans effect. Therefore, the most electrophilic site, trans to the quinolone ring will preferentially bind the alkene and therefore the lewis basic allylic moiety will not be able to coordinate to Pd7 (Figure 4, Figure 5B). The mechanism then is thought to follow through steps similar to the Tsuji-Wacker (Figure 2) except it is believed to go through a pseudo-palladacylic intermediate7, 23 Because TBHP is both the nucleophile and the oxidant, the un-coordinated oxygen atom will swing around and oxidize the double bond. This creates a cyclic intermediate (Figure 5C). This unstable intermediate rearranges into ! ! ! 4 the desired ketone product.7, 23 (Figure 5D). The project described herein was employed to investigate the scope of the TBHP-mediated Wacker oxidation of internal alkenes. ! Figure 5. Mechanism of TBHP-Mediated Wacker-like oxidation. ! ! Figure 6. Quinox ligand. ! Figure 7. Binding of TBHP to the Pd catalyst through the trans effect. Previous applications of Wacker oxidations to internal alkenes, have proven to be difficult due to long reaction times yielding mixtures of isomeric ketone products.24 ! ! ! 5 Previous experiments have shown that electronically biased internal alkenes produce one regioisomeric product with the carbonyl formed distal to the electron deficient functional group. When analyzing cyclic or non-electronically biased internal alkenes results generally trend toward lower yields, however four previous studies are worth noting (vide infra).3, 8-10 (Figure 8). The first reported Wacker oxidation of internal alkenes performed by Tsuji and co-workers produced good results with long reaction times.3 Tsuji later tried a reaction, which utilized TBHP (Figure 8)8 and observed modest yields, excellent regioselectivity, and a dramatic decrease in reaction time. However, the substrate scope was limited to only allylic esters and ketones. Feringa and co-workers employed conditions comparable to the Tsuji’s, including the Pd/Cu co-catalyst system, but the scope was limited to protected amine derivatives.9 Kaneda and co-workers developed a Wacker-type oxidation method without the use of Cu; this was appealing because the traditional Wacker system using two metals had limited success, as it was thought that the use of Cu slows down the reaction rate when used on internal alkenes.10 Kaneda’s system works well for electronically biased internal alkenes and cyclic alkenes but displays poor regioselectivity for unbiased olefins. All of these previous investigations are a step forward in harnessing the oxidation of internal alkenes. However, they are unattractive to some due to their reaction conditions – high catalyst loading, high temperature, and/or increased pressure – or their limited substrate scope. The reaction described herein is simple when it comes to experimental work for terminal alkenes. It is open to the air, perfomed at room temperature, with a low catalyst loading, while reactants are not added under any extreme ! ! ! 6 constraints. If the TBHP-mediated reaction works as well for internal alkenes, then there will be another useful tool for synthesis. Figure 8. Summary of previous investigations of Wacker oxidation of internal alkenes. ! ! 7! EXPERIMENTAL METHOD Dichloromethane (DCM) for Pd(Quinox)-TBHP Wacker-type reactions was reagent grade and used without further purification. TBHP was purchased and is 70 wt% TBHP, with the remaining solution as water. Dry CH2Cl2, THF, ether, toluene and hexanes were dried by passing through a column of activated alumina. Dry TEA was distilled from CaH2. Unless otherwise noted all chemicals were purchased from commercial sources and used without further purification. A procedure for a one-pot synthesis of Quinox is outlined in a recent publication.11 All silver salts were stored in a nitrogen filled glove box and protected from light. 4-N,N-dimethylaminopyridine (DMAP) was recrystallized from toluene. Analytical thin layer chromatography was performed with Whatman K6F Silica 60 Å plates. Flash Chromatography was performed using Silicycle Inc. flash silica gel 40-63um. All NMR were taken on one of the following instruments: Inova 500 MHz (TRIAX probe), Varian 500 MHz, or Unity 300 MHz and referenced to the residual solvent peak from CHCl3 at 7.27 ppm for 1H spectra and 77.23 ppm for 13C spectra. ALTHOUGH NO PROBLEMS OCCURRED DURING THESE STUDIES, HIGHLY CONCENTRATED SOLUTIONS OF TBHP IN THE PRESENCE OF TRANSITION METALS CAN BE EXPLOSIVE. General Procedure for Pd(Quinox)2Cl2 – TBHP Wacker-like Oxidation. In the dark, AgSbF6 (43 mg, 0.125 mmol, 0.125 equiv), Pd(Quinox)Cl2 complex (19 mg, 0.05 mmol, 0.05 equiv), and a magnetic stir bar were added to a 25-mL round-bottom flask. The flask was wrapped in aluminum foil for extra precautions. CH2Cl2 (3.3 mL) was charged to the flask and the mixture was stirred for 10 min, after which aqueous 70% wt/wt TBHP (1.7 mL, 12 mmol, 12 equiv) and remaining CH2Cl2 (5.0 mL) were added to the flask. The ! ! 8 deep orange mixture was stirred for 10 min before the substrate (1.0 mmol, 1 equiv) was added. At which point, the aluminum foil was removed and the lights turned back on. The reaction was monitored by TLC and upon complete consumption of starting material (or 24 hours), the reaction was cooled to 0 °C and quenched with Na2SO3 (15 mL) to consume excess TBHP. The mixture was transferred to a separatory funnel and diluted with hexanes (25 mL). The aqueous layer was back extracted with hexanes (25 mL). The combined organics were washed with H2O (4 × 10 mL) and brine (25 mL) and then dried over MgSO4. After filtration and concentrating under reduced pressure, the crude material was purified by silica gel flash chromatography and the product containing fractions were combined and concentrated under reduced pressure. General Procedure for Benzoyl Protection. Into an oven-dried 250 round bottom flask equipped with a magnetic stir bar, the alcohol (10.0 mmol, 1.0 equiv), 244 mg of DMAP (2.0 mmol, 2.0 equiv), 1.8 mL of Et3N (13.0 mmol, 1.3 equiv), and 50 mL of DCM. The flask was then equipped with a septum and connected to a N2 line. This mixture was cooled to 0 °C and a solution of 3.40 g of benzoic anhydride (15.0 mmol, 1.5 equiv) in 5 mL of DCM was added dropwise. The mixture was allowed to warm to room temperature and was allowed to stir overnight. The solution was then washed with sat. aq. NH4Cl (50 mL) and H2O (50 mL). The combined aqueous layers were extracted with DCM (50 mL). The combined organic layers were then washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel flash chromatography. ! ! ! 9 General Procedure for Mitsunobu Reaction. Into an oven dried 100 mL wide-necked round bottom flask equipped with a stir bar, were added the allylic alcohol (10.0 mmol, 1.0 equiv) and 40 mL of dry THF. Following, 4.02 g of triphenylphosphine (15.0 mmol, 1.5 equiv) and 1.47 g of phthalimide (10.0 mmol, 1.0 equiv) were weighed and added to the flask. The flask was then equipped with a septum and connected to a N2 line. The reaction was then cooled to 0 °C and 2.9 mL of diisopropyl azodicarboyxlate (DIAD) (15.0 mmol, 1.5 equiv) was added dropwise. The reaction was allowed to warm to room temperature and stir over night. Under reduced pressure, the solvent was evaporated off to produce the crude product. This product was then purified by silica gel flash column chromatography. (E)-dec-2-en-1-yl benzoate (8e). This compound was prepared with the general procedure for benzoyl protection using 1.56 g of (E)-dec-2-en-1-ol. The product was purified by silica gel flash chromatography eluting with 5% diethyl ether in hexanes to give the product as a colorless oil in 93% yield (2.42 g). Rf = 0.5 (10% Et2O in hexanes) 1 H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 6.6 Hz, 3H), 1.18-1.47 (m, 10H), 2.08 (q, J = 6.8 Hz, 2H), 4.76 (d, J = 6.4 Hz, 2H), 5.68 (dt, J = 15.6, 6.4 Hz, 1H), 5.86 (dt, J = 15.2, 6.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 8.05 (d, J = 7.2 Hz, 2H). 13 C NMR (75 MHz, CDCl3): δ 14.3, 22.9, 29.1, 29.3(2), 32.0, 32.5, 66.0, 123.9, 128.5, 129.5, 130.6, 133.1, 137.0, 166.7. IR (neat): 2924, 2853, 1717, 1450, 1377, 1265, 1107, 1068, 1025, 968, 935, 707, 686 cm-1. HRMS (ESI-TOF) m/z calculated for C17H24O2Na [M+Na]+ : 283.1674, obsvd. 283.1669. ! ! ! 10 (E)-1-(methoxymethoxy)dec-2-ene (8f). This compound was prepared according to the literature procedure.16 Analytical data are consistent with the literature.16 (E)-2-(dec-2-en-1-yl)isoindoline-1,3-dione (8g). This compound was prepared with the general procedure for the Mitsunobu reaction using 1.56 g of (E)-dec-2-en-1-ol. The product was purified by silica gel flash chromatography eluting with 5% ethyl acetate in hexanes to give the product as a colorless oil in 98% yield (2.80 g). Rf = 0.5 (5% EtOAc in hexanes) 1H NMR (500 MHz, CDCl3): δ 0.85 (t, J = 7.0 Hz, 3H), 1.18-1.37 (m, 10H), 1.99 (q, J = 7.2 Hz 2H), 4.23 (d, J = 6.0 Hz, 2H), 5.50 (dt, J = 15.5, 6.6 Hz, 1H), 5.74 (dt, J = 15.5, 7.1 Hz, 1H), 7.69-7.72 (m, 2H) 7.82-7.86 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 14.3, 22.8, 29.1, 29.3, 32.0, 32.3, 39.8, 71.4, 123.2, 123.4, 132.4, 134.0, 135.6, 168.2. IR (neat): 2923, 2853, 1771, 1709, 1466, 1390, 1354, 1186, 1099, 966, 716 cm-1. HRMS (AP-TOF) m/z calculated for C18H24NO2 [M+H]+ : 286.1807, obsvd. 286.1802. (E)-non-3-en-2-yl acetate (8h). This compound was prepared with the general procedure for benzoyl protection with the modification that 1.56 g of (E)-dec-2-en-1-ol was protected using 1.4 mL of acetic anhydride instead of benzoic anhydride. The product was purified by silica gel flash chromatography eluting with DCM to give the product as a colorless oil in 56% yield (1.03 g). Rf = 0.7 (DCM) 1H NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.23-1.41 (m, 11H), 2.03 (s, 3H), 5.31 (quint, J = 6.6 Hz, 1H), 5.45 (dd, J = 15.3, 6.8 Hz, 1H), 5.70 (dt, J = 15.3, 6.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.2, 20.6, 21.7, 22.7, 28.8, 31.6, 32.3, 71.4, 129.5, 133.7, 170.6. IR (neat): 2957, 2927, 2857, 1735, 1456, 1369, 1235, 1135, 1041, 1014, 967, 947, 841, 668, ! ! ! 11 609 cm-1. HRMS (ESI-TOF) m/z calculated for C11H20O2Na [M+Na]+ : 207.1361, obsvd. 207.1364. (E)-2-(pent-3-en-2-yl)isoindoline-1,3-dione (1). This compound was prepared with the general procedure for the Mitsunobu reaction.17 Analytical data are consistent with the literature.17 (Z)-pent-2-en-1-yl benzoate (8i). This compound was prepared with the general procedure for benzoyl protection using 861 mg of (Z)-pent-2-en-1-ol. The product was purified by silica gel flash chromatography eluting with 5% ethyl acetate in hexanes to give the product as a colorless oil in 90% yield (1.71 g). Analytical data are consistent with the literature.18 (Z)-hex-3-en-1-yl benzoate (8j). This compound was prepared with the general procedure for benzoyl protection using 1.00 g of (Z)-hex-3-en-1-ol. The product was purified by silica gel flash chromatography eluting with 5% ethyl acetate in hexanes to give the product as a colorless oil in 86% yield (1.76 g). Analytical data are consistent with the literature.19 (((7R,8S)-8-((E)-but-2-en-1-yl)-3-methoxy-4,7-dimethyl-4,4a,5,6,7,8-hexahydro-3Hisochromen-3-yl)oxy)triisopropylsilane (14). This compound was prepared according to the literature procedure.20 Analytical data are consistent with the literature.20 ! ! ! 12 Octan-4-one (9a). The general procedure for the TBHP-mediated Wacker oxidation was followed using 112 mg of (E)-oct-4-ene (1.0 mmol). The crude mixture was purified by flash chromatography eluting with 5% ethyl acetate in hexanes to afford the product as a colorless oil in 71% yield (91 mg). The spectral data were in accordance with the known commercially available compound. Cyclododecanone (9b). The general procedure for the TBHP-mediated Wacker oxidation was followed using 166 mg of cyclododecene (1.0 mmol). The crude mixture was purified by flash chromatography eluting with 5% ethyl acetate in hexanes to afford the product as a white solid in 76% yield (138 mg). The spectral data were in accordance with the known commercially available compound. 1-Hydroxydecan-3-one (9c). The general procedure for the TBHP-mediated Wacker oxidation was followed using 78 mg of (E)-dec-2-en-1-ol (0.5 mmol). The crude mixture was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to afford the product as a colorless oil in 32% yield (55 mg). Rf = 0.5 (40% EtOAc in hexanes) 1H NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.22-1.34 (m, 8H), 1.59 (quint, J = 7.3 Hz, 2H), 2.44 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 5.3 Hz, 2H), 3.85 (t, J = 5.3 Hz, 2H) 13C NMR (100 MHz, CDCl3): δ 14.3, 22.8, 23.9, 29.3, 29.4, 31.9, 43.6, 44.5, 58.2, 212.3. IR (neat): 3420, 2924, 2854, 1701, 1457, 1375, 1047, 668 cm-1. HRMS (ESI-TOF) m/z calculated for C10H20O2Na [M+Na]+ : 195.1361, obsvd. 195.1361. ! ! ! 13 3-oxodecyl acetate (9d). The general procedure for the TBHP-mediated Wacker oxidation was followed using 198 mg of (E)-dec-2-en-1-yl acetate (1.0 mmol). The crude mixture was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to afford the product as a colorless oil in 68% yield (146 mg). Rf = 0.3 (10% EtOAc in hexanes) 1 H NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H), 1.21-1.33 (m, 8H), 1.54-1.62 (m, 2H), 2.04 (s, 3H), 2.44 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 6.3 Hz, 2H), 4.34 (t, J = 6.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 14.2, 21.0, 22.7, 23.7, 29.2, 29.3, 31.8, 41.3, 43.4, 59.6, 171.0, 208.2. IR (neat): 2926, 2855, 1739, 1715, 1366, 1233, 1036, 668 cm-1. HRMS (ESI-TOF) m/z calculated for C12H22O3Na [M+Na]+ : 237.1467, obsvd. 237.1469. 3-oxodecyl benzoate (9e). The general procedure for the TBHP-mediated Wacker oxidation was followed using 130 mg of (E)-dec-2-en-1-yl benzoate (0.5 mmol). The crude mixture was purified by flash chromatography eluting with 20% diethyl ether in hexanes to afford the product as a colorless oil in 61% yield (84 mg). Rf = 0.5 (20% Et2O in hexanes) 1H NMR (400 MHz, CDCl3): δ 0.87 (t, J = 6.6 Hz, 3H), 1.20-1.32 (m, 8H), 1.57-1.64 (m, 2H), 2.47 (t, J = 7.4 Hz, 2H), 2.87 (t, J = 6.3 Hz, 2H), 4.60 (t, J = 6.3 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 8.00 (d, J = 5.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3): δ 14.2, 22.7, 23.8, 29.2(2), 31.8, 41.5, 43.4, 60.1, 128.4, 129.7, 130.1, 133.1, 166.5, 208.1. IR (neat): 2925, 2854, 1717, 1602, 1451, 1271, 1110, 964, 708, 686 cm-1. HRMS (ESI-TOF) m/z calculated for C17H24O3Na [M+Na]+ : 299.1623, obsvd. 299.1622. ! ! ! 14 1-(methoxymethoxy)decan-3-one (9f). The general procedure for the TBHP-mediated Wacker oxidation was followed using 100 mg of (E)-1-(methoxymethoxy)dec-2-ene (0.5 mmol). The crude mixture was purified by flash chromatography eluting with 10% diethyl ether in hexanes to afford the product as a colorless oil in 93% yield (100 mg). Rf = 0.2 (10% Et2O in hexanes) 1 H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 6.5 Hz, 3H), 1.21-1.34 (m, 8H), 1.55-1.62 (m, 2H), 2.45 (t, J = 7.4 Hz, 2H), 2.68 (t, J = 6.1 Hz, 2H), 3.37 (s, 3H), 3.80 (t, J = 6.0 Hz, 2H) 4.60 (s, 2H). 13 C NMR (125 MHz, CDCl3): δ 14.3, 22.8, 23.8, 29.2, 29.3, 31.9, 42.8, 43.6, 55.4, 62.9, 96.7, 209.4. IR (neat): 3743, 2925, 2855, 1715, 1457, 1379, 1213, 1149, 1110, 1041, 918, 668 cm-1. HRMS (ESI-TOF) m/z calculated for C12H24O3Na [M+Na]+ : 239.1623, obsvd. 239.1624. 4-oxononan-2-yl acetate (9h). The general procedure for the TBHP-mediated Wacker oxidation was followed using 92 mg of (E)-non-3-en-2-yl acetate (0.5 mmol). The crude mixture was purified by flash chromatography eluting with dichloromethane to afford the product as a colorless oil in 57% yield (57 mg). Rf = 0.3 (DCM) 1 H NMR (500 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H), 1.20-1.34 (m, 7H), 1.52-1.60 (m, 2H), 2.00 (s, 3H), 2.40 (t, J = 7.3 Hz, 2H), 2.52 (dd, J = 16.2, 5.8 Hz, 1H), 2.76 (dd, J = 16.3, 7.0 Hz, 1H), 5.27 (sext., J = 6.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.1, 20.3, 21.4, 22.6, 23.5, 31.5, 43.6, 48.7, 67.4, 170.5, 208.1. IR (neat): 2956, 2932, 2872, 1736, 1714, 1457, 1370, 1236, 1141, 1037, 956, 668, 607cm-1. HRMS (ESI-TOF) m/z calculated for C11H20O3Na [M+Na]+ : 223.1310, obsvd. 223.1305. ! ! ! 15 2-(4-oxopentan-2-yl)isoindoline-1,3-dione (2). The general procedure for the TBHPmediated Wacker oxidation was followed using 430 mg of (E)-2-(pent-3-en-2yl)isoindoline-1,3-dione (2.0 mmol). The crude mixture was purified by flash chromatography eluting with 15% ethyl acetate in hexanes to afford the product as a colorless oil in 66% yield (305 mg). The spectral data were in accordance with the previous report.17 2-(3-oxodecyl)isoindoline-1,3-dione (9g). The general procedure for the TBHP- mediated Wacker oxidation was followed using 258 mg of (E)-2-(dec-2-en-1yl)isoindoline-1,3-dione (1.0 mmol). The crude mixture was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to afford the product as a white solid in 79% yield (237 mg). Rf = 0.3 (10% EtOAc in hexanes). M. P. = 88-90 °C. 1 H NMR (400 MHz, CDCl3): δ 0.87 (t, J = 6.9 Hz, 3H), 1.19-1.31 (m, 8H), 1.56 (quint, J = 7.3, 2H), 2.41 (t, J = 7.6 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 3.96 (t, J = 7.4 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.83 (dd, J = 5.3, 3.1 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 14.3, 22.8, 23.9, 29.3, 29.4, 31.9, 33.3, 40.8, 43.2, 123.5, 132.3, 134.2, 168.4, 208.5. IR (neat): 2923, 2853, 1704, 1652, 1436, 1360, 1221, 1091, 721, 668 cm-1. HRMS (ESITOF) m/z calculated for C18H23NO3Na [M+Na]+ : 324.1576, obsvd. 324.1574. 3-oxopentyl benzoate (9i). The general procedure for the TBHP-mediated Wacker oxidation was followed using 190 mg of (Z)-pent-2-en-1-yl benzoate (1.0 mmol). The crude mixture was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to afford the product as a colorless oil in 31% yield (64 mg). Rf = 0.3 (10% ! ! ! 16 EtOAc in hexanes). 1H NMR (500 MHz, CDCl3): δ 1.09 (t, J = 7.3 Hz, 3H), 2.50 (q, J = 7.3 Hz, 2H), 2.88 (t, J = 6.5, 2H), 4.59 (t, J = 6.3 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H). 13 C NMR (125 MHz, CDCl3): δ 7.8, 36.6, 41.3, 60.2, 128.5, 129.8, 130.2, 133.2, 166.6, 208.5. IR (neat): 2976, 1711, 1601, 1451, 1314, 1369, 1111, 1070, 1025, 973, 708, 617 cm-1. HRMS (ESI-TOF) m/z calculated for C18H23NO3Na [M+Na]+ : 324.1576, obsvd. 324.1574. 4-oxohexyl benzoate (9j). The general procedure for the TBHP-mediated Wacker oxidation was followed using 204 mg of (E)-hex-3-en-1-yl benzoate (1.0 mmol). The crude mixture was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to afford the product as a colorless oil in 65% yield (143 mg). The spectral data were in accordance with the previous report.21 5-(o-tolyl)pentan-2-one (13). The general procedure for the TBHP-mediated Wacker oxidation was followed using 200 mg of (E)-1-methyl-2-(pent-3-en-1-yl)benzene (1.25 mmol). The crude mixture was purified by flash chromatography eluting with 5% ethyl acetate in hexanes to afford the product as a colorless oil in 92% yield (202 mg). The spectral data were in accordance with the previous report.22 4-((7R,8S)-3-methoxy-4,7-dimethyl-3-((triisopropylsilyl)oxy)-4,4a,5,6,7,8-hexahydro3H-isochromen-8-yl)butan-2-one (15). The general procedure for the TBHP-mediated Wacker oxidation was followed using 48 mg of (((7R,8S)-8-((E)-but-2-en-1-yl)-3- methoxy-4,7-dimethyl-4,4a,5,6,7,8-hexahydro-3H-isochromen-3- ! ! ! 17 yl)oxy)triisopropylsilane (14) (0.11 mmol). The crude mixture was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to afford the products as a colorless oil in 55% yield (27 mg) as a 1.6:1 mixture. The spectral data were in accordance with the previous report.20 NMR Spectra. All spectra of unknown compounds, 1H and Supporting Information. ! ! 13 C, are located in the ! 18 RESULTS To begin the investigation, a simple, symmetric internal alkene, 4-octene, was subjected to the previously optimized Pd(Quinox)-TBHP reaction conditions. A single product, 4-octanone, was isolated at 71% yield (Table 1, entry 1, 9a). Next, a symmetric cyclic internal alkene, cyclododecene, was evaluated, and the TBHP-mediated conditions yielded 76% of a single ketone isomer (Table 1, entry 2, 9b). An unsymmetrical, non-biased alkene, 2-octene, that reacted under the TBHP-methods, produced a similar result to previous studies - ~1:1 mixture of 2- and 3-octanone.8-10 The next step was to look at the same electronically biased alkenes that the TBHP method was developed for – allylic alcohols and their protected counterparts. The starting place was a simple, unprotected allylic alcohol. The previously optimized TBHP conditions produced a single ketone in the position distal from the alcohol but only in a decent yield, 48% (Table 1, entry 3, 9c). To evaluate if the alcohol was interfering with the reaction, a series of commonly used alcohol protecting groups were then installed – an acetate, benzoate, methoxy ether (MOM), and phthalimide. All of the products (Table 1, entries 4-7) had higher yields than the alcohol – acetate, 68% (9d) ; benzoate, 61% (9e); MOM, 93% (9f); phthalimide, 79% (9g) - each with a single ketone product in the same position distal from the allylic alcohol group. A secondary allylic acetate was then tested to see if sterics influenced yield and regioselectivity. The reaction produced the same distal ketone but in a 57% yield (Table 1, entry 8, 9h). The tolerance was also evaluated using a secondary allylic phthalimide, with a 66% yield (Table 1, entry 9, 2). Both of these secondary allylic substrates yielded less than their primary counterparts, but still greater than the primary free alcohol. ! ! ! 19 Finally, a cis- alkene, typically one of the most challenging substrates, was tried in a variety of ways. A cis- allylic benzoyl group was subjected to the TBHP-mediated reaction condition. The substrate produced a mediocre 31% yield, but the same single isomer was produced with selectivity of >20:1 (Table 1, entry 10, 9i ). When the catalyst loading was increased to 10 mol%, the yield for the cis- allylic substrate increased to 59%. The remaining mass balance of these two reactions was of unreacted starting material. The other two cis- substrates, a homoallylic (9j) and a cyclic (9k), were unsuccessful (Table 1, entry 11-12). Table 1. Scope of TBHP-Mediated Wacker Oxidation on Internal Alkenes. All yields are the average of two experiments on at least at 0.5 mmol scale.! ! ! ! ! ! 20 ! ! 21 Moving past the substrate scope, the next step was determining if there was a need for an electronic bias; this was probed by testing two homoallylic functional groups. When a homoallylic benzoate was subjected to the TBHP-mediated method, a 6:1 mixture of ethyl and propyl ketones was produced with a 76% yield (10 to 11, eq. 1). The oxidation of a homoallylic aryl group produced a 92% yield of a 5:1 mixture of methyl and ethyl ketone products (12 to 13, eq. 2). Although the selectivities diminished, they were still promising enough to test against an advanced precursor in the synthesis of an anti-malarial drug, artemisinin. The electronically unbiased precursor, 14, previously underwent a variant of the Wacker oxidation (PdCl2 and excess H2O2) for 4 days producing the desired methyl ketone in a 2:1 mixture with the isomeric ethyl ketone in a 92% total yield.20 Using the TBHP variant, a similar product resulted after 24 hours, 15, with a 55% yield as a 1.6:1 mixture of methyl:ethyl ketones (Scheme 1). 10 OBz 5 mol% Pd(Quinox)Cl2 12.5 mol% AgSbF6 12 equiv TBHP(aq) CH2Cl2, 0.1 M, rt OBz (1) O 11 76% yield (6:1) (ethyl:propyl) 5 mol% Pd(Quinox)Cl2 12.5 mol% AgSbF6 12 ! ! 12 equiv TBHP(aq) CH2Cl2, 0.1 M, rt 13 O 92% yield (5:1) (methyl:ethyl) (2) ! 22 Scheme 1. In the synthesis of artemisinin, intermediate 15 is accessed through the TBHPmediated Wacker Oxidation. Me Me Me 5 mol% Pd(Quinox)Cl2 12.5 mol% AgSbF6 12 equiv TBHP(aq) CH2Cl2, 0.1 M, rt O Me OTIPS MeO 14 Me O O 55% yield (1.6:1) (methyl:ethyl) Me OTIPS MeO 15 Me Me O Me O O Me O H Me O O MeO 15 ! ! two steps H Me OTIPS O artemisinin ! 23 DISCUSSION By evaluating the results, the obvious conclusions are that electronically biased alkenes give good yield and selectivity with our method; electronically nonbiased, symmetrical alkenes give good yield; electronically nonbiased, asymmetric alkenes are poor substrates; and selectivity erodes when the electronic group is moved away from the allylic position. Beginning with the first conclusion, substrates 9c-g provide the appropriate evidence (Figure 1). The unprotected alcohol, 9c, produced lower yields than the rest of the protected moieties, which is consistent with other Wacker oxidation variants.3,8-10 A possible explanation could be that the oxygen is still interacting with the Pd(Quinox)Cl2 catalyst and disrupting coordination to the alkene. This idea is further validated when all of the protecting groups had an increase in yield, suggesting that when the oxygen is tied up with a protecting group, then it cannot interfere with the catalyst. Figure 1. Electronically biased alkenes. ! ! ! ! 24 Products 9a and 9b correspond to the second conclusion of electronically nonbiased, symmetrical alkenes (Figure 2). The yields for both were good, simply meaning the reaction worked. Being symmetrical allows for regioselectivity to become moot because either regioisomer would produce the same product. Figure 2. Electronically unbiased, symmetrical substrates. ! As mentioned in the results section, the reaction of 2-octene yielded a product mixture of ~ 1:1 of 2- and 3-octanone, providing the evidence for the third conclusion (Figure 3). A ~1:1 mixture demonstrates poor selectivity and are difficult to separate and purifiy. Thus, electronically unbiased, asymmetric alkenes are poor substrates. Figure 3. Products of TBHPmediated Wacker-like oxidation on 2-octene. ! ! ! ! 25 The need and strength of the electronic bias, conclusion four, was demonstrated on two additional substrate classes. The first substrate class was comprised of shorter (shorter being a smaller aliphatic chain) internal alkenes with a protected oxygen or nitrogen atom on a secondary carbon, 9h and 2 (Figure 4); yields for these substrates were lower than substrates featuring a protected oxygen or nitrogen protected functional group on a primary carbon separated by a longer alkyl chain, but were still higher than the free alcohol (Figure 1). The erosion of yield was likely due to unfavorable steric interactions. The second substrate class consisted of homoallylic protected alcohols and aryl groups, 11 and 13, which resulted in decreased selectivity (Figure 5). Although the yields were still high, the ratio of the possible isomeric products was much lower; this suggests the need for the particular placement, and existence, of an electronic bias. Figure 4. Secondary protected allylic groups. ! ! Figure 5. Yield and selectivity of homoallylic substrates. ! ! ! 26 The last class of substrates, cis alkenes, 9i-k, was challenging for the TBHP method (Figure 6). While the other two substrates produced no product, 9i yielded a modest amount of product that had a high selectivity of >20:1. It is not exactly clear why these substrates proved to be difficult. The issue could be due to unfavorable steric interactions in the coordination sphere of Pd which thereby interferes with the catalysis; however, this issue can be bypassed with other Wacker oxidation methods.3,8-10, 24 Figure 6. Products of cis-alkenes. ! In summary, the TBHP-mediated Wacker Oxidation is successful in converting an alkene to a single isomeric ketone product, distal to a tethered protected alcohol or amine. The method was successful for trans allylic protected amines and alcohol substrates, while only moderately successful when used on free alcohols. Although challenging substrate classes remain, the TBHP-mediated method is still a useful tool to access a single ketone products due to the operational simplicity and predictability of the reaction. ! ! ! 27 REFERENCES 1. Michel, B. W.; Camelio, A.M.; Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2009, 131, 6076-6077. 2. Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Ruttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176. 3. Tsuji, J. Synthesis, 1884, 5, 369-394. 4. Friestad, G. K.; Jiang, T.; Mathies, A. K. Org Lett. 2007, 9, 777-780. 5. Hosokawa, T.; Aoki, S; Takano, M.; Nakahira, T.; Yoshida, Y.; Nurahashi, S. J. Chem. Soc., Che,. Commun. 1991, 1559-1560. 6. Muzart, J. Tetrahedron, 2007, 63 (32), 7505-7521 (limitations of Wacker) 7. Michel, B. W.; Steffens, L. D.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 83178325 8. Tsuji, J.; Nagashima, H.; Hori, K. Chemistry Letters, 1980, 257-260. 9. Weiner, B.; Baeza, A.; Jerphagnon, T.; Feringa, B. J. Am. Chem. Soc., 2009, 131, 9473-9474 10. Mitsudome, T.; Mizumoto, K.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Angew. Chem. Int. Ed., 2010, 49, 1238-1240 11. Michel, B. W.; McCombs, J. R.; Winkler, A.; Sigman, M. S. Angew. Chem., Int. Ed. 2010, 49, 7312. 12. Nutaitis, C. F.; Bernardo, J. E. J. Org. Chem. 1989, 54, 5629 13. Mayer, S. F.; Steinreiber, A.; Orru, R. V. A.; Faber, K. J. Org. Chem. 2002, 67, 9115. 14. Babler, J. H.; White, N. A.; Kowalski, E.; Jast, J. R. Tetrahedron Lett. 2011, 52, 745. 15. Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 15116. 16. Han, J. H.; Kwon, Y. E.; Sohn, J.-H.; Ryu, D. H. Tetrahedron 2010, 66, 1673. 17. (a) Tsuji, J.; Nagashima, H.; Hori, K. Tetrahedron Lett. 1982, 23, 2679. (b) Tsuji, J.; Nagashima, H.; Hori, K. Chem. Lett. 1980, 9, 257. 18. Heller, S. T.; Fu, T.; Sarpong, R. Org. Lett. 2012, 14, 1970. 19. Tokuyasu, T.; Kunikawa, S.; McCullough, K. J.; Masuyama, A.; Nojima, M. J. Org. Chem. 2004, 70, 251. 20. Zhu, C.; Cook, S. P. J. Am. Chem. Soc. 2012, 134, 13577. 21. Zhao, Y.; Yim, W.-L.; Tan, C. K.; Yeung, Y.-Y. Org. Lett. 2011, 13, 4308. 22. Kise, N.; Suzumoto, T.; Shono, T. J. Org. Chem. 1994, 59, 1407. 23. Michel, B. W.; Sigman, M. S. Al. Acta. 2011, 44, 3, 55-62. 24. (a) Morandi, B.; Wickens, Z. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2013, DOI: 10.1002/anie.201209541. (b) Gaunt, M. J.; Yu, J.; Spencer, J. B. Chem. Commun. 2001, 1844. (c) Nelson, D. J.; Li, R.; Brammer, C. J. Am. Chem. Soc. 2001, 123, 1564. (d) Betzemeier, B.; Lhermitte, F. d. r.; Knochel, P. Tetrahedron Lett. 1998, 39, 6667. (e) Okota, T.; Fujibayashi, S.; Nishiyama, Y.; Sakaguchi, S.; Ishii, Y. J. Mol. Catal. A: Chem. 1996, 114, 113. (f) Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim, T.-H. J. Org. Chem. 1995, 60, 4678. (g) Sommovigo, M.; Alper, H. J. Mol. Catal. 1994, 88, 151. (h) Hosokawa, T.; Nakahira, T.; Takano, M.; Murahashi, S.-I. J. Mol. Catal. 1992, 74, 489. (i) ! ! ! 28 Miller, D. G.; Wayner, D. D. M. Can. J. Chem. 1992, 70, 2485. (j) Kulkarni, M. G.; Sebastian, M. T. Synth. Commun. 1991, 21, 581. (k) Miller, D. G.; Wayner, D. D. M. J. Org. Chem. 1990, 55, 2924. (l) Takehira, K.; Hayakawa, T.; Orita, H.; Shimizu, M. J. Mol. Catal. 1989, 53, 15. (m) Grattan, T. J.; Whitehurst, J. S. J. Chem. Soc., Chem. Commun. 1988, 43. (n) Akermark, B.; Soederberg, B. C.; Hall, S. S. Organometallics 1987, 6, 2608. (o) Takehira, K.; Orita, H.; Oh, I. H.; Leobardo, C. O.; Martinez, G. C.; Shimidzu, M.; Hayakawa, T.; Ishikawa, T. J. Mol. Catal. 1987, 42, 247. (p) Tsuji, J.; Minato, M. Tetrahedron Lett. 1987, 28, 3683. (q) Keinan, E.; Seth, K. K.; Lamed, R. J. Am. Chem. Soc. 1986, 108, 3474. (r) Zahalka, H. A.; Januszkiewicz, K.; Alper, H. J. Mol. Catal. 1986, 35, 249. (s) Alper, H.; Januszkiewicz, K.; Smith, D. J. H. Tetrahedron Lett. 1985, 26, 2263. (t) Takehira, K.; Hayakawa, T.; Orita, H. Chem. Lett. 1985, 14, 1835. (u) Ogawa, H.; Fujinami, H.; Taya, K.; Teratani, S. Bull. Chem. Soc. Jpn. 1984, 57, 1908. 25. Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241. 26. (a) Yokokawa, F.; Asano, T.; Shioiri, T. Tetrahedron 2001, 57, 6311. (b) Banks, B. J.; Fenner, B. R.; Voss, V. F.; Witty, M. J. Synlett 1991, 875. (c) Kobayashi, Y.; Wang, Y. –G. Tetrahedron Lett. 2002, 43, 4381. (d) Kobayashi, Y.; Wang, Y. –G.;Acharya, H. P. Lett. Org. Chem. 2004, 1, 297. (e) Barth, R.; Mulzer, J. Tetrahedron 2008, 64, 4718. (f) Evans, D. A.; Nagorny, P.; McRae, K. J.; Sonntag, L. –S.; Reynolds, D. J.; Vounatsos, F. Angew. Chem., Int. Ed. 2007, 46, 545. (g) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y. –I.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem.—Eur. J. 1999, 5, 121. ! !       S1   SUPPORTING INFORMATION The information herein includes both the 1H and 13C NMR spectra for all new compounds. S2 0 10ppm 910 89 2.012.01 2.142.14 1.04 1.04 78 67 1.051.05 1.131.13 56 2.192.19 8e O 45 O 34 23 2.36 2.36 10.110.1 12 3.11 3.11 01 S3 220ppm 210220 0 200210 190200 180190 170180 160170 150160 140150 130140 120130 110120 8e 100110 O O 90100 8090 7080 6070 5060 4050 3040 2030 1020 010 0 10ppm S4 910 89 78 67 56 1.031.03 1.021.02 1.02 1.02 8h O O 45 34 23 3.52 3.52 10.810.8 12 3.29 3.29 01 S5 220ppm 210220 0 200210 190200 180190 170180 160170 150160 140150 130140 120130 8h 110120 O O 100110 90100 8090 7080 6070 5060 4050 3040 2030 1020 010 S6 0 10ppm 910 89 1.841.84 1.91 1.91 78 67 0.9540.954 0.967 0.967 56 8g 45 2.012.01 O N O 34 23 1.9 1.9 9.94 9.94 12 2.92 2.92 01 S7 220ppm 210220 0 200210 190200 180190 170180 160170 150160 140150 130140 120130 110120 100110 90100 8g 8090 O 7080 N O 6070 5060 4050 3040 2030 1020 010 S8 0 10ppm 910 89 78 67 O 9a 56 45 34 4.01 4.01 23 6.03 6.03 12 2.122.12 4.124.12 01 S9 0 10ppm 910 89 78 67 O 9b 56 45 34 4.01 4.01 23 4.01 4.01 14.4 14.4 12 01 S10 0 10ppm 910 89 78 67 9c 56 O OH 2.012.01 45 34 2.23 2.23 2.03 2.03 23 3.01 3.01 12 7.957.95 2.3 2.3 01 200 180 160 O 140 9c S11 120 OH 100 80 60 40 20 ppm S12 0 10ppm 910 89 78 67 O 9d 56 O Me 2.01 2.01 O 45 34 1.941.94 1.87 1.87 23 2.512.51 2.76 2.76 12 7.857.85 2.27 2.27 01 220ppm 0 S13 210220 200210 190200 180190 170180 160170 150160 140150 O 130140 9d 120130 Me 110120 O O 100110 90100 8090 7080 6070 5060 4050 3040 2030 1020 010 0 10ppm S14 910 89 1.66 1.66 1.841.84 0.9170.917 78 67 O 9e 56 O 2.012.01 O 45 34 1.961.96 1.971.97 23 2.332.33 12 2.92 2.92 8.128.12 01 S15 220ppm 0 210220 200210 190200 180190 170180 160170 150160 140150 130140 120130 110120 100110 O 90100 9e 8090 O O 7080 6070 5060 4050 3040 2030 1020 010 S16 0 10ppm 910 89 78 67 O 9f O 56 2.01 2.01 OMe 45 2.12 2.12 3.093.09 34 2.252.25 2.092.09 23 3.33 3.33 12 8.198.19 2.422.42 01 S17 220ppm 0 210220 200210 190200 180190 170180 160170 O 150160 9f 140150 O 130140 OMe 120130 110120 100110 90100 8090 7080 6070 5060 4050 3040 2030 1020 010 S18 0 10ppm 910 89 78 67 1.01 56 O 9h O Me 45 Me O 34 1.081.08 23 3.023.02 1 2.06 1 2.06 3.03 3.03 12 7.047.04 2.052.05 01 200 180 160 O 9h S19 140 O Me Me O 120 100 80 60 40 20 ppm S20 0 10ppm 910 89 1.87 1.87 2.082.08 1.02 1.02 78 O 67 9i O O Ph 56 2.142.14 45 34 2.13 2.13 2.042.04 23 12 3.01 3.01 01 S21 220ppm 0 210220 200210 190200 180190 170180 160170 150160 140150 130140 120130 110120 100110 O 9i O Ph 90100 O 8090 7080 6070 5060 4050 3040 2030 1020 010 S22 0 10ppm 910 89 3.943.94 78 O 67 N O 2 O 56 1.011.01 45 34 1.131.13 1.151.15 23 3.063.06 3.42 3.42 12 01 0 10ppm S23 910 89 1.711.71 1.84 1.84 78 67 9g O 56 O N O 45 2.012.01 34 2.01 2.01 2.052.05 23 2.86 2.86 12 8.028.02 2.06 2.06 01 S24 220ppm 0 210220 200210 190200 180190 9g O 170180 O 160170 N O 150160 140150 130140 120130 110120 100110 90100 8090 7080 6070 5060 4050 3040 2030 1020 010 0 10ppm S25 910 2.79 2.79 89 1.77 1.77 78 O 67 11 O O Ph 56 45 2.012.01 34 1.881.88 23 1.931.93 2.05 2.05 12 2.82 2.82 01 S26 220ppm 0 210220 200210 190200 180190 170180 160170 150160 140150 130140 120130 110120 100110 O 90100 11 8090 O O Ph 7080 6070 5060 4050 3040 2030 1020 010