DEVELOPING NEW SYNTHETIC METHODS INVOLVING ORGANOSILANE REAGENTS AND REACTANTS By Maria del Rosario Ivette Amado Sierra A DISSERTATION S ubmitted to Michigan State University i n partial fulfillment of the requirements f or the degree of Chemistry D octor of Philosophy 20 15 ABSTRACT DEVELOPING NEW SYNTHETIC METHODS INVOLVING ORGANOSILANE REAGENTS AND REACTAN T S By Maria del Rosario Ivette Amado Sierra A novel green method for the reduction of imines to amines by a Pd(OAc) 2 /PMHS/KF aq system was deve loped and studied. The optimization studies confirmed the crucial role of the fluoride in activating the PMHS. The addition of PMHS to a Pd(OAc) 2 solution results in the formation of polysiloxane encapsulated Pd - nanoparticles, and we were able to confirm t he existence of these nanoparticles using transmission electron microscopy (TEM). Additionally 29 Si NMR and 19 F NMR data obtained f rom our catalyst system gave some insight into the possible mechanism. F urther more, the one - pot preparation of several amides via reduction of imines followed by a ddition of an electrophile was achieved. We were able to develop a new one - pot allylation - hydrostannation sequence of alkynals where the tin byproduct, from the BF 3 2 promoted allylation step, was successfully recyc led by the introduction of PMHS and catalytic B(C 6 F 5 ) 3 to form Bu 3 SnH in situ; that was used on the hydrostannation reaction. In addition, our studies were the first to follow BF 3 2 med iated allylation by 119 Sn and 11 B NMR. Finally a new carbon - to - carbo n [1,2] - silyl migration was discovered. This migration was triggered by epoxidation using m - CPBA , the cyclopentanones formed have not been reported and contain a silyl group at the position of the carbonyl unit. iii ACKNOWLEDG MENTS The work described in th is dissertation would not have been possible without the guidance, advice and scientific support of my research advisor, Professor. Robert E. Maleczka, Jr. His strong work ethic and passion for science helped me evolve both as person and as a scientist. I would also like to thank the members of my t hesis committee Dr. Babak Borhan , Dr. William D. Wulff and Dr. Merlin L. Bruening , for always taking time to assist me with my scientific endeavors. A note of appreciation goes to the Chemistry Department and st aff at MSU, for providing me with this excellent educational opportunity. I particularly want to thank Dr . Dan Holmes, for his help and suggestions related to the NMR experiments. I am especially indebted to the Dr. Maleczka Research Group, for the late ni ghts working together and their support in the lab. Especially I want to thank Luis S., Luis M., Monica, Damith, Suzi and Aaron for their friendship. I would also like to thank Dr. Jun Tang for his mentorship during my one year internship at GSK. Last but certainly not least, I would like to thank my friends and family , for their unconditional love and prayers during the years. Thanks to the Latin community for helping me fee l at home, especially the Parchecito group. My parents Teresa and Marino have been exceptionally supportive; without their help I would have never made it through graduate school. I also thank my sister Magaly and my aunt Julia, for being great friends and always believing in me. Finally, I want to thank my husband Ian, for all his toler ance and encouragement . I also thank him for his support and changing my life for the better. I cannot express how deeply I appreciate everything that he has done for me. iv TABLE OF CONTENTS L IST OF T . .. . . ............. . ..... .vi L ... ............. . .vii .. . ..... .................................... ............ .. .. ... .. ix KEY TO A BBREVIATIONS .. .................. .. . ... .... ... . x i i CHAPTER 1: INTRODUCTION 1 1.1 Silicon: basic properties . 1 1.2 Allylsilanes . . 4 1.3 Brook . . ... 6 1.4 Silan es in cross - . 0 REFERENCES .. 1 4 CHAPTER 2 : IMINE REDUCTIONS 17 2.1 Introduction . 17 2.2 PMHS applications and . 18 2 . 3 Application of Pd(OAc) 2 /PMHS/KF (aq) system in the reduction of imines . . . . .. 2 5 2.3.1 Optimization of the Pd(OAc) 2 /PMHS/KF (aq) system .. ... .... .......... .. .. . ... .. . . . .. . . 2 5 2.3.2 Substrate scope .. .... 29 2.3.3 .. 3 7 2.3.4 Mechanistic s 41 2.3.5 Palladium nanoparticles: TEM and EDS studies . .. .. ..43 2.4 One - Pot synthesis of amides . 47 2.4.1 .. . 47 2.4.2 Substrate scope .. .. . 52 2.5 Conclusions .......... . . ........... ........ .... .......................................................................... ... ... ... ... 57 2.6 Experimental s . . R EFERENCES . . 9 2 CHAPTER 3 : MECHANISTIC STUDIES TOWARDS THE DEVELOPMENT OF ONE - POT ALLYLATION HYDROSTANNATION INVOLVING .. 10 0 3.1 Introduction . 10 0 3.2 Allylation reactions with allylstannanes . 10 3 3.2.1 .. 10 3 3.2.2 Reaction with aldehydes in the presence of Lewis acids .. 5 3.2.3 Palladium catalyzed reaction of allylstannanes with aldehydes .. ...109 3 .3 One - pot allylation hydrost . 1 1 3 .4 Stepwise analysis of one - pot allylation hydrostannation . . . . . 1 18 v 3.4.1 Stepwise allylation and hydrostannation reaction of 4 - ethynylbenzaldehyde .. 18 3.4. 2 Study of the stability of the allylation and allylation - hydrostannation product of 4 - ethynylbenzaldehyde in the rea ction media .. 12 0 3.4. 3 B(C 6 F 5 ) 3 - catalyzed hydrostannation of 1 - (4 - ethynelphenyl) - but - 3 - en - 1 - ol with tributyltin hydride in presence of PMHS .. 2 1 3.4.4 One - pot allylation - hydrostannation of 4 - ethynylbenzaldehyde without PMHS .. . .. 12 2 3 .5 NMR s tudies ( 119 Sn, 19 F and 11 B) . . 1 2 2 3 .6 . 4 3 .7 Experimental s ection . . 5 R EFERENCES .. 1 4 3 CHAPTER 4 : C ARBON - TO - C ARBON [1,2] - S ILYL M IGRATION IN A LPHA S ILYL ALLYLIC ALCOHOLS T RIG ERRED BY EPOXIDATION 1 47 4 . 1 47 4 . 2 Carbon - to - carbon [1,2] - s ilyl migration .. ... 1 5 1 4.2.1 .. 15 3 4.3 . 1 57 4 . 4 Conclusions . 59 4 . 5 Experimental s ection . 1 60 REFERENCES .. . 1 66 vi LIST OF TABLE S Tab le 1 . 1 Average bond dissociation energies and bond lengths . ................ ....... .... 1 Table 2. 1 Control experiments with the Pd(OAc) 2 /PMHS/KF (aq) system . ...... ........ .......... 27 Table 2. 2 Screening of different Pd catalysts for imine redu ction . . .......... ....... 29 Table 2.3 Synthesis of starting materials . 31 Table 2. 4 Imine reduction using the Pd(OAc) 2 /PMHS/KF (aq) system . ........... . . ... ...... 34 Table 2. 5 Hydrogenolysis of the secondary amine 42 b with time . 38 Table 2. 6 Synthesis of amides using acetic anhydride . . 53 Table 2.7 Different methods for amide synthesis using imines . 55 Table 2.8 Synthesis of amides using benzoic anhydride . . . Table 2. 9 . . 57 Table 3 . 1 Optimization of one - pot allylation - hydrostannation sequence . . 115 Table 3.2 One - pot allylation - hydrostannation protocol of alkynals . . 117 Table 4.1 Wittig rearrangement of t rans - disubstituted pyrans for selected substrates 15 . 55 Table 4.2 Effect of substitution at the double bond 15 . . 56 vii LIST OF FIGURES Figure 1 . 1 . . 2 Figure 1 . 2 The - anion ( * - p) . 3 Figure 1 . 3 The - stabilization effect ( - p) . . 4 Figure 1 . 4 Lewis acid - catalyzed addition to aldehydes . .. . . 5 Figure 1.5 Reaction pathway of allylsilanes addition to aldehydes . . 5 Figure 1.6 Hiyama cross - coup ling mechanism . . .......... ............ ...................................................... 11 Figure 1.7 Mechanism of the non - fluoride activated pall adium - catalyzed c oupling . . ............. .................................. . 12 Figure 2.1 Reported publications using PMHS through the years 29b . .. . . 20 Figure 2. 2 Palladium encapsulated nanoparticles reported by Chauha n and s elective - nanocomposite 44 2 4 Figure 2 . 3 TEM image of Pd nanoparticles using Gatan Digital MSC camera 51 . . Figure 2 . 4 TEM image of reaction mixture of Pd(OAc) 2 /PMHS in THF/H 2 O without KF (aq ) at X80k . .. . .. . . 45 Figure 2. 5 EDS of normal sample (spectrum top). EDS of coated film without selecting darker particles (spectrum bottom) .. . . .. 46 Figure 3.1 Favoring effect towards the synclinal transition state . 108 Figure 3.2 Preparation of bis - - allylpalladium complex ( 141 ) . 110 Figure 3.3 Proposed Pd catalyzed mechanism of allystannanes addition to al dehydes . Figure 3.4 119 Sn NMR spectrum of Intermediate I . 123 Figure 3.5 11 B NMR spectrum of Intermediate I . 5 Figure 3.6 119 Sn NMR spectrum of Intermediate mixture II . 6 viii Figure 3.7 11 B NMR spectrum of Intermediate I I . 1 27 Figure 3.8 1 9 F - decoupled 119 Sn NMR spectrum of Intermediate mixture II . 28 Figure 3. 9 119 Sn NMR spectrum of crude reaction after addition of PMHS b efore B(C 6 F 5 ) 3 . 1 29 Figure 3. 10 Expansion of 19 F spectra prior to (top) and after (bottom) addition of B(C 6 F 5 ) 3 and PMHS . . 1 30 Figure 3.11 119 Sn NMR spectra of crude product mixture with exponential multiplic ation set to 100 Hz (i.e. lb=100) (top). With lb=10 (bottom) . ...13 1 Figure 3.12 11 B NMR spectra of crude product mixture 39 .. 13 2 Figure 3.13 Mechanistic rationale of one - pot allylation hydrostannation reaction . 3 ix LIST OF SCHEMES Scheme 1. 1 . . .3 Scheme 1.2 Allylsilane intermediate towards the synthesis of lactone 11 6 Scheme 1.3 First reported [1,2] - 7 Scheme 1.4 Di fferent Brook rearrangements .. . . 8 Scheme 1.5 . . 9 Scheme 1.6 Five - . . .... .................. .... .........10 Scheme 1 . 7 Biaryl synthesis us ing organosilanols 1 2 Scheme 2. 1 Previous examples of reduction of imines with PMHS . .. 1 8 Scheme 2 . 2 Recent application in deoxygenations reaction 20 and PMHS structure 19 Scheme 2 . 3 Previous examples of nitroarenes r edu ctions using silyl hydrides .. ..21 Scheme 2 . 4 Reduction of nitro compounds with Pd/PMHS/KF (aq) at 2 1 Scheme 2. 5 Preliminary Pd(OAc) 2 /PMHS/KF (aq) 22 Scheme 2. 6 Applic ation of Pd(OAc) 2 /PMHS/KF (aq) system. 41 Scheme 2. 7 Lewis base catalysis .... 24 Scheme 2. 8 Reduction of N - phenyl - 4 - methoxybenzylideneamine with Pd/PMHS/KF system 26 Scheme 2. 9 Additio nal imines prepared ......................................... 32 Scheme 2.10 Additional secondary amines obtaine . 36 Scheme 2.11 Hydrogenolysis of secondary amines with time 38 Scheme 2.12 Hydrogenolysis of imine 60 a 39 Scheme 2.13 No h ydrogenolysis: Substituent effect 40 x Scheme 2.14 Model compounds for debenzylation reactions 41 Scheme 2.15 Proposed imine reduction catalytic cycle 42 Sch 47 Scheme 2.17 Amide bond formation against thermodynamics . 48 49 Scheme 2.19 Amide formation reaction using DCC as coupling reagent 49 Scheme 2.20 Mechanism of activation by HOBt ( 72 ) when used as an additive 50 Scheme 2.21 Most commonly used 1 H - b enzotriazole salts 5 1 . 51 Scheme 2.23 General procedure for one - 52 Scheme 3.1 Organotin synthesis based on the Grignard and Kocheshkov r eactions . ....... 10 1 Scheme 3.2 Orga notin synthesis based on reactions of tin hydrides and R 3 SnM 2 Scheme 3.3 Stabilization of PVC 10 3 Scheme 3.4 Hydrostannations by radical mechanism . 10 4 Scheme 3.5 Allylstannane preparation ................ ........ 104 Scheme 3.6 Aldol reaction and allylmetal aldehyde condensation Scheme 3.7 Stereochemical outcome of allylstannane addition to aldehydes 106 Scheme 3.8 Model studies on the reaction of allylstann anes with aldehydes 107 Sche me 3.9 Crotylstannanes reaction with cyclohexanecarboxaldehyde . ........ ...... 108 Scheme 3.10 11 1 Scheme 3.11 Allylation of aldehydes using Bu 2 SnCl 2 as additiv e and proposed Bu 3 11 2 Scheme 3.1 2 Initial attempts of allylation - hyd xi Scheme 3.1 3 Yamamoto hydrostannation reaction 114 Scheme 3.1 4 Allylation of 4 - ethy nyl benzaldehyde 18 Scheme 3.1 5 Preparation of tributyl 19 Scheme 3.1 6 Hydrostannation reaction of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol 119 Scheme 3.1 7 Stability of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol in the reaction media without Bu 3 SnH 120 Scheme 3.1 8 Stability of 161 12 1 Scheme 3.1 9 Hydrostannation attempt of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol 121 Scheme 3. 20 Hydrosta nnation attempt of 4 - ethynylbenzaldehyde without PMHS 122 Scheme 3. 21 119 Sn NMR study of one - pot allylation - hydrostannation protocol 123 Scheme 3.2 2 Normal Lewis acid reaction vs. transmetallation of allylstannane (metathesis) with L ewis acid 125 Scheme 3.2 3 Hydrostannation of phenylacetylene by Bu 3 SnF 134 Scheme 4.1 Possible Wittig rearrangement pathways of 178 Scheme 4.2 Known Wittig rearrangements of dihydropyrans ...149 Scheme 4.3 [1,4] - and [1,2] - Wittig rearrangements of model 2 - silyldihydropyrans Scheme 4.4 Novel [1,2] - silyl migration in - silyl allylic alcohols . 151 Scheme 4.5 Proposed mechanism for carbon - to - carbon [1,2] - silyl migrati on .... ............ .... ....... 152 Scheme 4.6 Synthesis of cyclic ethers 208 and 209 .... 154 Scheme 4.7 Synthesis of [1,4] and [1,2] - Wittig rearrangement products Scheme 4.8 Selected starting materials for 1,2 - silyl migra tion . 157 Scheme 4.9 Carbon - to - carbon [1,2] - silyl migration Scheme 4.10 [1,2] - silyl migration of 223 as a single diastereomer 159 xii KEY TO ABBREVIATIONS Ac A cetate Acac Acetylacetonate aq A queous B(C 6 F 5 ) 3 tris(pentafluorophenyl)borane BF 3 OEt 2 b oron trifluoride diethyl ether Boc tert - butoxycarbonyl Bu 3 SnH tributyltin hydride CH 2 Cl 2 d ichloromethane Cl 2 Pd(PPh 3 ) 2 dichlorobis(triphenylphosphine)palladium(II) dba d ibenzylideneacetone DBU 1,8 - diazabicycloundec - 7 - ene DCC N,N - dicyclohexylcarbodimide DMF N,N - dimethylformamide EDS energy dispersive spectroscopy ee enantiomeric excess equiv E quivalent EtOAc ethy l acetate EtOH E thanol Et 3 N triethylamine xiii Et 2 O diethyl ether g g ram (s) h h our (s) KF potassium fluoride HMPA hexamethylphosphoramide Hz H ertz m - CPBA 3 - chloroperbenzoic acid m in M i nutes M M olar mg M illigram mL M illiliter m mol M illimole Me M ethyl MeO M ethoxy n - BuLi n - butyllithium Naph N aphtyl NMR Nuclear Magnetic Resonance Pd(OAc) 2 palladium (II) acetate Ph P henyl PMHS polymethylhydrosiloxane r.b. round bottom RCM ring - closing metathesis xiv r.t. room temperature sec - BuLi sec - butyllithium SiEt 3 T riethylsilyl SiMe 2 Ph phenyldimethylsilyl TBAF tetrabutylammonium fluoride TEM transmission electron microscop y TFA trifluoroacetic acid THF tetrahydrofuran T LC thin layer chromatrography TMS trimethylsilyl TMSOTf trimethylsilyl trifluromethane sulfonate Ts T osyl 1 CHAPTER 1: INTRODUCTION 1.1 Silicon: basic propertie s Silicon (Si) belongs to the same periodic group as c arbon (C) and share s its ability to form four bo nds (tetravalent). Conversely, s ilicon has some unique properties that make organosilicon chemistry a rapidly growing field. Three of the major difference strengths to other elements (Table 1.1), Si is le ss electronegative (1.90) than c arbon (2.55) and the ability to extend its coordination to the so - called hypervalent silicon co mpounds. 1 Table 1.1 Average bond dissociation energies and bond lengths 1 Entry Bond strength (kcal/mol) Bond length (Å) Si - H 75 1.48 C - H 99 1.09 Si - C 76 1.85 C - C 83 1.54 Si - O 110 1.63 C - O 85.5 1.43 Si - F 135 1.60 C - F 116 1.35 2 T able 1.1 shows that s ilicon forms stronger bonds to o xygen and f luor ine than to carbon and h ydrogen. In addition, Si bonds have longer bond lengths in comparison to carbon bonds because the silicon atom is 1.5 times larger than the c arbon atom. 2 Due to the lower electronegativi ty of s ilicon the Si - H and Si - C bond are polarized (Figure 1.1) giving particular properties to these bonds. For example, organosilicon hydrides (at least one Si - H bond) have the ability to serve as mild air and water - stable sources of hydride. 3 Figure 1.1 Silicon bonds polarize d In the case of the Si - C bond , the polarization allows for nucleophilic attack at the Si center, breaking the bond heterolytically in a way tha t would be difficult with a C - H bond. 1 Early evidence of this rapid nucleophilic attack was reported in 1976 b y Fleming. 4 I n this study the - trimethylsilyl carbenium species ( 2 ) is attacked by the nucleophile to generate only one isomer ( 3 ) in a short time. With s pecies that lacked the trimethylsilyl group ( 4 ), the reaction was slower and not selective, thus form ation of different isomers ( 6 ) was observed (Scheme 1.1). 4 This polarization of the Si - C bond also generates two important properties of s ilicon, the stabilization of the negative c harge at the adjacent c arbon ( anions) and the stabilization of a positiv e charge at the position ( s ilicon effect). 3 Scheme 1.1 Evidence for rapid nucleophilic attack The - stabilization effect has been attributed to overlap between the antibonding * level of the C - Si bond and the adjac ent filled p - orbital of the carbanion, highly polarized carbon - metal bond (Figure 1.2). This interaction is favor able due to the difference in electronegativity between the Si and C, thus the antibonding * level of the C - Si bond has a relatively high coef ficient on the silicon increasing the overlap. 1,2 Figure 1.2 The - anion ( * - p) overlap The - stabilization effect arises from the interaction between the bonding level of the C - Si bond and the adjacent empty p - orbital of the carbonium ion (Figure 1.3 ). The 4 electronegativity of S i g ives a higher charge density to t h e c arbon in the C - Si bond , which facilitates the hyperconjug ative stabilization of the empty p - orbital . This stabilization is maximum when the empty p - orbital and the C - Si bond are coplanar to each other. 5 Figure 1.3 T he - stabilization effect ( - p) overlap The basic properties highlighted on the previous pages allow organosilicon compounds to be more moisture - and air - stable than other organometallic reagents. They can also be prepared from a wide range of often cheap starting materials and usually present low toxicity. 1,2 Some of the most common reactions of these organosilicon compounds are described in the following pages of this chapter. 1.2 Allylsilanes Allylsilanes have been extensively used in organic chemistry due to the weak polarization of the C - Si bond, which permits an easy handling and better stability of these organometallic - type reagents. 6 One the major applications of allylsilanes is the Lewis acid - catalyzed addition to aldehydes (Figure 1.4). In this proce ss the Lewis acid activates the aldehyde toward nucleophilic attack. I n case s where a chiral Lewis acid is employed, enantioselective addition is possible . 7 5 Figure 1.4 Lewis acid - catalyzed addition to aldehydes The additi on of allylic silanes to electrophiles has been shown to be a stepwise process. 8 I n the first step the addition of the silane to an activated aldehyde forms a carboca tion, which is stabilized by the - effect of the C - Si bond (Figure 1.4). Furthermore, this reaction usually proceeds through an anti S E 9 The initial step of addition occurs at the - terminus carbon, thus the orientation of the double bond and the location of the s ilicon group in the transition state define the stereochemical outcome of the final substitution reaction. The most stable open transition state demands an anti - a ddition to the electrophile, where the silicon group is located away from the ele ctrop hile in an antiperiplanar orientation. 9 Figure 1.5 Reaction pathway of allylsilanes addition to aldehydes 6 One recent example of the utility of allylsilanes is i n the preparation of a key allylic intermediate for the syn thesis of the tricyclic core of neoliacinic acid ( 11 ) . 10 The allylsilane ( 10 ) was prepared by treatment of the triisopropylsilyl - protected ester ( 7 ) with an organocerium reagent generated by the reaction of trimethylsilylmethylmagnesium chloride ( 8 ) with a nhydrous cerium chloride. This reaction generated a double Grignard addition of the TMSCH 2 , then the product formed ( 9 ) undergoes the Peterson elimination after the work up upon exposure to silica gel, giving the desired allylic silane ( 10 ) (Scheme 1.2). Scheme 1.2 Allylsilane intermediate towards the syn thesis of lactone 11 1.3 Brook rearrangement Another common transformation of silicon containing molecules is the Brook rearrangement. Due to the stronger affinity of Si to o xygen (O), as explained previous ly , Si 7 bonds to O have greater strength than those to C (see T able 1.1). This allows the formation of carbanions from alkoxides through the [1,2] - Brook rearrangement (Scheme 1.3). 11 Scheme 1.3 First reported [1,2] - Brook rearrangement The nucleophilic attack of the oxygen t o the - silicon atom requires the presence of a base to promote the required electron density on the oxygen atom . This rearrangement is reversible and which side of the equilibrium is more st able depends on several factors. S ome of them are i) the strength of the oxygen - metal ion pairing that stabilize the alkoxide , ii) how the carbon substituents can stabilize the negative charge of the carbanion , and iii) solvent polarity. 12 Previous studies indicated that the silyl migration usually occurs with retention of configuration at the silicon and inversion of configuration at the carbon. 12a Although the initial rearrangement was known for a 1,2 shift of Si, it was extended to a range of [1,3], [1,4] and [1,5] - silyl group to oxygen migration s (Scheme 1.4) 12b,13 8 Scheme 1.4 Different Brook rearrangements One excellent development of the Brook re arrangement is its application i n Anion Relay Chemistry (ARC) elaborated by the Smith group. 14 Here an anion stabilizing group (ASG) loc ated on the same carbon bearing a trialkyl silyl group, stabilizes the charge of the carbanion form ed after the [1,4] Brook rearrangement takes place. The new reactive anion is available to react with a new electrophile generating a series of sequence reac 14 9 Scheme 1.5 Anion relay chemistry (ARC) The ARC is basically divided in two groups regarding the charge migration, the latter - bond - I n the first scenario the transfer of the negative charge occurs like in a 1,4 addition reaction to enone , in which the negative charge is transfer ed via the unsaturated - system. Conversely, i d alkoxide to the carbon atom by silyl migration like in the Brook rearrangement. This second h - T ype I , where after addition of HMPA the negative charge is relayed back to the original location on t he nucleophile ( linchpin ) and type II where an external nucleophile is needed to generated an anion , that with the aid of a transfer agent the negative charge is relayed to a new position on the molecule after rearrangement 10 (Scheme 1. 5 ) . 14 O ne application of the type 1 ARC in natural product synthesis is the preparation of an important intermediate ( 34 ) employed in the total synthesis of mycoticin (Scheme 1.6) 15 Scheme 1.6 Five - component coupling using Type I ARC 1.4 Silane s in cross - coupling chemistry Due to their low toxicity, stability , and availability organosilicon compounds are considered excellent reagents for cross - coupling reactions, acting as the nucleophilic partners for various organic halides. 16 Reactions that employ palladium (Pd) or nickel (Ni) catalyzed coupling of organohalides or triflates with organosilanes are called Hiyama coupling s . 17 D ue to their lower reactivity, organosilanes traditionally needs to be activated by a fluoride source upon 11 heating, givi ng a more reactive pentacoordinated intermediate that is more capable in transmetalation s (Figure 1.6). Figure 1.6 Hiyama cross - coupling mechanism A n improvement of this coupling reaction by Denmark involves the employme nt of organosilanols that do not require the use of a fluoride source for activation of the silicon species (Figure 1.7). However, this Brønsted base - promoted reaction depends on the steric and electronic properties of the silicon center. 18 Kinetics studi es of these base mediated Hiyama coupling s , indicated that the intermediate s are not only a hypercoordinate Si species. Instead Denmark invokes first the formation of complex I (Figure 1.7) that contains a silicon - oxygen - palladium bond and the reaction pro ceed via an intramolecular transmetallation of a tetracoordinate Pd II species II . 18a,19 Some applications of these coupling reactions include the synthesis of particularly challenging aryl heterocycles (Scheme 1.7). Treatment of N - Boc - dimethyl(2 - indolyl)s ilanol ( 35 ) with NaH generates the active intermediate sodium N - Boc - dimethyl(2 - indolyl)silanolate ( 36 ). 12 The latter is an active reagent for cross coupling with aryl iodides containing nitriles, ethers and esters substituents. 20 Figure 1.7 Mechanism of the non - fluoride activat ed palladium - catalyzed coupling Scheme 1.7 Biaryl synthesis using organosilanols 13 The purpose of this introductory chapter was to highlight some of the unique prop erties of s ilicon as well as some of its important applications related to Pd - catalyzed reactions, allylation s of aldehydes, and 1,2 shift s of s ilicon. These three areas will be subjects i n the following chapters where the development of new methodologies in a quest to increase the use of s ilicon in the preparation of new intriguing organic molecules is described . 14 REFERENCES 15 REFERENCES (1) (a) Colvin, E. W. Silicon Reagents in Organic Synthesis; Academic Press: San Diego, 1988: Chapter 1. (b) Brook, M. A. Silicon in Organic, Organometallic and Polymer Chemistry; Wiley: New York, 2000: Chapter 1, 2 and 4. (2) (a) Corey, J. Y. Historical O verview and C omparison of S ilicone with C arbon , In The Chemistry of Organic Silicon Com pounds, Part 1; Patai, S.; Rappoport, Z., Eds.; Wiley: New York, 1989. (3) (a) Brook, M. A. Silicon in Organic, Organometallic and Polymer Chemistry; Wiley: New York, 2000: Chapter 7. (b) Larson, G. L.; Fry, J. L. Ionic and Organometallic - Catalyzed Organo silane Reductions, in Organic Reactions; Wiley: New York, 2008; Vol. 71, Chapter 1 pp 5 75. (4) Fleming, I.; Pearce, A; Snowden. R. L. J.C.S. Chem. Comm. 1976 , 182 183. (5) (a) Jorgensen, W. L.; Chandrasekhar, J.; Wierschke, S. G. J. Am. Chem. Soc. 1985 , 107 , 1496 1500. (b) Lambert, J. B.; Wang, G. - T.; Finzel, R. B.; Teramura, D. H. J. Am. Chem. Soc. 1987 , 109 , 7838 7845. (6) (a) Fleming, I. Allylsilanes, Allylstannanes and Related Systems, in Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.; Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 563 593. (b) Langkopf, E.; Schinzer, D. Chem. Rev. 1995 , 95 , 1375 1408. (7) (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003 , 103 , 2763 2793. (b) Chabaud, L.; James, P.; Landais, Y. Eur. J. Org. C hem. 2004 , 15 , 3173 3199. (8) Fleming, I.; Langley, J. A. J. Chem. Soc., Perkin Trans. 1 1981 , 1421 1423. (9) (a) Denmark, S. E.; Almstead, N. G. J. Org. Chem. 1994 , 59 , 5130 5132. (b) Buckle, M. J. C.; Fleming, I.; Gil, S.; Pang, K. L. C. Org. Biomol. C hem. 2004 , 2 , 749 769. (10) Clark, J. S.; Baxter, C. A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org. Chem. 2008 , 73 , 1040 1055. (11) (a) Brook, A. G. J. Am. Chem. Soc. 1958 , 80 , 1886 1889. (b) Brook, A. G .; Warner, C, M.; McGriskin, M. E. J. Am. Chem. Soc. 1959 , 81 , 981 983. (c) Brook, A. G.; Iachia, B. J. Am. Chem. Soc. 1961 , 83 , 827 831. 16 (12) (a) Brook. A. G. Acc. Chem. Res. 1974 , 7 , 77 84. (b) Moser, W. H. Tetrahedron 2001 , 57 , 2065 2084. (c) West, R. ; Lowe, R.; Steward, H. F.; Wright, A. J. Am. Chem. Soc. 1971 , 93 , 282 283. (13) (a) Hoffmann, R.; Bruckner, R. Chem. Ber. 1992 , 125 , 2731 2739.(b) Lautens, M.; Delanghe, P. H. M.; Goh, J. B.; Zhang, C. H. J. Org. Chem. 1995 , 60 , 4213 4227. (c) Smith, A. B., III; Xian, M.; Kim, W. - S.; Kim, D. - S. J. Am. Chem. Soc. 2006 , 128 , 12368 12369. (14) (a) Smith, A. B., III; Xian, M. J. Am. Chem. Soc. 2006 , 128 , 66 67. (b) Smith, A. B., III; Wuest, W. M. Chem. Commun. 2008 , 5883 5895. (15) Smith, A. B., III; Pi tram, S. M. Org. Lett. 1999 , 1, 2001 2004 . (16) (a) Hiyama, T.; Shirakawa, E. Top. Curr. Chem 2002 , 219 , 61 85. (b) Denmark , S. E.; Sweis, R. F. Acc. Chem. Res. 2002 , 35 , 835 846. (17) Hatanaka. Y.; Hiyama, T. J. Org. Chem. 1988 , 53 , 918 920. (18) (a) Denmark, S. E.; Neuville, L.; Christy, M. E. L.; Tymonko, S. A. J. Org. Chem. 2006 , 71 , 8500 8509. (b) Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008 , 41 , 1486 1499. (19) (a) Denmark, S. E.; Sweis, R. F.; Wehrli, D. J. Am. Chem. Soc. 2004 , 126 , 4865 4875. (b) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004 , 126 , 4876 4882. (20) Denmark, S. E.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008 , 73 , 1440 1455. 17 CHAPTER 2 : IMINE REDUCTIONS 2 .1 Introduction The importance of the amino functionality in the pharmaceutical industry is considerable. Secondary amines are vital building blocks for alkaloid and pharmaceutical drug syntheses. 1 One of the most noteworthy pathways for the synthesis of these nitrogen - containing building blocks is their preparation from imine compounds. Conventional approaches to obtain secondary amines by reduction of imines often require s reagents that are difficult to handle or lack chemoselectivity (e.g. NaBH 4 , 2 LiAlH 4 , 3 BH 3 (CH 3 ) 2 NH/CH 3 COOH (glacial), 4 Ra - Ni/al uminum isopropoxide/iPr - OH, 5 NH 3 /Ra - Ni, 6 BH 3 S(CH 3 ) 2 . 7 ) These protocols also tend to generate copious waste and involve difficult work up to isolate the desired amine. An alternative route applied towards imine reduction is the use of silanes and siloxane s as reducing reagents. Different methods have employed triethylsilane in combination with Zn, 8 Mo, 9 Ti 10a - b catalysts or metal free conditions. 11 In the quest for environmentally friendly and inexpensive procedures, polymethylhydrosiloxane (PMHS) represen ts a safe and economic hydride source. Consequently several protocols have been reported using PMHS in combination with Zn, 12 Sn, 13 Ti, 10a - d In, 14 and Cd 14 catalysts, in addition to metal free conditions wherein PMHS is activated only by trifluoroacetic ac id 15 (Scheme 2 .1). Noteworthy o f the latter example, as well as in two recent publications 16 one - pot reductive amination is achieved. Several efforts have also been extended to the development of asymmetric syntheses of secondary amines using chiral catal yst s and ligands by reductive amination. 10a - c,14,17 Applications of 18 reductive amination in both academic research and chemical industries 1,18 highlight once again the importance of imines as key intermediates that can provide direct access to chiral amines . Scheme 2 .1 Previous examples of reduction of imines with PMHS 2.2 PMHS applications and background PMHS is a powerful reagent that can perform a wide range of reactions, such as dehalogenation, 19 deoxygenations, 20 opening of aziridines, 21 reduction of ketones, 22 double bonds, 23 carboxylic esters, 24 carboxamides, 25 and organotin halides and oxides. 26 It is a (approximately $7.2 per mol o f hydride). 27 Moreover, PMHS is air and moisture stable (can be stored on the bench for years); and is assumed to be non - toxic (Scheme 2 .2). 19 Scheme 2 .2 Recent application in deoxygenations reaction 20 and PMHS structure PMHS was first synthesized by Sauer 28 in 1946 but its utility in synthesis has only been exploited in the last decades. 29 A search in SciF inder ® highlights, that over the past 22 years the use of PMHS has grown dramatically (Figure 2.1). 29b One of the mos t cited papers that used PMHS for the enantio selective reduction of ketones in the presence of chiral zinc catalysts, has b een cited 191 times up to now. 29c Several protocols using PMHS in combination with Ti, 10,24 Pd, 21,23,30 Zn, 22a - b,31 Cu, 22c - d Sn, 22e,2 6a,32 Zr, 24 Ru, 25 Fe, 33 and I 2 34 are reported. It is also known that PMHS can be activated to a hypercoordinate species with a fluoride source. 22f,26b,35,36 Maleczka and co - workers 36 showed that the combination of KF and PMHS, in ethereal solution, yielded tributyltin hydride from the corresponding tributyltin chloride. 20 Figure 2.1 Reported publications using PMHS through the years 29b Another important application of PMHS is in nitro reductions. An attractive route for those reductions involves the use of silanes and siloxanes as hydride source. Early examples by Lipowitz and Bowman 37 recounted the use of PMHS with a Pd/C catalyst towards the reduction of nitrobenzene to an iline. Almost 20 years later, B l u m and Volhardt 38 highlighted again the use of PMHS to reduce nitrobenzene using a rhodium catalyst for this transfer hydrogenatio n reaction (Scheme 2 .3). Another successful methodology was reported years later by Brinkman and Miles, 39 who employed triethylsilane with of several nitrobenzenes. 21 Scheme 2 .3 Previous examples of nitroarenes redu ctions using silyl hydrides Encouraged by these results, the Maleczka group developed a methodology that facilitates the reductions of nitrogen - cont aining functional groups under milder conditions and shorter reaction times based on Pd - catalyzed reductions using PMHS in presence of aqueous KF 40 (Scheme 2.4). Scheme 2 . 4 Reduction of nitro compounds with Pd/PMHS/KF (aq ) at room temperature The combination of these reagents was initially tested on the hydrodehalogenation of aryl chlorides. 19b During those chlorodehalogenation studies, the reduction of the nitro group in 1 - 22 chloro - 4 - nitrobenzene was also observed (Scheme 2 .5). Therefore, nitrobenzene was subjected to the optimized dehalogenation conditions to yield the desired amine. 40a Scheme 2 . 5 Preliminary Pd(OAc) 2 /PMHS/KF (aq) nitro reduction In order to optimize this nitro reduction; d ifferent palladium catalysts, fluoride sources, and siloxanes/silanes were screened using 2 - nitrotoluene as the control substrate. 40a It was found that the combination of Pd(OAc) 2 /PMHS/KF (aq) gave the highest yields and shortest reaction times. This metho dology displayed a broad substituent group (EDG and EWG) tolerance independent of their ring position affording the aniline products in quantitative yield. Chemoselective reductions of the nitro group were also observed, in which carboxylic acids, esters, amides, and fluoro substituents survive; however ketones, nitriles, bromo, chloro, olefins and triple bonds gave side products. Exceptions to th e broad reactivity are substrates containing sulfur, which are assumed to poison the catalyst. 40 This methodolog y was extended to heteroaromatic 40 and aliphatic nitro compounds 40 giving the corresponding anilines and N - hydroxylamines. In the second case the optimization conditions required exchange of PMHS for a non - polymeric silicon hydride such as triethylsilane a nd removal of the fluoride source. Furthermore, one - pot reductive conversion of nitroarenes to amides, carbamates or sulfonamides was also reported by the Maleczka group 41 (Scheme 2 . 6 ). 23 Scheme 2 . 6 Application of Pd(OAc) 2 /P MHS/KF (aq) system 41 It is important to mention that these results demonstrate the significance of the fluoride source to activate the PMHS. 22f,26b,35,36 T he preference of the s ilicon atom to form pentacoordinate species activated by the presence of anionic ions had been reported . 42,43 Previous examples reported on hydrosilylation catalyzed by fluoride salts proposed that the F - ion coordinate to the Si atom making the Si - H bond weaker. Indeed, this pentacoordination make the Si center more electrophilic, th erefore reaction towards nucleophiles followed by delivery of the hydride takes place faster and a mechanism via Lewis base catalysis is suggested (Scheme 2 . 7 ). 43 24 Scheme 2 . 7 Lewis base catalysis I n our catalyst system the presence of Pd suggested a different scenario due to the formation of Pd nanoparticles, as reported by Chauhan; 44 when Pd(OAc) 2 and PMHS were combined (Figure 2. 2 ). The formation of this highly activated palladi um nanoparticles, seems to influence the sel ectivity of these reductions. Figure 2. 2 . Palladium encapsulated nanoparticles reported by Chauhan and s elective reduction - . 44 25 2. 3 Application of Pd(OAc) 2 /PMHS/ KF (aq) system in the reduction of imines. The successful studies on the reduction of nitro compounds using the Pd/PMHS/KF system sparked our interest to further investigate its application to the synthesis of secondary amines from the direct reduction of imines. To the best of our knowledge there has been no report of using Pd(OAc) 2 /PMHS/KF (aq) for this reduction. Therefore, the study of the reduction of aromatic imines using this catalyst system was undertaken. 45 The goal of this chapter is to report our results on imine reductions as well as their advantages of short reaction times, low catalyst loadings and own establishment of th e formation of Pd nanoparticles. 2. 3.1 Optimization of the Pd(OAc) 2 /PMHS/KF (aq) system Initially N - phenyl - 4 - methoxybenzylide neamine was selected as a model substrate and it was prepared in quantitative yield following standards procedures. 46 Then the freshly synthesized imine was subjected to our reduction methodology in 1 mmol scale (Scheme 2. 8 ). The first experiment with 5 mo l % of Pd(OAc) 2 , 2 equiv of PMHS and 10 mol% of KF gave complete conversion in just 30 min (Table 2.1, entry 1). Following attempts to reduce the Pd(OAc) 2 loads to 2.5 mol % and 1 mol % still showed traces of starting material at 30 min as monitored by 1 H NMR (Table 2.1, entry 2 and 3). Absence of Pd shutdown the reaction and no conversion was observed after 24 h (Table 2.1, entry 4). This result indicated that PMHS in the presence of aqueous KF does not hydrolyze the imine. When PMHS was not added to the 26 r eaction vial no reduction of the imine was observed after 12 hours while using lower quantities of PMHS increased the reaction time (Table 2.1, entries 5 and 6). It is worth noting that in the absence of KF (aq) the reaction does take place. H owever, such r eaction cannot be driven to complete conversion even after 24 h (Table 2.1, entry 7). Therefore, the addition of KF as additive to activate the PMHS presumably via a pentacoordinate species was necessary to accelerate the delivery of the hydride. When only 5 mol % of KF was employed traces of imine can be observed at 30 min (Table 2.1, entry 8). Increasing the quantities of KF (aq) to 15 mol % furnished the desired product in 30 min, however at higher loads gel formation was occasional observed . It is report ed that PMHS can form hydroxysiloxanes in the presence of a H 2 O/THF solvent mixture catalyzed by Pd, 47 therefore adding more aqueous KF can promote the formation of hydrosiloxanes that would generate a difficult isolation of the product . Finally we were able to confirm that the initial quantities of 5 mol % Pd(OAc) 2 , 2 equiv of PMHS and 10 mol % of KF employed gave us the best results for this imine reduction. T he order of addition was important in that mixing the Pd(OAc) 2 with the imine solution in THF/K F(aq) followed by addition of PMHS in sured shorter reaction times. Scheme 2. 8 Reduction of N - phenyl - 4 - methoxybenzylideneamine with Pd/PMHS/KF system 27 Table 2.1 Control experiments with the Pd(OAc) 2 /PMHS/KF (aq) sys tem Entry Pd (OAc) 2 PMHS KF Time Result (ratio 38 / 39 ) a 1 5 mol % 2 equiv 10 mol % 30 min 0:1 2 2.5 mol % 2 equiv 10 mol % 30 min 0.2:1 3 1 mol % 2 equiv 10 mol % 30 min 0.1:1 4 --- 2 equiv 10 mol % 24 h No reaction 5 5 mol % --- 10 mol % 12 h No react ion 6 5 mol % 1 equiv 10 mol % 30 min 0.1:1 7 5 mol % 2 equiv --- 24 h 1:1 8 5 mol % 2 equiv 5 mol % 30 min 0.2:1 9 5 mol % 2 equiv 1 5 mol % 30 min 0:1 a Reactions were perform in a 1 mmol scale, at room temperature and using THF as solvent. Ratios wer e calculated by 1 H NMR of crude mixture. These preliminary results indi cated that the presence of the f luoride ion is necessary to accelerate the reaction. At this point a question needs to be addressed: Does changing the F - source for a stronger base l ike tetrabutylammonium fluoride ( TBAF ) improve this reduction even more? Using 5 mol % of TBAF, but keeping the same quantities of i mine (1 mmol), Pd(OAc) 2 (5 mol %) and PMHS (2 equiv), just 30% of conversion was detected at 30 min. Even after 24 h no more than 50 % conversion was reached (imine/secondary amine ratio 1:1). Increasing the TBAF up to 10 mol % generate d a polymer like substance that shutdown the reaction. Therefore, until now the combination of Pd/PMHS/KF gave us the best results for this redu ction. 28 In order to confirm that Pd(OAc) 2 was the best catalyst for these reductions, we tested different Pd catalysts under the same reaction conditions of PMHS/KF (aq) previously established (Table 2.2). Using 5 mol % of each catalyst and 1 mmol of N - ph enyl - 4 - methoxybenzylideneamine, control reactions were performed and monitored by 1 H - NMR between 30 min and 2 hours. In the first two attempts using Pd(Cl) 2 and Pd(CN) 2 (Table 2.2, entries 1 and 2) the 1 H NMR spectrum of the crude reaction mixture displaye d only the signals of the starting material. Therefore we continued both reactions for an additional 30 min, however, no conversion was observed and the palladium precipitated after 2 hours in both cases. When phosphine ligands were employed (entries 3 and 4), no conversion to the desired amine was observed after 30 min, instead hydrolysis of the imine generated a complicated mixture as judged by 1 H NMR. The same result was observed when Pd(NH 3 ) 2 Cl 2 was used as a catalyst (entry 5). On the other hand, when Pd 2 (dba) 3 , Pd(OH) 2 /C, Pd black, and Pd/C activated were employed, partial reduction of the imine was observed at 30 min. The secondary amine to imine ratio was 1:1; complete conversion was observed by 1 H NMR after 1 hour (entries 6 to 9). However, in the l ast two cases we observed a Pd black and Pd/C batch dependence even when new bottles of these catalysts were used . U sing a different bottle of Pd black , no conversion was observed even after 24 h; for the latter case a mixture of secondary amine and imine (2:1) was obtained after leaving the reaction overnight. The last catalyst tested, Pd(acac) 2 , gave a higher conversion in 30 min. The ratio of secondary amine to imine was 4 to 1 and the reaction was complete after 45 min. In summary, these findings confir med that Pd(OAc) 2 was the best catalyst, giving complete conversion in as little as 30 min. 29 Table 2.2 Screening of different Pd catalyst s for imine reduction Entry Catalyst Time % conversion Observation 1 Pd(Cl) 2 30 min 0 Pd precipitation 2 Pd(CN) 2 30 min 0 Pd precipitation 3 Pd(PPh 3 ) 2 (C 6 H 5 )Cl 30 min 0 Hydrolysis 4 Pd(PPh 3 ) 2 Cl 2 30 min 0 Hydrolysis 5 Pd(NH 3 ) 2 Cl 2 30 min 0 Hydrolysis 6 Pd 2 (dba) 3 30 min 50 Done in 1 h 7 Pd(OH) 2 /C 30 min 50 Done in 1 h 8 Pd black 30 min 50 Done in 1 h 9 Pd/C activated 30 min 50 Done in 1 h 10 Pd(acac) 2 30 min 80 Done in 45 min 11 Pd(OAc) 2 30 min 100 Done in 30 min With these results in hand, we next analyzed the substrate scope. Several imines were prepared not only to study reductive aminations, but also to furthe r investigate the chemoselectivity of this reduction in the presence of other functional groups such as alkenes, alkynes, ketones, esters, nitriles, halogens and nitro substituents. 2. 3. 2 Substrate scope and chemoselectivity studies The synthesis of t he starting materials is indicated on T able 2.3. From entries 1 to 8 different imines with electron donating groups ( EDG ) or electron withdrawing groups ( EWG ) 30 incorporated into their structure were prepared. The second part of this table was prepared in or der to investigate the possible chemoselective reduction of the imine in the presence of other functionalities. Furthermore, imines with more than one substituent on the benzaldehyde or aniline core, as well as some imines derived from benzylamine, cinnama ldehyde and 2 - napthaldehyde were synthesized (Scheme 2. 9 ). Using the previously established reaction conditions of 5 mol % Pd(OAc) 2 , 2 equiv of PMHS and 10 mol % of KF in a 1 mmol scale of each starting materia l; the reductions were complete after 15 min t o 2 hours and the secondary amine yield ranged from 23 to 93% (Table 2.4 and Scheme 2. 10 ). The products were identified by 1 H - NMR and isolated after acid/base work up. The 1 H - NMR spectrum usually display an imine proton (RN=C H ) around 8.4 ppm for the start ing material. After reduction, this signal disappears and a new peak for the methylene protons (RNH - C H 2 R) of the secondary a mine is observed around 4.3 ppm. As previously men tioned, the second part of T able 2.4 showcases the reactivity of the imine in the presence of other functional groups. Previous studies of this methodology in the presence of halogen substituents showed dehalogenation as a side reaction. However, under the optimized imine reduction conditions no dehalogenated products where observed in the case of F (imine 44 a ) and Cl ( 43 a and 46 a ) containing substrates. 31 Table 2.3 Synthesis of starting materials On the other hand, the imine reduction with Br containing substrate ( 45 a ) displayed a complicated mixtu re in the 1 H NMR spectrum, where four different compounds could be 32 identified: two secondary amines ( 40 b , 45 b ) and two imines ( 40 a , 45 a ) as a consequence of dehalogenation. Scheme 2. 9 Additional imines prepared The initi al work up for the N - p henyl - 4 - methoxybenzylideneamine reduction included addition of ether, which precipitated the catalyst upon stirring. A quick filtration of the Pd through a plug of Celite (top layer) and neutral alumina (b ottom layer) gave a high r eco very of crude product ; however the yield of product after column chromatography was <50% and some contamination with PMHS was observed by 1 H NMR. To circumvent this problem, a new work up was attempted in which a mixture of H 2 O/Et 2 O (1:1) was added to the crude reaction mixture . After stirring, the organic phase was separated, dried with MgSO 4 , filtered and concentrated. The crude product was dissolved in EtOAc and treated with a 3M HCl solution. The white solids that formed were filtered, washed with EtOAc and dried overnight to give the desired secondary amine as a hydrochloride salt. The salt was dissolved in a H 2 O/methanol (1:1) mixture and NaHCO 3 (sat) solution was added. The solution was concentrated under reduced pressure to a minimum volume , and then extracted with EtOAc. The organic layers were dried and 33 concentrated to give the secondary amine in 65% yield . Optimization of the work up with a shorter acid/base procedure increased the yield of N - (4 - methoxybenzyl)phenylamine to 80% . I n this work up a m ixture of Et 2 O/1M HCl (1:1) was added and stirred for 10 min. The organic phase was separated and washed with 1M HCl. Then the aqueous layers were combined, made basic with addition of KOH (s) , and extracted with EtOAc. Finally, the combined organic layers were dried, filtered and concentrated. The next substrates selected from T able 2.4 contained NO 2 groups in the para and meta position of the aniline or benzaldehyde ring. Better chemoselectivity was observed when the nitro substituent was at the para posit ion ( 48 a and 49 a ). Regardless of whether the p - NO 2 group was on an aniline or benzaldehyde ring, the nitro group survived the reduction conditions and no over reduced product was observed within one hour of reaction, however some starting imine remained. C onversely, leaving the mixture for longer time reduced the yield of the target secondary amine and increased the formation of the amino derivative (Table 2.4, entries 9 and 10). When the electron withdrawing group was on the meta position, reduction of bot h functionalities was observed in 1 hour. In the case of m - NO 2 anilines (imine 50 a ), only the over reduction product ( 50 c ) was observed. In contrast m - NO 2 benzaldehydes (imine 51 a ) gave a 1:1 mixture of the nitro secondary amine ( 51 b ) and the over reductio n product ( 51 c ). 34 Table 2.4 Imine reductions using the Pd(OAc) 2 / PMHS /KF (aq) system 35 Table 2.4 36 Scheme 2. 10 Additional secondary amines obtai ned To our delight, a different set of results were observed with nitrile ( 52 a ) and ester ( 53 a ) substituents where chemoselective reduction of the imine s were obtained in high yield s (Table 3, entry 13 and 14). Unfortunately a limitation of this methodolo gy was observed in the presence of conjugated double ( 56 a ) and triple bonds ( 55 a ). In the former case, the presence of the conjugated double bond accelerates the reaction, yielding complete reduction in only 15 min (Scheme 2.3, 56 b ). An important observati on was that the complete formation of the secondary amine ( 56 b ) was detected even before the typical bubbling and color change could be observed. On the other hand, normal reaction conditions were observed for the triple bond containing substrate imine 55 a , however in only 1 h the alkyne was reduce to the alkane (Table 2.4 , entry 16 ). Further analysis of this substrate by following the reaction by 1 H NMR proved interesting. It was observed that the reduction of the triple bond occurred first without reducti on of the imine, and only after consumption of the triple bond was the imine red uced . This type of reaction has been reported before for - alkynyl - imino esters in the presence of a Brønsted acid, both functional groups were reduced to afford an alkenyl - amino ester. An investigation of the 37 reaction mechanism indicated that the reduction of the C - C triple bond to alkene was faster than the reduction of the imine bond. 48 Continuing our studies on chemoselectivity, reductions of imines in the presence of ketones (imine 54 a ) were carried out. 1 H NMR a nalysis of the crude material after 30 min indicated a mixture of selective imine reduction 54 b and the over reduced product (conversion of ketone to alcohol and imine reduction) in a ratio 1:0.3. The usual wor k up developed for the isolation of the secondary amines allowed us to obtain 54 b (64% yield) ; however the alcohol product did not survive these conditions . 2. 3. 3 Hydrogenolysis results: substituent effects A different result was obtained when N - benzylid ene - 4 - methoxyaniline (imine 42 a ) was subjected to the reduction conditions. At 30 min, the target secondary amine 42 b was observed by 1 H NMR, along with 4 - methoxyaniline as an impurity (Table 2.5). The presence of small quantities of starting imine 42 a led us to leave t he reaction for another 30 min. Surprisingly, another compound was detected in the crude mixture but after purification and concentration of the solvent, only the secondary amine 42 b , imine 42 a and 4 - methoxyaniline were recovered. In a batch that was left for 5 hours, the desired product 42 b was not detected. Instead, toluene and 4 - methoxyaniline were the major components in the mixture, along with a small percent of starting material. Leaving the reaction overnight le d to the complete consump tion of 42 b and 42a , yielding only toluene and 4 - methoxyaniline (Table 2.5). 38 Table 2.5 Hydrogenolysis of the secondary amine 42 b with time Entry NMR Crude N - benzylidene - 4 - methoxyaniline 42a Secondary amine 42 b Toluene 4 - M ethoxyaniline 1 at 30 min 5.8% 44% 9.8% 39.6% 2 at 1 h 5.1% 37.8% 16% 41.2% 3 at 5 h 3.7% --- 43.6% 52.7% 4 at 21 h --- --- 46.8% 53.2% During these studies, we observed that for those imines that did not have substituents on the benzaldehyde ring, running the reductions for longe r times led to consumption of the secondary amines. In all cases hydrogenolysis of the benzylic C N bond and formation of toluene was observed (Scheme 2. 11 ). As we had previously established that PMHS in the presence of aqueous KF does not hydrolyze the im ine (discussed on part 2. 3. 1), this reduction is almost certainly the result of hydrogenolysis. The secondary amines were complete consumed after 20 hours. Scheme 2. 11 Hydrogenolysis of secondary amines with time 39 Furthermo re, reduction of the imine derived from 2 - napthaldehyde ( 60 a ) afforded, after 3 hours of exposure to the Pd - catalyzed reduction conditions, a 2:2:1 ratio of the fully reduced products and the secondary amine (Scheme 2. 12 ). Scheme 2.12 Hydrogenolysis of imine 60 a On the other hand, we observed that for imines with substituents on the benzaldehyde ring once the secondary amines was formed, no further hydrogenolysis products could be detected. The secondary amines obtained were isolated and after purification were subjected to our Pd - catalyzed conditions again without further conversion (Scheme 2. 13 ). This second group of imines substrates were subjected to the hardest conditions in attempt to promote hydrogenolysis, however neith er increasing the reaction time, raising the temperature to 60 o C, nor using chlorobenzene (as a additive previously employed in the nitro reduction) yielded the hydrogenolysis products. Our hydrogenolysis conditions appear to be sele ctive for benzyl ated anilines since in the case of N - (4 - methoxybenzyl) - benzylamine ( 58 b ) no hydrogenolysis was observed (Scheme 2.13) . 40 Scheme 2. 13 No h ydrogenolysis: Substituent effect Turning back into the literature we found a previo us r eference where starting from a secondary benzyl amine using ethanol as a solvent and H 2 in Pd/C at room temperature, the cleavage of the N - benzyl linkage was possible only for a unsubtituted benzyl group. 49 This paper suggested that any substituent on t he benzyl core stabilizes the ring preventing the cleavage of the benzylic C - N to occur. As a result heating to 75 ° C was required to remove the benzyl group with p - OMe or p - OH substituents. They also highlighted that the only group more labile than the un substituted benzyl was the naphthyl group that is easily removed at room temperature. Based on these results we decided to explore our conditions for the selective removal of a benzyl or a napthyl protective group on amines and alcohols. W e decided to star t with some N - benzylated heterocycles and one protected alcohol (Scheme 2. 14 ). 41 Scheme 2. 14 Model compounds for debenzylation reactions We subjected 62 , 63 and 64 to our reduction methodology. U nfort unately increasing the temperature, using c hlorobenzene and leaving the reaction for longer time proved to be futile as only the starting materials were recovered. 2. 3. 4 Mechanistic studies As we discussed in the optimization of our catalyst system, t he presence of fluoride is essential for accelerating the reaction. Therefore, we suggested that in this first step the Si center of the PMHS is activated by the fluoride source ( I ). Then the active catalyst is generated when Pd(OAc) 2 reacts with PMHS/KF f orming the Pd 0 - PMHS nanoparticles ( II ), evidence of the formation of related encapsulated Pd - siloxane nanoparticles was reported previously by Chauhan. 44 Excess PMHS will form the hydrido - silyl complex ( III ) that coordinates later across the double bond o f the imine ( IV ). From here the complex IV can undergo migratory insertion of the imine into the Pd - H bond (hydrometallation) to give the amine - silyl species ( V ). Reductive 42 elimination will give the hydrosilylation product VI , which is hydrolyzed to the am ine during the acid/base work - up (Scheme 2.15) . Scheme 2. 15 Proposed imine reduction catalytic cycle We decided to analyze the mixture of PMHS (2 mmol) and KF (10 mol %) by 29 Si NMR and 19 F NMR with the purpose of probi ng the formation of the presumed pentacoordinate Si species I . In the 19 F NMR we were able to observe the signal of a Si - F bond at - 159 ppm, the usual area assigned for pentacoordinate Si species. On the other hand, in the 29 Si NMR, we observe d the signals for Si - H ( - 34.7 ppm), Si - OH ( - 65.63 ppm) and SiO 2 ( - 110 ppm) 43 characteristic for polymeric materials. 50 Finally the 1 H NMR spectrum of this mixture showed a - H bond. Prepa ring a similar mixture but now adding 5 mol% of Pd (same quantities employed for imine reduction) did not change the signals previously observed. In order to probe the suggested oxidative addition of the activated PMHS to the Pd nanoparticles, an equimolar mixture of Pd/PMHS/KF was prepared. To our delight, in the 1 H NMR and 29 Si NMR spectr a the signal for Si - H disappeared suggesting the oxidativ e addition to Pd. These results support our initial proposed mechanism . 2.3 . 5 Palladium nanoparticles : TEM and E DS studies We observed that the addition of PMHS to a Pd(OAc) 2 solution generates polysiloxane encapsulated Pd - nanoclusters , related to those previously reported in the literature. 44 Using Transmission Electron Microscopy (TEM) to explore the morphology o f the catalyst medium, we were able to confirm the existence of the Pd - nanoparticles (Figure 2. 3 ). The presence of these nanoparticles could explain the selectivity of this reaction system, however, the stability and exact composition of these Pd - nanopart icles remains unexplored. 44 Figure 2 . 3 TEM images of Pd nanoparticles using Gatan Digital MSC camera 51 Samples were prepared under the same reaction conditions without the substrate. One hour after the addition of PMHS to a solution of Pd(OAc) 2 /KF ( aq ) in THF, an aliquot was taken 20 nm 20 nm 45 from the reaction mixture and added dropwise to a coated copper grid (carbon film support). The concentration of the sample is about 0.7 mM of the catalyst. Using tweezers, we dispersed the sample on the grid , but in some area s saturation was observed. TEM images of the catalyst at high resolution displayed Pd nanoparticles with an average size between 2 to 4 nm (Figure 2. 3 ). One important finding in this project was the crucial role of the additive KF. When the samples were pr epared without KF solution, agglomeration of the Pd - nanoparticles was observed (Figure 2. 4 ). Finally, X - ray energy dispersive spectroscopy (EDS) gave the chemical composition highlighting the presence of K, Si, O and Pd. The spectrum collected at different locations confirmed that the darker particles were the Pd - nanoparticles (Figure 2.5 ). Figure 2 . 4 TEM image of reaction mixture of Pd(OAc) 2 /PMHS in THF/H 2 O without KF (aq) at X80k magnification 200 nm 46 Figure 2 . 5 EDS of normal sample (spectrum top). EDS of coated film without selecting dar ker particles (spectrum bottom) 47 2.4 One - Pot synthesis of amides 2.4.1. Background Amide bond formation is one of the most useful reaction s in organic chemistry, not only for being part of biological active compounds but al so for their presence in around 25% of top - selling drugs. 52 E xamples of drugs containing amides bonds are Atorvastatin ( 65 ), the generic name of Lipitor® a cholesterol - lowering drug of Pfizer; 53 and Valsartan ( 66 ) the generic name of Diovan®, made by Nova rtis commonly used for high blood pressure and heart failure 54 (Scheme 2.16). An analysis of drug candidates made for leading pharmaceutical companies like GlaxoSmithKline, Pfizer and AstraZeneca indicated that the amide bond formation was employed in the synthesis of 66% of the drug candidates that required acylation reactions . 55 Scheme 2.1 6 Examples of top selling drugs containing an amide bond The formation of an amide bond 56 typically involves the reaction of a carbo xylic acid and an amine, however when mixing these two functional groups an acid - base reaction occurs to form a stable salt (Scheme 2.17) and the direct condensation can only take place at high 48 temperatures (160 - 180 o C), 57 limiting the reaction only to sub strates that can survive such harsh conditions. Scheme 2.17 Amide bond formation against thermodynamics Therefore the activation of the acid with a good leaving group at the acyl carbon of the acid is usually the method used to allow amine bond formation (Scheme 2.18). These reagents included acid halides, aryl azides, anhydrides, mixed anhydrides, active esters, etc. 56,58 Acylation of amines with activated carboxylic acids is the most common method employed in the pharma ceutical industry for the preparation of drug candidates containing amides bonds. 59 Some new promising methods for amide bond formation include the use of boronic acids as coupling reagents, 60 generation of activated carboxylates from functionalized aldehy des using N - heretocyclic carbenes (NHC) as catalyst, 61 and the direct coupling of an alcohol and amine under ruthenium catalysis . 62 This chapter will focus on the acylation of amines with carboxylic acid derivatives. One of the first coupling reagents em ployed was dicyclohexylcarbodiimide (DCC) 63 and the mechanism is highlighted on Scheme 2.19. However, the formation of byproducts like DCU ( 69 ) and N - acyl urea ( 70 ) as well the r equirement of 2 equiv of the acid are some of the disadvantage s of this method . 49 Scheme 2.18 Acid activation and amide bond formation Scheme 2.19 Amide formation reaction using DCC as coupling reagent 50 Subsequently, the use of additives to increase the yield of th e reaction and reduce epimerization was achieved with 1 - hydroxy - 1 H - benzotriazole (HOBt), 64 which react with the O - acylurea ( 71 ) to give a more active ester OBt ( 73 ). It is believe that this active ester enhances the reactivity via hydrogen bonding with the amine (Scheme 2.20). Therefore several coupling reagents based on 1 H - benzotriazole salts have being prepared including am i nium, phosphonium and immonium salts. 58a The more reactive salts frequently used are HATU ( 74 ) and HBTU ( 75 ), however a critical issu e regarding this 1 H - benzotriazole salts is their potential explosive properties (Scheme 2.21). 65 Scheme 2.20 Mechanism of activation by HOBt ( 72 ) when used as an additive 51 Scheme 2.21 Most commonly used 1 H - benzotriazole salts A similar approach involves starting from the commercially available anhydride or a mixed anhydride , which has de advantage of being less expensive . Direct reaction of the selected anhydride with the amine would fo rm the desired amide. In this scenario the presence of base is not required due to the formation in situ of a carboxylate anion, which is promptly protonated (Scheme 2.22). 56 This method is one of the most efficient and mild, however in terms of atom econo my one half of the anhydride is wasted. One way to overcome this waste proble m is using mixed anhydrides, where the second carboxylic moiety could come from a cheap reagent and should be easy to couple. 56 Scheme 2.22 An hydride coupling with amines Conversely, most of the preparation methods for amides are expensive, require the used of toxic or corrosive reagents and produce large quantities of hazardous waste. As consequence, in 2007 the ACS GCIPR (American Chemical Soc iety Green Chemistry Institute Pharmaceutical 52 Round - table) voted as a top research priority, that the amide bond formation reaction was in urgent need for better reagents because most of them avoid the so called atom economy. 66 Therefore in the search for a more environmentally friendly and non - expensive route on the synthesis of amides, we proposed a one - pot synthesis of tertiary amides starting from aromatic imines. In our synthesis the imines were reduced by our Pd(OAc) 2 /PMHS/KF (aq) methodology (as expl ained before in part 2.3 of this chapter) then upon addition of the selected anhydride the te rtiary amides were obtained (S cheme 2.23). Scheme 2.23 General procedure for o ne - pot synthesis of amides 2.4.2 Substrate s cope S earching in the literature for the use of imines as a source for amides synthesis only few examples are reported (Table 2.7) . One of the earliest studies employs catalytic quantities of cobalt carbonyl and phase - transfer catalysis conditions for the di acyl ation of the imines. 67 A second paper reported the oxidation of the imines to amides using m - CPBA and BF 3 2 . 68 The third one, involves the reaction of imines with isocyanates using TaCl 5 /Zn. 69 A few years ago a group reported the first synthesis of am ides via a transition metal catalyzed hydrosilylation of imines. 70 Using an Et 3 SiH/Zn system, Ghaffarzadeh et.al. 70 published a simple and efficient approach for the direct synthesis of amides using imines and acyl chlorides. As was explained in the introd uction part of this chapter ( see part 2.1 page 16 ), metal catalyzed hydrosilylation of 53 imines to amines has been reported over the years. However using this methodology for the direct conversion of imines to amides was not reported before. Although our methodology is not the first reported hydrosilylation of imines to amides, it is still the first study using a palladium catalyst with PMHS as silicon based reducing agent. Here we report our preliminary results with the synthesis of 11 tertiary amides us ing 3 different anhydrides. Reaction times vary between 2 and 5 hours and yields were between 40 % up to 87%. The common work up involves quick filtration through a plug with celite/neutral alumina to get rid of Pd and PMHS, followed by concentration of the crude reaction mixture and a final purification by flash column chromatography. Full characterization of each a mide is indicated in the appendix . Table 2.6 Synthesis of amides using acetic anhydride Entry R1 R2 Product Yield Time 1 OCH 3 H 76 86 % 2 h 2 CF 3 H 77 58 % 4 h 3 CN H 78 56 % 3 h 4 H F 79 60 % 3 h 5 Cl H 80 40 % 2 h 6 F H 81 55 % 2 h 54 Furthermore, most of these structures are new as only one was reported (amide 76 ) on the previous synthetic method that used a Zn/Et 3 SiH system. 70 In this communication a shorter reaction time of 30 min and slightly lower yield in comparison to our methodology was reported. Ghaffarzadeh et.al. 70 made a comparison of the efficiency of previous methods reported for the synthesis of amides from imines, highlighting that their method was the simplest and more efficient (Table 2.7). I nc luding our methodology results i n the last row of T able 2.7, our synthesis can be classified as well as one of the simplest and efficient. In addition, t he Zn/Et 3 SiH system 70 maybe faster than our reaction system but the y only report methyl or ethyl groups at the acyl position. O ur methodology is clearly open to different substituents at the acyl position, because our starting material is an anhydride whic h tend to be more stable and easier to handle than an acyl chloride s . Consequently, the second anhydride used in our methodology was benzoic anhydride, commercially available at low cost (100 g/ $32.70) 7 1 and used w ithout further purification. T he two ami des prepared (see Table 2.8) were obtained in less than 5 h with high yields. T hree more examples in where R 1 =Cl /R 2 =H, R 1 =CN /R 2 =H and R 2 =F /R 1 =H were explored ; these reactions were done in 2 hours. However after purification by column, the 1 H NMR analysis s howed the benzoic acid by - product as a minor contaminant . Improving our purification methods should give us access to these three new amides. 55 T able 2.7 Different methods for amide synthesis using imines. 56 Table 2.8 S ynthesis of amides using benzoic anhydride Entry R 1 R 2 Product Yield Time 1 OCH 3 H 82 74 % 2 h 2 CF 3 H 83 73 % 5 h The last anhydride used was di - tert - butyl dicarbonate (Boc anhydride), it is commercially available a nd was used without further purification. T hree new amides were prepared (see Table 2.9) using 1.5 equiv of the Boc anhydride with reaction times between 2 to 5 hours and an average yield 60 - 70%. As in previous examples th e s e amides are new structures tha t were obtained after a quick plug filtration and flash column chromatography. This methodology could be further improve d as mention ed before by using mixed anhydrides, as well using several of the substituted imines prepared for us on table 2.3 and schem e 2.9. 57 Table 2.9 Synthesis of amides using Boc anhydride Entry R 1 R 2 Product Yield Time 1 OCH 3 H 84 60 % 2 h 2 CF 3 H 85 70 % 5 h 3 H F 86 60 % 3 h 2.5 Conclusions A novel green method for the reduction of imines to amines by a Pd(OAc) 2 /PMHS/KF aq system was developed and studied. The optimization studies confirmed the crucial role of the fluoride ion in activating the PMHS. With only 5 mol % of Pd(OAc) 2 , 2 equiv of PMHS and 10 mol % of KF reduction times fo r a variety of imines ranged between 15 min to 2 hours. This methodology is selective and can operate in the presence of nitriles, ester, fluoride, chloride and p - nitro substituents yielding the target secondary amine in short reaction times at room temp erature. With ketone substituents, their reduction was slower than the imine functionality thus reaction s of these substrates must be stopped after 30 min to avoid over reduction to the alcohol derivative. Unfortunately double bonds, triple bonds and bromi de do not survive under the optimized conditions established for imine reduction. Furthermore, 58 h ydrogenolysis of secondary amines was obser ved after longer reaction times. These reductions appears to be highly selective for benzyl (and napthyl) protected a nilines. The 29 Si NMR and 19 F NMR obtained from our catalyst system gave us some insights into the possible mechanism. A hydrosilylation catalytic cycle seems consistent with the data obtained during our NMR studies. However, taking into account the f ormation of Pd - PMHS nanoparticles gave us a different scenario that probably surface chemistry studies could explain. Finally, the one - pot preparation of several amides via reduction of imines followed by addition of an electrophile were achieved. These r eactions were run at room temperature for 2 to 5 hours and average of 40 % to 87 % yield. This methodology is the first reported hydrosilylation of imines to amides using a palladium catalyst with PMHS as silicon based reducing agent. Furthermore, such amide s can be prepared using mixed anhydrides. 2.6 Experimental s ection General Materials and Methods All starting materials were used as received, unless otherwise stated. Diethyl ether and tetrahydrofuran were distilled from sodium and benzophenone under nitrogen. Toluene was distilled from calcium hydride. All reactions were carried out in oven - dried or flame dried glassware under nitrogen atmosphere, unless otherwise stated. All reactions were performed with magnetic stirring and monitored by 1 H - NMR an d GC - FID. Palladium (II) acetate purchased from Strem, anhydrous A.C.S. grade potassium fluoride and polymethylhydrosiloxane (PMHS) purchased from Sigma - Aldrich were used without purification. Flash chromatography was performed with silica gel 60 Å (230 - 40 0 mesh) purchased from Silicycle, monitored by thin - 59 layer chromatography using 0.25 - nm pre - coated silical gel aluminum plates and developed with uv and/or phosphomolybdeneic acid. Yields refer to chromatographically and spectroscopically pure compounds unl ess otherwise stated. 1 H NMR, 13 C NMR spectra were recorded on Varian spectrometers: Inova - 300 (300.11 MHz for 1 H and 75.47 MHz for 13 C), Varian VXR - 500 (499.74 MHz for 1 H and 125.67 MHz for 13 C), Varian Inova - 600 (599.89 MHz for 1 H and 150.84 MHz for 13 C) . 29 Si NMR and 19 F NMR were recorded on the last two spectrometers. Chemical shifts are reported relative to the residue peaks of solvent CDCl 3 ( 7.24 ppm for 1 H and 77.0 ppm for 13 C), TMS - CDCl 3 ( 0.00 ppm for 29 Si) and 0.05% Trifluorotoluene in Benzene - d 6 ( - 63.73 ppm for 19 F). TEM sample were acquired at the Michigan State University Center for Advanced Microscopy using a JEOL 2200FS TEM microscope. Melting points were determined using a Thomas Hoover capillary melting point apparatus and are uncorrecte d. General procedure for imine formation: Method A: a dried r.b. flask was charged with the corresponding aromatic aldehyde (1.0 mmol), the appropriate aniline (1.0 mmol) and 10 mL of Ethanol. The reaction mixture was stirred at room temperature and chec ked by 1 H - NMR until the reaction was finished (usually 24 h). Then the solvent was removed under reduced pressure and the pure imine was obtained without an additional purification. For some imines recrystallization was required and it was indicated in eac h case. Method B: a dried r.b. flask was charged with the corresponding aromatic aldehyde (1.0 mmol), the appropriate aniline (1.0 mmol) and 50 mL of Toluene. The reaction mixture was refluxed at 60 120 C for 24 hours using a Dean Strak apparatus. Then th e solvent was evaporated in reduce pressure and the pure imine was obtained. General procedure for the reduction of aromatic imines to amines: A dry 25 mL round bottom flask was charged with Pd(OAc) 2 (0.05 mmol, 0.011g), an imine (1 mmol) and 5 mL of fres hly distilled THF. The flask was sealed, and placed under nitrogen while stirring. Then a KF (aq) solution (0.1 mmol, 0.1 mL) was added via syringe. This aqueous solution was previously degassed using vacuum and liquid N 2 . The nitrogen outlet was replaced by a balloon filled with N 2 . After 5 min PMHS (2 mmol, 0.12 mL, 1 mmol is equal to 0.06 mL) was added dropwise via syringe. Bubble formation is observed and the mixture turns black. The reaction was stirred for 30 min or until completed conversion as judge d by NMR or GC analysis. Three different work - up procedures were employed. Alternate work up procedure I The reaction mixture was diluted with ether (5 mL). The organic phase was filtrated through a plug with celite (top layer) and neutral alumina (botto m layer) in a 1 cm diameter column by flushing with EtOAc. The mixture was then dried over MgSO 4 and concentrated. Finally the crude was purified by silica gel column chromatography. Alternate work up procedure II A mixture of 10 mL H 2 O/Et 2 O (1:1) was add ed to the crude, the layers were separated, and the aqueous layer back extracted with Et 2 O. After stirring the organic phase was separated, dried with MgSO 4 , filter and concentrated. The crude was dissolved in EtOAc and treated with a 3M 61 HCl solution. The white solids formed were filtered, washed with EtOAc and dried over night to give the desired secondary amine as hydrochloride salt. The latter was dissolved in a H 2 O/methanol (1:1) mixture and NaHCO 3 (sat) solution was added. The volume was reduced to the minimum and extracted with EtOAc (4 x 10 mL), dried and concentrated. Alternate work up procedure I I I Upon addition of 10 mL Et 2 O/1M HCl (1:1) and stirring for 10 min, the organic phase was separated and extracted with 1M HCl (3 x 10 mL). Then the aqueo us layers were combined, made basic with addition of KOH (s) , and extracted with EtOAc (4x 15 mL). Finally, the organic layers were dried, filtered and concentrated. Experimental details and spectroscopic data: N - Pheny lbenzylideneamine ( 40 a ) : Using the general procedure for imine formation (Method A) a light white solid was obtained after recrystallization from hexanes. Yield: 80%. 1 H - NMR (500 MHz, CDCl 3 ): 8.42 (s, 1 H, CH - i mine), 7.94 (m, 2 H, Ar - H), 7.51 7.50 (m, 3 H, Ar - H), 7.45 7.41 (m, 2 H, Ar - H), 7.28 7.24 (m, 3 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 160.3, 152.1, 136.3, 131.4, 129.2, 128.8, 128.7, 125.9, 120.8. mp = 51 °C. Spectroscopic data were consistent with those previously reported. 72 62 N - Phenylbenzylamine ( 40 b) : N - P henylbenzylideneamine (181 mg, 1 mmol) was reduced following the general procedure for imine reduction (2 h reaction time) . After work up procedure I , the crude material was purified by column chromatograp hy ( 9:1 hexanes/EtOAc) which afforded the amine as a yellow oil . Yield: 90%. 1 H - NMR (500 MHz, CDCl 3 ): 7.39 7.33 (m, 4 H, Ar - H), 7.27 (t, J = 7.0 Hz, 1 H, Ar - H), 7.18 (t, J = 7.0 Hz, 2 H, Ar - H), 6.72 (t, J = 7.5 Hz, 1 H, Ar - H), 6.68 (d, J = 8.5 Hz, 2 H, Ar - H), 4.27 (s, 2 H, Ar - CH 2 ), 4.07 ( br s , 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 148.1, 139.4, 129.2, 128.6, 127.5, 127.2, 117.5, 112.8, 48.3. Spectroscopic data were consistent with those previously reported. 72a N - Phen yl - 4 - methoxybenzylideneamine ( 41 a) : Using the general procedure for imine formation (Method A) a white solid was obtained after recrystallization from hexanes. Yield: 100%. 1 H - NMR (500 MHz, CDCl 3 ): 8.34 (s, 1 H, CH - imine), 7.84 (d, J = 8.5 Hz, 2 H, Ar - H) , 7.38 7.34 (m, 2 H, Ar - H), 7.21 7.16 (m, 3 H, Ar - H), 6.97 (d, J = 8.5 Hz, 2 H, Ar - H), 3.86 (s, 3 H, Ar - 63 OCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 162.3, 159.7, 152.4, 130.5, 129.3, 129.1, 125.5, 120.9, 114.1, 55.4. mp = 5 6 C . Spectroscopic data were consistent with those previously reported. 72 N - (4 - methoxybenzyl)phenylamine ( 41 b) : N - Phenyl - 4 - methoxybenzylideneamine (211 mg, 1 mmol) was reduced in 30 min, following the general procedure for imine reduction. After work up pro cedure I II, the crude material was purified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amine as a light brown oil . Yield: 80%. 1 H - NMR (500 MHz, CDCl 3 ): 7.31 (d, J = 9.0 Hz, 2 H, Ar - H), 7.19 (t, J = 7.5 Hz, 2 H, Ar - H), 6.90 (d, J = 8. 5 Hz, 2 H, Ar - H), 6.74 (t, J = 7.5 Hz, 1 H , Ar - H), 6.65 (d, J = 9 .0 Hz, 2 H, Ar - H), 4.26 (s, 2 H, Ar - CH 2 ), 4.00 ( br s , 1 H , - NH), 3.81 (s, 3 H, Ar - OCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 158.7, 148.2, 131.3, 129.2, 128.7, 117.4, 113.9, 112.7, 55.2, 47.7. Spectr oscopic data were consistent with those previously reported. 72a 64 N - (4 - methoxyphenyl)benzylideneamine ( 42 a) : Using the general procedure for imine formation (Method A) a yellow solid was obtained. Yield: 98%. 1 H - NMR ( 500 MHz, CDCl 3 ): 8.50 (s, 1 H , CH - imine), 7.91 7.89 (m, 2 H, Ar - H), 7.48 7.47 (m, 3 H, Ar - H), 7.26 (d, J = 6.5 Hz, 2 H, Ar - H), 6.96 (d, J = 7 .0 Hz, 2 H, Ar - H), 3.86 (s, 3 H, Ar - OCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 158.3, 144.9, 136.4, 130.9, 128.7, 128.5, 122.1, 114.3, 55.4. mp = 70 C . Spectroscopic data were consistent with those previously reported. 72 N - benzyl - (4 - methoxyphenyl)amine ( 42 b) : N - ( 4 - M ethoxyphenyl)benzylideneamine (211 mg, 1 mmol) was reduced in 30 min, fo llowing the general procedure for imine reduction. After work up procedure I II, the crude material was purified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amine as a yellow oil . Yield: 48% . 1 H - NMR (500 MHz, CDCl 3 ): 7.41 7.35 (m, 4 H, Ar - H), 7.30 7.27 (m, 1 H, Ar - H), 6.81 (d, J = 7 .0 Hz, 2 H, Ar - H), 6.63 (d, J = 7 .0 Hz, 2 H, Ar - H), 4.31 (s, 2 H, Ar - CH 2 ), 3.86 (s, 1 H, - NH), 3.76 (s, 3 H, Ar - OCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 152.0, 142.4, 139.6, 128.6, 127.5, 122.2, 114.8, 114.1, 55.7 , 49.2. Spectroscopic data were consistent with those previously reported. 72a 65 N - (4 - Chlorophenyl) - benzylideneamine ( 43 a) : Using the general procedure for imine formation (Method A) a light yellow solid was obtained after recrystallization from hexane. Yield: 97%. 1 H - NMR (500 MHz, CDCl 3 ): 8.41 (s, 1 H, CH - imine), 7.88 7.86 (m, 2 H, Ar - H), 7.48 7.45 (m, 3 H, Ar - H), 7.34 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.14 (d, J = 7 .0 Hz, 2 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 160.7, 150.5, 135.9, 131.6, 131.4, 129.2, 128.9, 128.8, 122.1. mp = 5 9 C . Spectroscopic data were consistent with those previously reported. 72b,73 N - benzyl - (4 - chlorophenyl)amine (4 3 b) : N - (4 - C hlorophenyl)benzylideneamine (215 mg, 1 mmol) reduced in 1 h, following the general procedure for imine reduction. After work up procedure I , the crude material was purified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amine as a light brown oil . Yield: 50%. 1 H - NMR (500 MHz , CDCl 3 ): 7.28 7.26 (d, 2 H, J = 2 .0 Hz, Ar - H), 7.07 7.03 (td, J = 2.0, 6.5 Hz, 4 H, Ar - H), 6.48 6.45 (td, J = 2.0, 6.8 Hz, 3 H, Ar - H), 4.56 (s, 2 H, Ar - CH 2 ), 4.08 ( br s , 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 146.7, 138.9, 129.1, 128.7, 127.5, 127.4, 1 22.1, 113.8, 48.3. Spectroscopic data were consistent with those previously reported. 74 66 N - (4 - Fluorophenyl) - benzylideneamine ( 44 a) : Using the general procedure for imine formation (Method A) a brown solid was obtained. Yield: 100%. 1 H - NMR (500 MHz, CDCl 3 ): 8.42 (s, 1 H, CH - imine), 7.88 7.86 (m, 2 H, Ar - H), 7.47 - 7.44 (m, 3 H, Ar - H), 7.19 7.17 (m, 2 H, Ar - H), 7.08 7.04 (m, 2 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 162.6, 160.1, 148.5, 136.5, 131.4, 128.7, 122.3, 122.2, 115 .9, 115.7. mp = 60 C . Spectroscopic data were consistent with those previously reported. 75 N - benzyl - (4 - Fluorophenyl)amine ( 44 b) : N - (4 - Fluorophenyl) - benzylideneamine (199 mg, 1 mmol) was reduced in 1 h, following the g eneral procedure for imine reduction. After work up procedure II, the crude material was purified by column chromatography ( 7:3 hexanes/EtOAc) which afforded the amine as a brown oil . Yield: 69%. 1 H - NMR (500 MHz, CDCl 3 ): 7.43 7.39 (m, 4 H, Ar - H), 7.35 7 .32 (m, 1 H, Ar - H), 6.95 6.90 (m, 2 H, Ar - H), 6.62 6.59 (m, 2 H, Ar - H), 4.33 (s, 2 H, Ar - CH 2 ), 3.96 ( br s , 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 157.3, 144.4, 139.2, 128.6, 127.4, 115.7, 115.4, 113.6, 48.8. Spectroscopic data were consistent with those pr eviously reported. 74 67 N - phenyl - 4 - bromobenzylideneamine ( 45 a) : Using the general procedure for imine formation (Method A) a white solid was obtained. Yield: 98%. 1 H - NMR (500 MHz, CDCl 3 ): 8.43 (s, 1 H, CH - imine), 7.80 (d , J = 8.5 Hz, 2 H, Ar - H), 7.63 (d, J = 8.5 Hz, 2 H, Ar - H), 7.42 (t, J = 8.5 Hz, 2 H, Ar - H), 7.28 7.22 (m, 3 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 158.9, 151.6, 135.1, 132.0, 130.1, 129.1, 126.2, 125.8, 120.8. mp = 73 C . Spectroscopic data were consistent with those previously reported. 72b,73 N - phenyl - 4 - chlorobenzylideneamine ( 46 a) : Using the general procedure for imine formation (Method A) a light yellow solid was obtained. Yield: 97%. 1 H - NMR (500 MHz, CDCl 3 ): 8.4 5 (s, 1 H, CH - imine), 7.88 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.48 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.43 (t, J = 7.5 Hz, 2 H, Ar - H), 7.29 7.27 (m, 1 H, Ar - H), 7.24 (d, J = 8.5 Hz, 2 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 158.7, 151.6, 137.3, 134.7, 129.9, 129.1, 129.0 , 126.1, 120.8. mp = 62 C . Spectroscopic data were consistent with those previously reported. 72 68 N - (4 - chlorobenzyl)phenylamine ( 46 b) : N - P henyl - 4 - chlorobenzylideneamine (215 mg, 1 mmol) was reduced in 2 h, following th e general procedure for imine reduction. After work up procedure I , the crude material was purified by column chromatography ( 7:3 hexanes/EtOAc) which afforded the amine as a brown oil . Yield: 55% . 1 H - NMR (500 MHz, CDCl 3 ): 7.18 7.13 (m, 4 H, Ar - H), 6.75 6.59 (m, 3 H, Ar - H), 6.61 (d, J = 8 .0 Hz, 2 H, Ar - H), 4.29 (s, 2 H, Ar - CH 2 ), 4.05 ( br s , 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 147.8, 138.0, 131.6, 129.3, 128.8, 128.7, 117.7, 112.8, 47.5. Spectroscopic data were consistent with those previously reporte d. 72a N - Phenyl - 4 - trifluoromethylbenzylideneamine ( 47 a) : Using the general procedure for imine formation (Method A) a white solid was obtained. Yield: 99%. 1 H - NMR (500 MHz, CDCl 3 ): 8.54 (s, 1 H, CH - imine), 8.05 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.76 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.46 7.43 (m, 2 H, Ar - H), 7.31 7.26 (m, 3 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 158.5, 151.3, 139.2, 132.0, 129.2, 128.9, 126.5, 125.7 (q, J C F = 3. 8 Hz), 120.8. mp = 79 C . Spectroscopic data were co nsistent with those previously reported. 46a,76 69 N - (4 - trifluoromethylbenzyl)phenylamine ( 47 b) : N - P henyl - 4 - trifluoromethylbenzy - idene amine (252 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine r eduction After work up procedure I II, the amine was obtained as a light brown oil . Yield: 90%. 1 H - NMR (500 MHz, CDCl 3 ): 7.57 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.47 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.15 (td, J = 7.5, 1 .0 Hz, 2 H, Ar - H), 6.72 (t, J = 7.5 Hz, 1 H, Ar - H), 6.59 (dt, J = 9.0, 1 .0 Hz, 2 H, Ar - H), 4.39 (s, 2 H, Ar - CH 2 ), 4.00 ( br s , 1 H, - NH) 13 C NMR (125 MHz, CDCl 3 ): 147.6, 143.7, 129.3, 127.4, 125.5 (q, J C F = 3. 8 Hz), 117.9, 112.8, 47.7. Spectroscopic data were consistent with those previously reported . 7 7 N - (4 - nitrophenyl) - benzylideneamine ( 48 a) : Using the general procedure for imine formation (Method B) a yellow solid was obtained. Yield: 100%. 1 H - NMR (500 MHz, CDCl 3 ): 8.45 (s, 1 H, CH - imine), 8.30 (d, J = 9.5 Hz , 2 H, Ar - H), 7.96 7.94 (m, 2 H, Ar - H), 7.58 7.54 (m, 3 H, Ar - H), 7.27 (d, J = 9 Hz, 2 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 162.6, 157.9, 146.0, 135.4, 132.4, 129.2, 128.9, 125.0, 121.2. mp = 138 C . Spectroscopic data were consistent with those previous ly reported. 78 70 N - phenyl - 4 - nitrobenzylideneamine (49 a) : Using the general procedure for imine formation (Method A) a yellow solid was obtained. Yield: 87%. 1 H - NMR (500 MHz, CDCl 3 ): 8.59 (s, 1 H, CH - imine), 8.36 (d, J = 8.5 Hz, 2 H, Ar - H), 8.11 (d, J = 8.5 Hz, 2 H, Ar - H), 7.46 (t, J = 8 Hz, 2 H, Ar - H), 7.34 7.27 (m, 3 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 157.3, 150.9, 141.6, 129.4, 129.3, 127.0, 124.0, 120.9, 105.0. mp = 89 C . Spectroscopic data were consistent with those previously reported. 79 N - (4 - nitrobenzyl)phenylamine ( 49 b) : N - P henyl - 4 - nitrobenzylideneamine (226 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine reduction. After work up procedure I II, the crude material was purified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amine as a brown oil . Yield: 33%. 1 H - NMR (500 MHz, CDCl 3 ): 8.21 (d, J = 8.5 Hz, 2 H, Ar - H), 7.55 (d, J = 8.5 Hz, 2 H, Ar - H), 7.19 (t, J = 7.5 Hz, 2 H, Ar - H), 6.76 (t, J = 8.4 Hz, 1 H, Ar - H), 6.60 (d, J = 8.5 Hz, 2 H, Ar - H), 4.49 (s, 2 H, Ar - CH 2 ), 4.25 ( br s , 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 147.4, 147.2, 129.3, 129.2, 127.6, 123.8, 118.1, 112.8, 47.5. Spectroscopic data were consistent with those previo usly reported. 80 71 N - (3 - nitrophenyl) - benzylideneamine ( 50 a): Using the general procedure for imine formation (Method A) a white - yellow solid was obtained. Yield: 97%. 1 H - NMR (500 MHz, CDCl 3 ): 8.47 (s, 1 H, CH - imine), 8. 07 (td, J = 2.0, 7.5 Hz, 1 H, Ar - H), 8.22 (t, J = 2 .0 Hz, 1 H, Ar - H), 7.91 (dd, J = 2 .0, 6.5 Hz, 2 H, Ar - H), 7.55 7.47 (m, 5 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 162.5, 153.1, 148.9, 135.4, 132.1, 129.8, 129.1, 128.9, 127.5, 120.4, 115.3. mp = 70 C . Spec troscopic data were consistent with those previously reported. 78c N - benzyl - (3 - aminophenyl)amine ( 50 b) : N - (3 - N itrophenyl) - benzylideneamine (226 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine re duction. After work up procedure I II, the amine was obtained as a light brown oil . Yield: 52%. 1 H - NMR (500 MHz, CDCl 3 ): 7.39 7.34 (m, 5 H, Ar - H), 6.98 (t, J = 7.5 Hz, 1 H, Ar - H), 6.15 6.09 (m, 2 H, Ar - H), 6.00 5.99 (m, 1 H, Ar - H), 4.31 (s, 2 H, Ar - CH 2 ), 3.60 ( br s , 3 H, - NH, - NH 2 ). 13 C NMR (125 MHz, CDCl 3 ): 149.0, 147.5, 140.0, 130.1, 128.6, 127.5, 127.1, 105.1, 104.0, 99.4, 48.2. Spectroscopic data were consistent with those previously reported. 81 72 N - phenyl - 3 - nitrob enzylideneamine ( 51 a) : Using the general procedure for imine formation (Method A) a brown solid was obtained. Yield: 91%. 1 H - NMR (500 MHz, CDCl 3 ): 8.80 (s, 1 H, CH - imine), 8.59 (s, 1 H, Ar - H), 8.38 (d, J = 7.2 Hz, 1 H, Ar - H), 8.30 (d, J = 7.8 Hz, 1 H, A r - H), 7.71 (t, J = 8.1 Hz, 1 H, Ar - H), 7.48 (t, J = 7.8 Hz, 2 H, Ar - H), 7.36 7.29 (m, 3 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 157.1, 150.8, 148.7, 137.8, 134.0, 129.7, 129.2, 126.8, 125.5, 123.4, 120.9. mp = 64 C . Spectroscopic data were consistent with t hose previously reported. 82 N - (3 - nitrobenzyl)phenylamine (51b) and N - (3 - amino benzyl)phenylamine ( 51 c) : N - P henyl - 3 - nitrobenzylideneamine (226 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine reduction. After work up procedure I II, the crude material was purified by column chromatography ( 4:1 hexanes/EtOAc) which afforded the amines as orange oils . Compound 12b was obtained as a mixture 1:1 with 12c Yie ld: 84% of crude material. 12b : 1 H - NMR (500 MHz, CDCl 3 ): 8.26 (s, 1 H, Ar - H), 8.14 (dd, J = 2.5, 8.5 Hz, 1 H, Ar - H), 7.74 (dt, J = 1.0, 7.5 Hz, 1 H, Ar - H), 7.52 (t, J = 8 Hz, 1 H, Ar - H), 7.21 7.17 (m, 2 H, Ar - H), 6.77 (dt, J = 1.0 , 7.5 Hz, 1 H, 73 Ar - H), 6. 75 6.61 (m, 2 H, Ar - H), 4.48 (s, 2 H, Ar - CH 2 ). 13 C NMR (125 MHz, CDCl 3 ): 147.1, 141.8, 133.2, 129.5, 129.4, 129.3, 122.3, 122.1, 118.3, 113.1, 47.6. Spectroscopic data were consistent with those previously reported. 12a 12 c : 1 H - NMR (500 MHz, CDCl 3 ): 7. 16 (t, J = 10 Hz, 2 H, Ar - H), 7.10 (t, J = 10 Hz, 1 H, Ar - H), 6.72 (m, 3 H, Ar - H), 6.63 (d, J = 7.5 Hz, 2 H, Ar - H), 6.58 (d, J = 7.5 Hz, 1 H, Ar - H), 4.22 (s, 2 H, Ar - CH 2 ), 3.90 ( br s , 1 H, NH). 13 C NMR (125 MHz, CDCl 3 ): 146.6, 140.5, 129.5, 129.2, 117.8, 117.7, 114.1, 114.0, 113.0, 53.5, 48.5. Spectroscopic data were consistent with those previously reported. 8 N - phenyl - 4 - nitrilebenzylideneamine ( 52 a) : Using the general procedure for imine formation (Method A) a yellow solid was obtained. Yield: 90%. 1 H - NMR (500 MHz, CDCl 3 ): 8.51 (s, 1 H, CH - imine), 8.03 (d, J = 6.5 Hz, 2 H, Ar - H), 7.78 (d, J = 7.5, 2 H, Ar - H), 7.44 (t, J = 8 .0 Hz, 2 H, Ar - H), 7.32 7.25 (m, 3 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 157.8, 151.0, 139.9 , 132.5, 129.2, 129.1, 126.8, 120.9, 118.4, 114.4. mp = 87 C . Spectroscopic data were consistent with those previously reported. 75b,83 74 N - (4 - nitrilebenzyl)phenylamine ( 52 b) : N - P henyl - 4 - nitrilebenzylideneamine (206 mg, 1 mmol) was reduced in 2 h, following the general procedure for imine reduction. After work up procedure I , the crude material was purified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amine as a light yellow oil . Yield: 72%. 1 H - NMR (500 MHz, CDCl 3 ): 7.64 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.51 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.20 (t, J = 7.5 Hz, 2 H, Ar - H), 6.77 (t, J = 7.5 Hz, 1 H, Ar - H), 6.61 (d, J = 8 .0 Hz, 2 H, Ar - H), 4.41 (s, 2 H, Ar - CH 2 ), 4.30 ( br s , 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 147.3, 145.3, 132.4, 129.3, 127.6, 118.8, 118.1, 112.8, 110.9, 47.9. Spectroscopic data were consistent with those previously reported. 84 Methyl 4 - (benzylideneamino )benzoate ( 53 a) : Using the general procedure for imine formation (Method B) a white solid was obtained. Yield: 89%. 1 H - NMR (500 MHz, CDCl 3 ): 8.42 (s, 1 H, CH - imine), 8.06 (dt, J = 2.0, 8.5 Hz, 2 H, Ar - H), 7.89 (dt, J = 2.0, 6.5 Hz, 2 H, Ar - H), 7.51 7.45 (m, 3 H, Ar - H), 7.19 (dt, J = 2.0, 9 .0 Hz, 2 H, Ar - H), 3.90 (s, 2 H, ArCOOCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 166.7, 161.6, 156.2, 131.8, 130.8, 129.0, 128.9, 128.8, 127.3, 120.6, 52.0. mp = 104 C . Spectroscopic data were consistent with those previously reported. 85 75 Methyl 4 - (benzylamino)benzoat e ( 53 b) : Methyl 4 - (benzylideneamino)benzoate (239 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine reduction. After work up procedure I II, the amine was obtained as a light yellow solid . Yield: 92% . 1 H - NMR (500 MHz, CDCl 3 ): 7.88 (dd, J = 2.0 , 6. 8 Hz, 2 H, Ar - H), 7.37 7.36 (m, 4 H, Ar - H), 7.32 (m, 1 H, Ar - H), 6.61 (dd, J = 2.0 , 7 .0 Hz, 2 H, Ar - H), 4.40 (s, 2 H, Ar - CH 2 ), 3.85 (s, 3 H, Ar - COOCH 3 ), 3.82 ( br s , 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): =167.3, 151.8, 138.4, 131.6, 128.7, 127.5, 127.4, 118.6, 111.6, 51.5, 47.6. mp = 125 C . Spectroscopic data were consistent with those previously reported. 86 . 4 - (N - benzylideneaminoacetophenone ( 54 a) : Using the general procedure for imine formation (Met hod B) a white solid was obtained. Yield: 98%. 1 H - NMR (500 MHz, CDCl 3 ): 8.41 (s, 1 H, CH - imine), 7.99 (d, J = 8.5 Hz, 2 H, Ar - H), 7.90 (dd, J = 1.5, 8 .0 Hz, 2 H, Ar - H), 7.50 7.48 (m, 3 H, Ar - H), 7.21 (d, J = 9 .0 Hz, 2 H, Ar - H), 2.60 (s, 2 H, Ar - COCH 3 ). 13 C NMR (125 MHz, 76 CDCl 3 ): 197.2, 161.7, 156,4, 135.7, 134.6, 131.9, 129.7, 129.1, 128.8, 120.8, 26.57. mp = 94 C . Spectroscopic data were consistent with those previously reported. 87 4 - ( N - benzylamino)acetophenone ( 54 b) : 4 - ( N - B enzylideneaminoacetophenone (223 mg, 1 mmol) was reduced in 30 min, following the general procedure for imine reduction. After work up procedure I II, the crude material was purified by column chromatography ( 4:1 hexanes/EtOAc) which afforded t he amine as a light orange solid . Yield: 64%. 1 H - NMR (500 MHz, CDCl 3 ): 7.80 (dd, J = 1.5, 7.5 Hz, 2 H, Ar - H), 7.36 7.32 (m, 4 H, Ar - H), 7.30 7.27 (m, 1 H, Ar - H), 6.58 (dd, J = 1.5 , 7 .0 Hz, 2 H, Ar - H), 4.60 (s, br 1 H, NH), 4.39 (d, J = 5.5 Hz, 2 H, Ar - CH 2 ), 2.47 (s, 3 H, Ar - COCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 196.2, 151.9, 138.2, 130.7, 128.8, 127.5, 127.3, 127.0, 111.6, 47.6, 26.0. mp = 77 C . Spectroscopic data were consistent with those previously reported. 86b,88 77 N - (4 - ethynylbenzylidene)amine ( 55 b) : Using the general procedure for imine formation (Method A) a yellow solid was obtained. Yield: 99%. 1 H - NMR (500 MHz, CDCl 3 ): 8.46 (s, 1 H, CH - imine), 7.88 (d, J = 8.5 Hz, 2 H, Ar - H), 7.60 (d, J = 8 .0 , 2 H, Ar - H), 7 .42 (t, J = 7.5 Hz, 2 H, Ar - H), 7.27 7.22 (m, 3 H, Ar - H), 3.23 (s, 1 H, 13 C NMR (125 MHz, CDCl 3 ): 159.2, 151.1, 136.3, 132.5, 129.2, 128.6, 126.2, 124.9, 120.8, 83.2, 79.4. mp = 67 C . Spectroscopic data were consistent with those previously repo rted. 89 N - (4 - ethylbenzyl)phenylamine ( 55 c) : N - (4 - E thynylbenzylidene)amine (205 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine reduction After work up procedure I II, the crude material was pu rified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amine as a orange oil . Yield: 23%. 1 H - NMR (500 MHz, CDCl 3 ): 7.28 (d, J = 8 .0 Hz, 2 H, Ar - H), 7.24 7.18 (m, 4 H, Ar - H), 7.14 (d, J = 2 .0 Hz, 1 H, Ar - H), 6.74 (td, J = 1.0 , 6 .0 Hz, 1 H, Ar - H), 6.67 (dd, J = 1.0, 8.5 Hz, 2 H, Ar - H), 4.31 (s, 2 H, Ar - CH 2 N), 4.00 ( br s , 1 H, - NH), 2.69 (q, J = 7.5 Hz, 2 H, Ar - CH 2 CH 3 ), 1.26 (t, J = 7.5 Hz, 3 H, Ar - CH 2 CH 3 ). 13 C NMR (125 MHz, 78 CDCl 3 ): 143.3, 138.0, 129.2, 128.1, 127.6, 127.5, 117.5, 112.8, 4 8.1, 28.5, 15.6. Spectroscopic data were consistent with those previously reported. 90 N - 1, 3 - diphenyl - (E) - 2 - propenimine ( 56 a) : Using the general procedure for imine formation (Method A) an orange solid was obtained. Yield: 100%. 1 H - NMR (500 MHz, CDCl 3 ): 8.32 (d, J = 6.5 Hz, 1 H, CH - imine), 7.58 (d, J = 7.5 Hz, 2 H, CH=CH), 7.43 7.40 (m, 5 H, Ar - H), 7.30 7.18 (m, 5 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 161.6, 151.7, 143.9, 135.5, 129.5, 129.1, 128.8, 128.5, 127.4, 1 26.1, 120.8. mp = 102 C . Spectroscopic data were consistent with those previously reported. 91 N - 1 - [(E) - 3 - p henyl - 2 - propenyl]phenylamine (56 b) : N - 1, 3 - D iphenyl - ( E ) - 2 - propenimine (207 mg, 1 mmol) was reduced in 15 min, fol lowing the general procedure for imine reduction. After work up procedure I II, the amine was obtained as a brown oil . Y ield: 67%. 1 H - NMR (500 MHz, CDCl 3 ): 7.32 7.29 (m, 2 H, Ar - H), 7.27 7.16 (m, 5 H, Ar - H), 6.72 6.69 (m, 1 H, Ar - H), 6.59 (d, J = 8.5 Hz , 2 H, Ar - H), 3.64 (s, 1 H, - NH), 3.17 (t, J = 7.5 Hz, 2 H, - N - CH 2 ), 2.75 (t, J = 7.5 79 Hz, 2 H, Ar - CH 2 ), 2.01 - 1.94 (m, 2 H, - CH 2 ) . 13 C NMR (125 MHz, CDCl 3 ): 148.3, 141.6, 129.2, 128.4, 126.0, 117.1, 115.0, 112.7, 43.3, 33.3, 31.0. Spectroscopic data were consistent with those previously reported. 92 N - benzylbenzylideneamine ( 57 a) : Using the general procedure for imine formation (Method A) a yellow oil was obtained. Yield: 92%. 1 H - NMR (500 MHz, CDCl 3 ): 8.43 (s, 1 H, CH - imine), 7.83 7.81 (m, 2 H, Ar - H), 7.47 7.44 (m, 3 H, Ar - H), 7.39 - 7.37 (m, 4 H, Ar - H), 7.31 7.28 (m, 1 H, Ar - H), 4.87 (s, 2 H, Ar - CH 2 ). 13 C NMR (125 MHz, CDCl 3 ): 162.0, 139.1, 130.7, 128.6, 128.5, 128.3, 128.0, 127.0, 65.0. Spectroscopic data were co nsistent with those previously reported. 93 Dibenzylamine ( 57 b) : N - B enzylbenzylideneamine (195 mg, 1 mmol) was reduced in 2 h, following the general procedure for imine reduction. After work up procedure I , the amine was obtained as a yellow oil . Yield: 76% . 1 H - NMR (500 MHz, CDCl 3 ): 7.40 7.35 (m, 8 H, Ar - H), 7.31 7.28 (m, 2 H, Ar - H), 3.85 (s, 4 H, Ar - CH 2 ), 1.80 ( br s , 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 140.2 (2C) , 128.4 (2C) , 128.1 (2C) , 126.9 (2C) , 53.1 (2C) . Sp ectroscopic data were consistent with those previously reported. 94 80 N - (4 - methoxybenzyl) - benzylideneamine ( 58 a) : Using the general procedure for imine formation (Method A) a yellow oil was obtained. Yield: 75%. 1 H - NMR ( 500 MHz, CDCl 3 ): 8.41 (s, 1 H, CH - imine), 7.85 7.84 (m, 2 H, Ar - H), 7.47 7.46 (m, 3 H, Ar - H), 7.33 (d, J = 8. 3 Hz, 2 H, Ar - H), 6.95 (d, J = 8.5 Hz, 2 H, Ar - H), 4.83 (s, 2 H, Ar - CH 2 ), 3.83 (s, 3 H, - OCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 161.4, 158.6, 136.1, 131.2, 130.5, 129.1, 128.4, 128.1, 113.7, 64.2, 55.1. Spectroscopic data were consistent with those previously reported. 95 N - (4 - methoxybenzyl)benzylamine ( 58 b): N - (4 - M ethoxybenzyl) - benzylideneamine (225 mg, 1 mmol) wa s reduced in 1 h, following the general procedure for imine reduction. After work up procedure I II, the amine was obtained as a brown oil . Yield: 90%. 1 H - NMR (500 MHz, CDCl 3 ): 7.22 (m, 4 H, Ar - H), 7.13 (t, J = 8.5 Hz, 3 H, Ar - H), 6.76 (d, J = 7 .0 Hz, 2 H , Ar - H), 3.67 ( br s , 7 H, CH 2 NCH 2 , Ar - OCH 3 ), 1.40 (s, 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 158.5, 139.8, 131.9, 129.2, 128.3, 128.1, 126.8, 113.7, 55.0, 52.7, 52.2. Spectroscopic data were consistent with those previously reported. 96 81 N - Phenyl - 2,4,6 - trimethylbenzylideneamine ( 59 a): Using the general procedure for imine formation (Method A) a light yellow solid was obtained. Yield: 100%. 1 H - NMR (500 MHz, CDCl 3 ): 8.80 (s, 1 H, CH - imine), 7.46 7.42 (m, 2 H, Ar - H), 7.2 7 7.23 (m, 1 H, Ar - H), 7.21 7.18 (m, 2 H, Ar - H), 6.95 (s, 2 H, Ar - H), 2.56 (s, 6 H, Ar - CH 3 ), 2.34 (s, 3 H, Ar - CH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 160.8, 153.1, 139.8, 138.6, 130.5, 129.7, 129.1, 125.5, 120.7, 21.2, 21.0. mp = 50 C . Spectroscopic data were consistent with those previously reported. 97 N - (2,4,6 - trimethylbenzyl)phenylamine ( 59 b) : N - P henyl - 2,4,6 - trimethylbenzyl i deneamine (223 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine reducti on. After work up procedure I II, the amine was obtained as a orange oil . Yield: 93%. 1 H - NMR (500 MHz, CDCl 3 ): 7.37 7.33 (m, 2 H, Ar - H), 7.03 (s, 2 H, Ar - H), 6.86 (t, J = 7.5 Hz, 1 H, Ar - H), 6.79 (d, J = 7.5 Hz, 2 H, Ar - H), 4.32 (s, 2 H, Ar - CH 2 ), 3.4 (s , 1 H, - NH), 2.48 (s, 6 H, Ar - CH 3 ), 2.42 (s, 3 H, Ar - CH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 148.5, 137.4, 137.2, 132.1, 129.2, 129.0, 117.1, 112.3, 42.2, 20.8, 19.3. Spectroscopic data were consistent with those previously reported. 98 82 N - phenyl - 1 - napthylideneamine ( 60 a ): Using the general procedure for imine formation (Method A) a white solid was obtained. Yield: 97%. 1 H - NMR (500 MHz, CDCl 3 ): 8.64 (s, 1 H, CH - imine), 8.22 (s, 1 H, Ar - H), 8.19 (d, J = 8.5 Hz, 1 H, Ar - H), 7. 95 (t, J = 7.5 Hz, 2 H, Ar - H), 7.90 (d, J = 7.5 Hz, 1 H, Ar - H), 7.60 7.54 (m, 2 H, Ar - H), 7.46 7.42 (m, 2 H, Ar - H), 7.30 7.27 (m, 3 H, Ar - H). 13 C NMR (125 MHz, CDCl 3 ): 160.3, 152.0, 135.0, 133.9, 133.0, 131.2, 129.1, 128.7, 128.6, 127.9, 127.5, 126.6, 1 25.9, 123.9, 120.9. mp = 114 C . Spectroscopic data were consistent with those previously reported. 72b N - (1 - napthylmethyl) - phenylamine ( 60 b) : N - P henyl - 1 - napthylideneamine (231 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine reduction. After work up procedure I , the crude material was purified by column chromatography ( 4:1 hexanes/EtOAc) which afforded the amine as a light orange solid . Yield: 78%. 1 H - NMR (500 MHz, CDCl 3 ): 7.85 7.83 (m, 4 H , Ar - H), 7.52 7.46 (m, 3 H, Ar - H), 7.19 (t, J = 7.5 Hz, 2 H, Ar - H), 6.74 (t, J = 8 .0 Hz, 1 H, Ar - H), 6.70 (t, J = 8 .0 Hz, 2 H, Ar - H), 4.52 (s, 2 H, Ar - CH 2 ), 4.15 (s, 1 H, - NH). 13 C NMR (125 MHz, CDCl 3 ): 148.4, 136.9, 133.5, 132.8, 129.3, 128.4, 127.8, 12 7.7, 126,1, 83 125.9, 125.8, 125.7, 117.6, 112.9, 48.7. mp = 60 C . Spectroscopic data were consistent with those previously reported. 99 N - Phenyl - 3,4 - dimethoxybenzylideneamine ( 61 a) : Using the general procedure for imine formation (Method A) a brown solid was obtained. Yield: 78%. 1 H - NMR (500 MHz, CDCl 3 ): 8.34 (s, 1 H, CH - imine), 7.60 (d, J = 2 .0 Hz, 1 H, Ar - H), 7.36 (t, J = 8 .0 Hz, 2 H, Ar - H), 7.29 (dd, J = 2.0, 7.0 Hz, 1 H, Ar - H), 7 .19 7.17 (m, 3 H, Ar - H), 6.92 (d, J = 8.5 Hz, 1 H, Ar - H) 3.94 (s, 3 H, - OCH 3 ), 3.93 (s, 3 H, - OCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 159.8, 152.3, 152.0, 149.5, 129.6, 129.1, 125.6, 124.4, 120.8, 110.5, 108.9, 56.1, 56.0. mp = 80 C . Spectroscopic data were consistent with those previously repo rted. 100 N - ( 3,4 - dimethoxybenzyl)phenylamine ( 61 b) : N - Phenyl - 3,4 - dimethoxybenzyl ideneamine (241 mg, 1 mmol) was reduced in 1 h, following the general procedure for imine reduction . After work up procedure I II, the amine wa s obtained as a light brown solid . Yield: 91%. 1 H - NMR (500 MHz, CDCl 3 ): 7.21 (t, J = 7.5 Hz, 2 H, Ar - H), 6.95 6.94 (m, 2 H, Ar - H), 6.86 (d, J = 9 .0 Hz, 1 H, Ar - H), 6.76 (t, J = 7.5 Hz, 1 H, Ar - H), 6.68 (d, J = 7.5 Hz, 2H), 4.28 (s, 2 H, Ar - CH 2 ), 84 3.90 (s , 3 H, - OCH 3 ), 3.89 ( br s , 4 H, - NH, - OCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 149.1, 148.3, 148.2, 131.9, 129.2, 119.7, 117.6, 112.9, 111.2, 110.7, 55.9, 55.8, 48.2. mp = 73 C . Spectroscopic data were consistent with those previously reported. 101 General proc edure for the one - pot synthesis of amides : A dry 25 mL round bottom flask was charged with Pd(OAc) 2 (0.05 mmol, 0.011g), an imine (1 mmol) and 5 mL of freshly distilled THF. The flask was sealed, and placed under nitrogen while stirring. Then a KF (aq) so lution (0.1 mmol, 0.1 mL) was added via syringe. This aqueous solution was previously degassed using vacuum and liquid N 2 . The nitrogen outlet was replaced by a balloon filled with N 2 . After 5 min PMHS (2 mmol, 0.12 mL, 1 mmol is equal to 0.06 mL) was adde d dropwise via syringe. Bubble formation is observed and the mixture turns black. The reaction was stirred for 30 min or until completed imine reduction as judged by NMR or GC analysis. Then the appropriated anhydride (between 5 mmol to 2 mmol) was added v ia syringe. Once the amide formation was detected by 1 H NMR (between 2 and 5 hours) the reaction mixture was diluted with ether (5 mL). The organic phase was filtrated through a plug with celite (top layer) and neutral alumina (bottom layer) in a 1 cm di ameter column by flushing with EtOAc. The mixture was then dried over MgSO 4 and concentrated. Finally the crude was purified by silica gel column chromatography. 85 Experimental details and spectroscopic data: N - (4 - meth oxybenzyl) - N - phenyl acet ami d e (76) : N - Phenyl - 4 - methoxybenzylidene - amine (211 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of acetic anhydride (0.19 mL, 2 mmol), amide formati on was observed in 2 h. Finall y it was isolated using the general work up procedure for amides and purified by column chromatography ( 9 : 1 hexanes/EtOAc) which afforded the amide as a colorless oil . Yield: 8 6 %; 1 H - NMR (500 MHz, CDCl 3 ): 7. 2 9 7 .26 ( m , 3H, Ar - H), 7. 08 ( d , J = 8 .5 Hz, 2 H , Ar - H), 6.9 4 (d, J = 7 .5 Hz, 2 H, Ar - H), 6. 75 ( d , J = 9 .0 Hz, 2 H , Ar - H), 4. 79 (s, 2 H, Ar - CH 2 ), 3. 72 (s, 3 H, Ar - OCH 3 ) , 1.83 (s, 3 H, CH 3 CO) . 13 C NMR (125 MHz, CDCl 3 ): 170.2, 158.8 , 1 42.7, 130.1, 129.4, 128.3 , 127.8, 113.8, 113.6, 55.1, 52.1, 22.7 . N - (4 - trifluoromethylbenzyl) - N - phenylacet amide (77) : N - Phenyl - 4 - trifluoro methyl - benzylidene amine (2 49 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of acetic anhydride ( 0.19 mL, 2 mmol), amide formati on was 86 observed in 4 h. Finally it was isolated using the general work up procedure for amides and purified by column chromatography ( 8:2 hexanes/EtOAc) which afforded the amide as a yellow oil . Yield: 58 %; 1 H - NMR (500 MHz, C DCl 3 ): 7. 49 (d, J = 8 .0 Hz, 2 H, Ar - H), 7. 34 7 .29 ( m , 5 H, Ar - H), 6 . 98 (d, J = 7.0 Hz, 2 H, Ar - H), 4. 91 (s, 2 H, Ar - CH 2 ), 1.88 ( s , 3 H, CH 3 CO ) 13 C NMR (125 MHz, CDCl 3 ): 170.6, 14 6 . 2 , 14 1 . 5 , 129. 7 , 128.9, 128.1, 127. 9 , 125. 3 (q, J C F = 3. 0 Hz), 123.0, 5 2.4, 22.6. N - (4 - nitrilebenzyl) - N - phenylacetamide (78) : N - phenyl - 4 - nitrilebenzylideneamine (206 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of acetic anhydride (0.19 m L, 2 mmol), amide formation was observed in 3 h. Finally it was isolated using the general work up procedure for amides and purified by col umn chromatography ( 8:2 hexanes/EtOAc) which afforded the amide as a yellow oil . Yield: 56%; 1 H - NMR (500 MHz, CDCl 3 ): 7. 51 (d, J = 8 .0 Hz, 2 H, Ar - H), 7. 34 7 .29 ( m , 5 H, Ar - H), 6. 9 7 ( d , J = 7 .5 Hz, 2 H, Ar - H), 4. 89 (s, 2 H, Ar - CH 2 ), 1 . 87 ( s , 3 H, CH 3 CO ). 13 C NMR (125 MHz, CDCl 3 ): 170.4, 14 2 . 7 , 142.3, 132. 1 , 129. 6 , 129.1, 12 8 . 1 , 127.7, 118.5, 111.0, 52.44, 22.4 . 87 N - benzyl - N - (4 - fluorophenyl)acetamide (79) : N - (4 - f luorophenyl) - benzylideneamine (199 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of acetic anhydride (0.19 mL, 2 mmol), am ide formation was observed in 3 h. Finally it was isolated using the general work up procedure for amides and purified by column chromatography ( 7:3 hexanes/EtOAc) which afforded the amide as a yellow oil . Yield: 60%; 1 H - NMR (500 MHz, CDCl 3 ): 7.26 7.21 ( m, 3 H, Ar - H), 7.16 ( d , J = 7.5 Hz, 2 H, Ar - H), 6.97 (t, J = 8.2 Hz, 2 H, Ar - H ), 6. 92 6. 90 (m, 2 H, Ar - H), 4. 84 (s, 2 H, Ar - CH 2 ), 1 . 85 ( s , 3 H, CH 3 CO ) . 13 C NMR (125 MHz, CDCl 3 ): 170.1, 1 62.6, 13 7 . 1 , 12 9 . 8 , 12 8 . 6 , 128.7, 127.3, 11 6 . 3 , 11 6.2, 52.6, 22.5. N - (4 - chlorobenzyl) - N - phenylacetamide (80) : N - phenyl - 4 - chlorobenzylideneamine (215 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of acetic anhydride (0.19 mL, 2 mmol), am ide formation was observed in 2 h. Finally it was isolated using the general work up procedure for amides and purified by column chromatography ( 7:3 hexanes/EtOAc) which afforded the amide as a yellow oil . Yield: 40%; 1 H - NMR (500 MHz, CDCl 3 ): 1 H - NMR (500 M Hz, CDCl 3 ): 7. 36 7. 30 (m, 3 H, Ar - H), 7.21 ( d, J = 8 .5 Hz, 2 H, Ar - 88 H), 7 . 14 7 . 08 (m, 2 H, Ar - H), 6. 96 (d, J = 7 . 5 Hz, 2 H, Ar - H), 4. 83 (s, 2 H, Ar - CH 2 ), 1 . 86 ( s , 3 H, CH 3 CO ). 13 C NMR (125 MHz, CDCl 3 ): 170 . 4 , 142 . 6 , 136.0, 133.1 , 130.2 , 129.6, 128.5, 1 28.1 , 128.0 52.1 , 22.8 . N - (4 - fluorobenzyl) - N - phenylacetamide (81) : N - phenyl - 4 - fluoro benzylideneamine (199 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of acetic anhyd ride (0.19 mL, 2 mmol), amide formation was observed in 2 h. Finally it was isolated using the general work up procedure for amides and purified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amide as a yellow oil . Yield: 55%; 1 H - NMR (500 MHz, CDCl 3 ): 1 H - NMR (500 MHz, CDCl 3 ): 7. 30 7. 25 (m, 3 H, Ar - H), 7. 1 5 7. 10 (m, 2 H, Ar - H), 6.9 3 6. 86 (m, 4 H, Ar - H), 4. 80 (s, 2 H, Ar - CH 2 ), 1 . 83 ( s , 3 H, CH 3 CO ) . 13 C NMR (125 MHz, CDCl 3 ): 170.2, 1 60.9, 14 2 .4, 13 3 .2, 130.3, 129.4 , 127.8 , 11 5.0, 114.8, 51 .8, 22.49. N - (4 - methoxybenzyl) - N - phenylbenzamide (82) : N - Phenyl - 4 - methoxybenzylidene - amine (211 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after 89 addition of benzoic anhydride (0. 34 g, 1.5 mmol), amide formation was observed in 2 h. Finally it was isolated using the general work up procedure for amides and purified by column chromatography ( 7:3 hexanes/EtOAc) which afforded the amide as a colorless oil . Yield: 74%; 1 H - NMR (500 MHz, CDCl 3 ): 7. 34 ( d , J = 7 .5 Hz, 2 H, Ar - H) , 7. 2 5 7 .2 0 ( m , 3H, Ar - H), 7. 15 7 .06 ( m , 5H, Ar - H) , 6.9 1 (d, J = 8.0 Hz, 2 H, Ar - H), 6. 81 ( d , J = 8.5 Hz, 2 H , Ar - H), 5 . 0 9 (s, 2 H, Ar - CH 2 ), 3. 72 (s, 3 H, Ar - OCH 3 ). 13 C NMR (125 MHz, CDCl 3 ): 170. 3 , 158. 6 , 1 4 3 . 0 , 13 5 . 7 , 133.1, 129. 8 , 129.6, 128. 7 , 128.1, 127. 7 , 127.5, 126.4 , 113.6, 5 4 . 8 , 5 3 . 0. N - (4 - trifluoromethylbenzyl) - N - phenylbenzamide (83) : N - Phenyl - 4 - trifluoro methyl - benzylidene amine (2 49 mg, 1 mmol) was reduced following t he general procedure for imine reduction. Then after addition of benzoic anhydride (0.34 g, 1.5 mmol), amide formation was observed in 5 h. Finally it was isolated using the general work up procedure for amides and purified by column chromatography ( 9:1 he xanes/EtOAc) which afforded the amide as a colorless oil . Yield: 73 %; 1 H - NMR (500 MHz, CDCl 3 ): 7. 50 7 .43 ( m , 3 H, Ar - H) , 7. 33 (d, J = 8 .0 Hz, 2 H, Ar - H), 7. 25 (d, J = 8 .0 Hz, 2 H, Ar - H) , 7. 20 7 . 12 ( m , 5 H, Ar - H), 6 . 9 2 (d, J = 8 . 5 Hz, 2 H, Ar - H), 5 . 18 (s, 2 H, Ar - CH 2 ) . 13 C NMR (125 MHz, CDCl 3 ): 170. 7 , 14 3 . 2 , 1 35 . 4 , 133.7, 130.1, 129. 9 , 129.2, 128. 8 , 128. 6 , 128.4, 127. 8 , 127.5, 126.9, 125. 4 (q, J C F = 3. 8 Hz), 5 3 . 5 . 90 N - (4 - methoxybenzyl) - N - (phenyl) tert - butyl carbamate ( 84) : N - Phenyl - 4 - methoxy benzylideneamine (211 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of Boc anhydride (0.33 g, 1.5 mmol), amide formation was observed in 2 h. Finally it was isolated using the gener al work up procedure for amides and purified by col umn chromatography ( 9:1 hexanes/EtOAc) which afforded the amide as a yellow oil . Yield: 60%; 1 H - NMR (500 MHz, CDCl 3 ): 7. 27 ( t , J = 7 .5 Hz, 2 H, Ar - H), 7. 20 7 .14 ( m , 5H, Ar - H), 6. 84 (d, J = 8 .5 Hz, 2 H, A r - H), 4. 78 (s, 2 H, Ar - CH 2 ), 3. 77 (s, 3 H, Ar - OCH 3 ) , 1.43 (s, 9 H, t - Bu) . 13 C NMR (125 MHz, CDCl 3 ): 1 58.7 , 154 .8 , 1 42.7, 130.1 , 128 . 9 , 128. 6 , 12 6 .8 , 125 .8 , 113.7 , 80.3, 55.1 , 53 . 3, 28.3 . N - (4 - trifluoromethylbenzyl) - N - (phenyl) tert - butyl carbamate (85) : N - Phenyl - 4 - trifluoro methyl benzylidene amine (2 49 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of Boc anhydride (0.33 g, 1.5 mmol), amide 91 formation was observed in 5 h. Finally it was isolated using the general work up procedure for amides and purified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amide as a yellow oil . Yield: 70 % 1 H - NMR (500 MHz, CDCl 3 ): 7. 58 (d, J = 8 .0 Hz, 2 H, Ar - H), 7 . 38 (d, J = 8 .0 Hz, 2 H, Ar - H) , 7 . 30 ( t , J = 8 .0 Hz, 2 H, Ar - H), 7. 25 7 .17 ( m , 3 H, Ar - H), 4. 90 (s, 2 H, Ar - CH 2 ), 1.44 ( s , 9 H, t - Bu ) 13 C NMR (125 MHz, CDCl 3 ): 1 54.7 , 14 2.7, 129. 4 , 129.3, 12 9 . 2 , 128. 7 , 12 6 . 1 , 125. 3 (q, J C F = 3. 8 Hz), 123.0, 80.8, 5 3 . 6 , 2 8 . 2 . N - benzyl - N - (4 - fluorophenyl) tert - butyl carbamate ( 86 ) : N - (4 - f luorophenyl) - benzyl - ideneamine (199 mg, 1 mmol) was reduced following the general procedure for imine reduction. Then after addition of Boc anhydride (0. 33 g , 1.5 mm ol), amide formation was observed in 3 h. Finally it was isolated using the general work up procedure for amides and purified by column chromatography ( 9:1 hexanes/EtOAc) which afforded the amide as a yellow oil . 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(b) Bradsher, C. K.; Hunt, D. A. J. Org . Chem. 1981 , 46 , 327 330 . ( 101 ) Moreno, I.; Tellitu, I.; Etayo, J.; SanMartín, R.; Domínguez, E. Tetrahedron 2001 , 57 , 5403 5411. 100 CHAPTER 3 : MECHANISTIC STUDIES TOWARDS THE DEVELOPM ENT OF ONE - POT ALLYLATION HYDRO STANNATION INVOLVING RECYCLING OF TIN WASTE 3 .1 Introduction Tin (Sn) belongs to the same periodic group as silicon, with four electron s in the outer electronic shell and ha ve common charge on the - carbon, see page 4), as well as better stability than other organometallics compounds. 1 Although the Sn - C bond is weaker than the C - C or Si - C, it is relatively non - pola r so it is stable in the presence of air and moisture. Therefore the reactivity and application of organotin compounds R n SnX 4 - n (n=3, 2 or 1) depend s on the stability of the Sn - C bond, the lability of the anion X and the impact of hypercoordination (simi lar to silicon). 2 Scheme 3.1 highlights the major routes into the principal groups of organotin (IV) compounds via the nucleophilic alkylation of tin tetrachloride ( 87 ) with an organometal lic reagent, most commonly a Grignard reagent ( 88 ). 2 This reacti on usually gives the tetraorganotin compound ( 8 9 ), which then is heated with tin tetrachloride to yield organotin chlorides R n SnCl 4 - n (n= 3, 2 or 1). The latter ones are obtained by redistribution of the R and Cl groups via the Kocheshkov reaction. 2 The ch lorides can then be replaced by nucleophiles (X = RO , RCO 2 , etc) to give the derivatives R n SnX 4 - n by anion exchange. Hydrolysis of the organotin chlorides ( 90 and 91 ) with OH - yield s the hydroxides, which are often unstable and dehydrate to give the oxid es R 3 SnOSnR 3 ( 93 ) or (R 2 SnO) n ( 94 ). 2 101 One of the most important reaction s is the reduction of the tin halides with a metal hydride such as lithium aluminium hydride, sodium borohydride or by employing our own methodology using PMHS to obtain the correspondi ng organotin hydride 95 . 3 Later these hydride donors can reduce the tin halides to tin hydrides (hydrostannolysis), which react with alkenes or alkynes (hydrostannation products 99 and 100 ) after radical chain reactions, involving R 3 Sn 101 ) radicals to p rovide another way of forming Sn - C bonds (Scheme 3.2). 2 Scheme 3.1 Organotin synthesis based on the Gr ignard and Kocheshkov reactions 102 Furthermore, the organotin hydrides ( 95 ) and dialkyltin dihydrides ( 96 ) eliminate hydro gen, under the presence of a base, to give distannanes 97 ( R 3 SnSnR 3 ) and oligostannanes 98 (R 2 Sn) n . Finally the tin halides ( 90 ) and hydrides ( 95 ) can react with alkali metals (M) to give R 3 SnM ( 102 ) metallic derivatives, which can react with alkyl halides giving access to another route for Sn - C bond formation (Scheme 3.2). 2 Scheme 3.2 Organotin synthesis based on reactions of tin hydrides and R 3 SnM One of the major industrial applications of organotin compounds is as st abilizers of polyvinyl chloride (PVC). While working with PVC , high temperatures are required. A t these conditions degradation occurs through progressive loss of HCl, leading to a system of conjug ated double bonds that results i n the lo ss of physical prope rties . The organotin stabilizer s ( 103 ) trap the HCl released reducing the degradation and also replace the labile chloride atoms by SR groups that are less prone to undergo elimination (Scheme 3.3). 1,4 103 Scheme 3.3 Stabiliz ation of PVC T his chapter is based on the hydrostannation reaction and the addition of allylstannanes to aldehydes. The chemistry involve d in the preparation and the reaction mechanism of the addition of allylstannanes w ill be discussed. 3.2 Allylation reactions with allylstannanes 3.2.1 Preparation of allylstannanes As mention before o ne of the principal methods to form Sn - C bonds is the hydrostannation of alkenes or alkynes ( S cheme 3.2). As a result, allylstannanes 106 can also be prepared by the rad ical reaction of an organotin hydride with allenes 104 ( S cheme 3.4). 5 Another conventional route to allylstannanes is the reaction of an allylmetallic compound with a tin halide or the reaction of s tannylmetallic compound with an allyl halide. 6 104 Scheme 3.4 Hydrostannations by radical mechanism Various allylstannanes bearing functional groups 10 9 (e.g. CN, CO 2 CH 3 or SO 2 Ar) can be prepared as well by th e radical - chain reaction of allyl sulfones 107 with tributyltin hydride 108 in refluxing benzene (Scheme 3.5) 7 Scheme 3.5 Allylstannane preparation Among the extensive use s of allylstannanes in organic and organometallic synthesis, 6 one of the most noteworthy applications is the electrophil ic addition reaction with aldehydes. 8 In the quest for a controlled construction of open - chain systems bearing sequences of stereocenters (acyclic stereocontrol), the addition of allylstannanes to aldehydes is one of the most efficient strategies giving co ntrol of diastereo - and enantioselectivity. 8 A llylstannane reaction s are synthetically analogous to the aldol reaction since the resulting homoallyl alcohol ( 114 ) can be 105 converted to the aldol product ( 112 ). A nother advantage of allymetal additions is that the homoallylic alcohol can be converted to hydroxyaldehydes ( 11 5 ) via olefin cleavage , 9 or - lactones ( 11 6 ) 10 via hydroformylation, or can be epoxidized ( 11 7 ) 11 to introduce a third chiral center, making this reaction ideal for synthetic planning (S cheme 3.6). 8b The mechanism of allystannane additions to aldehydes is intriguing and differs with the conditions used, e.g thermal, 12 high pressure, 13 Lewis acid 14 or transition - metal catalyzed. 15 Scheme 3.6 Aldol reaction a nd allylmetal aldehyde condensation 3.2.2 Reaction with aldehydes in the presence of Lewis acids In 1980 Yamamoto report a new approach to the stereoselective addition of crotyl tributylstannanes (E) - and (Z) - ( 11 9 ) to aldehydes ( 118 ) induced by Lewis ac ids. 16 I n this early rep ort it was highlighted that BF 3 2 promoted addition of 119 to benzaldehyde to afford >90% of the syn homoallylic alcohol 122 . T his result was not affected at all by the geometry of the but - 2 - enyl unit, as either cis or trans reag ents gave the same result (Scheme 3.7). Due to this 106 result they proposed an acyclic transition state in which the Lewis acid coordinate s to the oxygen atom preventing the coordination of the Sn atom. Furthermore, they proposed that the antiperiplanar trans ition state ( 120 ) is the most stable conformation leading to the syn alcohol. 14b,17 Scheme 3.7 Stereochemical outcome of allylstannane addition to aldehydes Once this reaction pathway w as proposed a controversy bega n related to the putative transition state. Denmark 14c,18 studied a model system 124 ( S cheme 3.8) to evaluate which transition state is more stable , the synclinal geometry 125 or antiperiplanar 126 as proposed by Yamamoto. 14b,17 ults, Denmark studies indicated that the most stable conformation is the synclinal orientation of the double bond concluding that t he alcohol ( 127 ) is obtained through the synclinal transition state ( 125 ) via anti - S E substitution (S cheme 3.8). 107 Scheme 3.8 Model studies on the reaction of allylstannanes with aldehydes It was proposed that the possible origins for this synclina l preference could be due to a C oulomb ic attraction effect and secondary orbital interaction s. 18 The first effect is based on the charge accumulation in the transition state ( 129 ). B ecause the reactions are done in non - polar solvents , Denmark argue d that charge separation should be energetically disfavored (Scheme 3.10). The second effect is rela ted to the HOMO of the allylmetal and the LUMO of the complexed aldehyde. In the favored synclinal orientation there is an overlap between the oxygen and the metal - bearing carbon ( 131 ), which is absent on the antiperiplanar orientation ( 130 ) (Figure 3.1) 18 ,14a 108 Figure 3.1 Favoring effect towards the synclinal transition state Finally, s tudies performed by Keck 14a,19 with enriched mixtures of E and Z - 2 - butenylstannanes ( 1 19 ) and various simply aldehydes like 132 indicate the preference for the synclinal conformation. These reactions were also selective for the syn homoallylic alcohol . D iastereoselectivity was increased when the (E) - stannane was present in a higher percent (S cheme 3.9). Scheme 3.9 Crotylstannanes reaction with cyclohexanecarboxaldehyde 109 T he stability of the different conformations leading to the products depends also on the bulkiness of the Lewis acid - aldehyde complex (the steric and electronic effects present within the substituents on the aldehyde and the Lewis acid), the stoichiometry of the reactants, the order of addition and the reaction conditions all may favor either the synclinal transition state or the antiperiplanar arrangement. 6 3.2.3 Palladium c atalyzed reaction of allylstannanes with aldehydes A different approach for the allylation of aldehydes with allylstannanes is the use of transitions metals complexes. 20 O ne important study was done by Yamamoto using Pd (II) and Pt (II) complexes to cataly zed the reaction of allystannanes with aldehydes. 15 The findings of this study indicated that the bis - - allylpalladium complex ( 141 ) would be the key intermediate for the allylation reaction (Figure 3.2). The reasoning behind the formation of this key in termediate 141 was based on 1 H NMR studies and experimental results. When allylstannane ( 135 ) was mixed with the Pd(II) catalyst ( 136 ) a - allylpalladium chloride complex ( 138 ) was formed along with PPh 3 ( 139 ) and tributylstannyl chloride ( 140 ), all detect ed by 1 H NMR. Initially it was assumed that the - allylpalladium chloride complex ( 138 ) could be the key intermediate however addition of benzaldehyde to 138 or to the mixture of 138 with PPh 3 and Bu 3 SnCl did not produce the homoallylic alcohol. Conversely , when allylstannane ( 135 ) was added to the mixture of benzaldehyde with 138 (or the mixture including PPh 3 and Bu 3 SnCl) the allylation reaction took place quickly. This proved that the bis - - allylpalladium complex ( 141 ) formed was the key intermediate and the one able to react directly with benzaldehyde (Figure 3.2). Conversely, when the addition of benzaldehyde to 141 was monitor ed by 1 H NMR the 110 signals of the bis - - allylpallad ium complex disappeared, suggest ing that 141 rearranges in the presence of the benzaldehyde to afford a - allyl(alkoxy)palladium complex ( 142 ) , which would be the actual species reacting with the aldehyde. 15 Figure 3.2 Preparation of bis - - allylpalladium complex ( 141 ) The catalytic cycle propose d starts from the - allyl(alkoxy)palladium complex ( 142 ) reacting with the aldehyde to give the - allyl - - allyl palladium complex ( 144 ). The latter may produce the homoallyloxy palladium ( 145 ) that finally reacts with allylstannane ( 135 ) to yield the homoa llyloxystannane 146 and 142 (Figure 3.3). 15 111 Figure 3. 3 Proposed Pd catalyzed mechanism of allystannanes addition to aldehydes Among the different applications of allylation chemistry , one particular synthesis caught our attention. The synthesis of p almerolide A analogues by Nicolaou and co - workers, 21 requires the preparation of a vinyl stannane fragment II via an aldehyde allylation followed by an alkyne hydrostannation (Scheme 3.10) . Scheme 3.10 To tal synthesis of Palmerolide A analogues 112 We became interested in the development of a one - pot allylati on - hydrostannation sequence, where the tin waste from the allylation reaction could be converted to an organotin hydride that could perform the hydrostannation reaction. This combined process would help in minimize the use of tin reagents employed in synthesis in comparison with those protocols in where the two steps are perform ed separately. 22,23 3.3 One - pot allylation - hydrostannation prot ocol In t he quest for a simpler method for an allylation - hydrostannation sequence, we were able to develop a one - pot allylation and hydrostannation of alkynals where the tin byproduct formed in the first step of the reaction was recycled and used i n the se cond step of the sequence. 24 Our initial thinking was that the stannyl ether intermediates 146 observed by Yamamoto on the Pd - catalyzed allylation (Figure 3.3) , 15 or either the byproduct Bu 3 SnCl (observed by Baba and co - workers 25 on the allylation of aldeh ydes with allyltributylstannane and catalytic amounts of Bu 2 SnCl 2 ) could be reduced in situ to Bu 3 SnH (Scheme 3.11) . 26 Scheme 3.11 A llylation of aldehydes using Bu 2 SnCl 2 as additive and proposed Bu 3 SnH generation in situ . 113 However, attempts to react a mixture of 1 35 , 14 8 , and 1 49 under the conditions of these two methodologies, which in theory would be followed by the hydrostannation of 1 49 via the addition of PMHS, PMHS/TBAF, or Et 3 SiH as the reducing agent ( 151 ) with Pd or Pt as the hydrostannation catalyst failed ( S cheme 3.1 2 ). That said only the allylation of 148 to 15 0 15 0 Neither of these methods could be made to work for a one - pot al lylation - hydrostannation sequence , therefore we decided to explore BF 3 2 induced allylation s . 16 However the tin intermediates formed in these reactions are not fully characterized and are matter of controversy . 27 Schem e 3.1 2 Initial attempts of allylation - hydrostannation sequence T hinking that a common hydrostannation catalyst like PdCl 2 (PPh 3 ) 2 26b or MoBI 3 28 would not survive in the presence of BF 3 2 , we decide to explore Lewis acid mediated hydrostannations. B(C 6 F 5 ) 3 was chosen as the hydrostannation catalyst. 26a,29 A report of the use of B(C 6 F 5 ) 3 catalyzed hydrostannation was reported by Yamamoto. 26a In this protocol they found that 10 mol % of B(C 6 F 5 ) 3 effectively catalyzed the hydrostannation of alkynes with Bu 3 S nH generate d in situ from Bu 3 SnCl and Et 3 SiH as the hydride source (Scheme 3.1 3 ). 114 Scheme 3.1 3 Yamamoto hydrostannation reaction After significant optimization of the reaction conditions 24 were explored different sources o f reducing agents (Et 3 SiH, PMHS , and PMHS/TBAF) for the one - pot allylation - hydrostannation sequence (Table 3.1), we found that 1.05 equiv of BF 3 2 , 20 mol % of B(C 6 F 5 ) 3 and 2 equiv of PMHS in toluene at - 35 °C followed by quenching with 1.4 equiv of NEt 3 produced the highest combined yield of the expected homoallylic alcohol 15 0 (78%) and vinylstannane 15 2 (100%) as monitored by NMR using (CH 3 ) 3 SiOSi(CH 3 ) 3 as internal standard (Table 3.1 entry 15). 24 After isolation 71% of 15 0 and 99% of 15 2 were recove red . Yamamoto 26a tried to do hydrostannation reaction with Bu 3 SnH generated in situ from the reduction of tributyltin oxide with PMHS, under the Lewis acid catalyzed conditions using B(C 6 F 5 ) 3 as a catalyst, however no hydrostannations products were detecte d, presumably due to 26a in our results PMHS is not inhibited by B(C 6 F 5 ) 3 as a catalyst for the hydrostannation reaction and the reaction proceed s smoothly (Table 3.1). 115 Table 3.1 Optimization of one - pot allylation - hydrostannation sequence 116 Once this new one - pot allylation hydrostannation sequence was achieved where the aldehyde and alkyne moieties were in separated molecules , we want ed to de monstrate that this sequence could be applied to alkynals like 15 3 - 16 0 . The synthesis of alkynals 15 4 , 15 5 , 15 7, 158, 159 , and 160 are explained in detail in our recent publication Gosh et al . 24 The results described in T able 3.2 highlight that (Z) - vinylstannanes were the exclusive or predominant product of these Lewis acid catalyzed reactions as reported earlier by Yamamoto. 29 Furthermore, the allylation step tends to be fast (usually between 15 to 60 min, except for entry 9), however the secon d step was influenced by sterics and electronic effects of the starting materials. For example, we observed that the reaction of 15 3 under our one - pot allylation hydrostannation conditions only takes 1 h (Table 3.2, entry 1), however when the ethynyl moiet y was moved closer to the aldehyde the reaction became slower (14 h for 15 4 and 1 day for 15 6 ). When an electron - withdrawing group was introduced the reaction was finally completed only af ter 3 days (Table 3.2, entry 3). W hen an electron - donating group was present the hydrostannation step was inhibited (Table 3.2, entry 5 and 6). On the other hand, for aliphatic alkynals 1 59 and 16 0 yields were lower in comparison with the aromatic alkynals, and the second step was the slowest at 3 days (Table 3.2, entry 7 and 8). Finally, on the crotylation of 153 with (E) - crotylstannane ( 135b ) the allylation step was slower than other substrates (90 min, entry 9). 24 In addition, most of the alkynals selected favorably undergo the allylation - hydrostannation sequence, howeve r the yields were moderated. Therefore, in order to understand this drawback on the final product yields a step wise analysis of the sequence was deemed necessary. 117 Table 3.2 One - pot allylation - hydro stannation protocol of alkynals 118 3.4 Step wise analysis of one - pot allylation hydrostannation Searching for a better understanding of this allylation hydrostannation protocol a step wise analysis was performed. The reactivity and stability of the p roposed intermediates were studied un der different comb inations of the reagents used in this methodology, either by excluding one of the reagents or by resubmitting the products to the reaction conditions. 3.4.1 Step wise allylation and hydrostannation reaction of 4 - ethynylbenzaldehyde As e xplained on the beginning of this chapter the allylation of aldehydes with allylstannanes can be achieved in the presence of Lewis acids. 24 Following the order of addition for our one - pot allylation hydrostannation protocol, we expect the formation of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol as intermediate upon treatment of 4 - ethy ny lbenzaldehyde ( 153 ) with a llylstannane ( 135a ) in the presence of BF 3 2 . As expected in this first step, the allylic alcohol ( 169 ) was isolated after 30 min at - 35 °C in toluene. P uri fication after column chromatography yielded 86% of 169 ( S cheme 3.1 4 ) . Scheme 3. 1 4 Allylation of 4 - ethy ny lbenzaldehyde The next step i nvolve d submitting the homo allylic alcohol ( 169 ) to the hydrostannation step in the presence of B(C 6 F 5 ) 3 followed by addition of tributyltin hydride. Initial attempts did 119 not work and only homoallylic alcohol 169 was recovered. We previously mention ed Yamamoto 26a results highlighting that B(C 6 F 5 ) 3 can be use d as hydrostannation catalyst in the presence of Bu 3 SnH formed in situ ( S cheme 3.1 3 ). K nowing that this reaction should work , it was de cide d to prepare fresh tributyltin hydride following the method develop ed by our lab 3 ( S cheme 3.1 5 ), expecting that this would reverse the previous ne gative results. Scheme 3.1 5 Preparation of tributyltin hydride Upon using this freshly distilled Bu 3 SnH in the presence of B(C 6 F 5 ) 3 the hydrostannate products 161 and 17 0 were isolated in 42% yield as a mixture of Z/E i somers in a ratio 1.4:1, along with 36% of starting material and other tin impurities ( S cheme 3.1 6 ). Scheme 3.1 6 Hydrostannation reaction of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol This result highlights that the formation of hydrostannation products via the in situ generation of Bu 3 SnH is possible, and also shows an advantage of the one - pot protocol in that only the Z product was detected. On the other hand, when the reaction is done one step at a time, 120 an Z/E mixture is obser ved. Even though, Yamamoto report ed a Z:E ratio of 95:5 with 70% yield ( S cheme 3.1 3 ) , i n our hands the same substrate reacted with fresh Bu 3 SnH and B(C 6 F 5 ) 3 yielding 6 9 % of a Z:E mixture in a 1:1 ratio . 3.4.2 Study of the stability of the allylation and allylation - hydrostannation product of 4 - ethynylbenzaldehyde in the reaction media Next we wanted to study the stability of the homo allylic alcohol ( 169 ) under the reaction conditions , but in the absence of tributyltin hydride. Even a fter 1 hour under the r eaction conditions at - 35 °C in toluene, only starting material was detected . A fter column chromatography 71.4% of 169 was recovered as a clear oil ( S cheme 3.1 7 ) . Scheme 3.1 7 Stability of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol in the reaction media without Bu 3 SnH This result indicated that degradation of the alkynol 169 under our reaction conditions can not fully explain the moderate yields observed for the final products i n T able 3.2. Therefore , we decide to look into the s tabi lity of the final products i n the reaction media. When we resubmitted product 161 to the reaction conditions, and purified the final crude by column chromatography, only 40% of 161 was recover d as a clear oil ( S cheme 3.1 8 ) . This indicated that the degrada tion of the final product 161 in the reaction mixture is consistent with the moderated yields observed in our one - pot allylation - hydrostannation protocol. 121 Scheme 3.1 8 Stability of 161 in the reaction media 3 .4.3 B(C 6 F 5 ) 3 - catalyzed hydrostannation of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol with tributyl - tin hydride in presence of PMHS W e next studied the hydrostannation of homo allylic alcohol 169 in the presence of 20 mol % of B(C 6 F 5 ) 3 , 2 equiv of PMHS and 1 equiv of freshly Bu 3 SnH . Even a fter 1 hour under these reaction conditions at - 35 °C in toluene, only 169 was isolated after column chromatography ( 7 9 % yield ) and only traces amounts of (Z) - stannane 161 w ere observed by 1 H NMR ( S cheme 3.1 9 ) . These results in dicated that on ly the in situ formed Bu 3 SnH is involved in the hydrostannation step under our reaction conditions. Scheme 3.1 9 Hydrostannation attempt of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol 122 3 .4.4 One - pot allylation - hydrostannation of 4 - ethynylbenzaldehyde without PMHS Finally we wanted to confirm that the presence of PMHS was necessary for the in situ formation of Bu 3 SnH. In the absence of PMHS only homoallylic alcohol 169 was obtained in high yield 93 % ( S cheme 3. 20 ). This proved that PMHS is involved in the generation of Bu 3 SnH. Scheme 3. 20 Hydrostannation attempt of 4 - ethynylbenzaldehyde without PMHS 3.5 NMR studies ( 119 Sn, 19 F and 11 B) Along with the reaction analyse s just described , NMR stud ies were perform ed in order to probe the intermediates of the allylation hydrostannation protocol. 119 Sn, 11 B and 19 F NMR were obtained after addition of each reagent to the crude reaction mixture allowing us to confirm the in situ generation of Bu 3 SnH. Fo llowing S cheme 3. 21 , i n the absence of BF 3 2 , the reaction mixture of benza ldehyde (0.04 mL, 0.375 mmol) and stannane (0.12 mL, 0.375 mmol) only showed the characteristic pe ak for allyltributylstannane ( - 1 7 ppm) by 119 Sn NMR. 30 When the Lewis acid BF 3 Et 2 (0.05 mL, 0.393 mmol) ( Intermediate I ) was added a doublet at 1 64 ppm slowly grew as the peak corresponding to allyltributylstannane decayed (Figure 3.4 ). The coupling constant ( J ) of this doublet was found to be in the range of 1 430 Hz. Such a large c oupling constant is 123 consistent with many Sn F species. 31 Both of the peaks at - 1 7 ppm and 164 ppm appeared broad. These broad peaks suggest that these species are not monomeric and may be aggregates. Scheme 3. 21 119 Sn NM R study of one - pot allylation - hydrostannation protocol Figure 3.4 119 Sn NMR spectrum of Intermediate I 124 A 11 B NMR study of the same mixture ( Intermediate I ) showed two peaks at 0.14 and 1.22 pp m respectively. The peak at 0.14 ppm is attributed to unreact ed BF 3 ·OEt 2 . The peak at - 1.22 ppm is consistent with formation of an oxygen bound BF 3 (Figure 3.5 ). 32 These boron - o xygen interactions were observed before by Denmark and co - workers, in the spectroscopic investigation of the addition of allylstannanes to a ldehydes induced by Lewis acid. 27b Using 13 C NMR they were able to identified the formation o f boron ethers species while no stannyl ethers were observed when BF 3 2 was used as a Lewis acid (pathway A on Scheme 3.20). Instead when SnCl 4 was employed as the Lewis acid they found evidence of an interaction between the Lewis acid and the allylic stannane before reacting with the aldehyde (pathway B on Scheme 3.2 2 ). 27b The latter involves a transmetallation of the allylstannane (metathesis) with the Lewis ac id to form a new reagent species 174 . T his scenario is not observed under our reaction conditions. 125 Figure 3.5 11 B NMR spectrum of Intermediate I Scheme 3.2 2 Normal Lewis a cid reaction vs. transmetallation of allylst a nnane (metathesis) with Lewis a cid 126 The next step involved the addition of B(C 6 F 5 ) 3 (38 mg, 20 mol %) to reaction mixture followed by PMHS (0.05 mL) ( Intermediate mixture II ). A significant change in 119 Sn NMR was observed as a new pea k could be seen at - 88 ppm that is a characteristic peak for tributyltin hydride. 30 Th e doublet peak s lightly shift ed to 165 ppm and the coupling constant ( J ) of this doublet increase d to 1538 Hz. (Figure 3.6 ). As noted earlier, this transformation was slow and needed precision in reagent addition and mixing. If the tin hydride is not produced, the reaction will not proceed to the desired product. Chandrasekar and co - workers demonstrated that B(C 6 F 5 ) 3 functions as a PMHS activator. 33 We anticipate that B(C 6 F 5 ) 3 serves a similar role in our reactions. Thus, it is likely that B(C 6 F 5 ) 3 activates PMHS to reduce the Sn - F species to tributyltin hydride during the course of the reaction. Furthermore, the 11 B NMR study of the Intermediate mixture II (Figure 3.7 ) showed, t wo peaks slightl y shifted to 0.23 and 1.36 ppm . The dominant 11 B species in the reaction mixture are oxygen coordinated BF 3 , since BF 3 is used stoichiometrically, whereas only 20 mol % B(C 6 F 5 ) 3 is used . Figure 3.6 119 Sn NMR spectrum of Intermediate mixture II 127 Figure 3.7 11 B NMR spectrum of Intermediate mixture II To confirm that the splitting of the peak at 165 ppm in the 119 Sn NMR spectrum was due to fluorine scalar coupling, we performed a fluorine - decoupled 119 Sn NMR spectrum of the mixture . Since the peaks span 32 500 Hz, broadband fluorine decoupling is not feasible. We, therefore, performed a band - selective decoupling on the region around - 194 ppm. This region was selected based on a doublet at - 193 ppm having a scalar coupling similar to that observed in the 11 9 Sn spectrum. 34 The doublet collapsed in the 119 Sn NMR to a singlet upon the selective decoupling (Figure 3.8 ). This result conclusively demonstrates that a Sn - F species is produced during the reaction. 128 Figure 3.8 19 F - decoupled 119 Sn NMR spectrum of Inte rmediate mixture II. Considering the possibility that the Sn - F species contains Sn - O bonds and, as such, could react with PMHS to form the reactive organotin hydride, 35,36 w e decided to reverse the order of addition of B(C 6 F 5 ) 3 and PMHS. W hen PMHS was ad ded to a mixture of benzaldehyde, allylstannane, and BF 3 2 no change in the multiplicity of the doublet in the 119 Sn spectrum was observed, even after an hour , and no formation of organotin hydride was evident. The chemical shift of the doublet, however , moved ~ 6 ppm downfield, possibly due to coordination between Sn and the oxygen atom s of PMHS (Figure 3.9) . The peak corresponding to tributyltin hydride only formed when B(C 6 F 5 ) 3 was added before the PMHS . This is further evidence that B(C 6 F 5 ) 3 is invol ved in the reduction of the Sn - F species to tributyltin hydride. Since PMHS cleaves Sn - O bonds without any assistance from B(C 6 F 5 ) 3 generating organotin hydrides (even at 35 C as we have observed) 35 and 119 Sn chemical shifts for oxygen bound tins are ty pically observed in the range of 70 - 150 ppm ( our tin doublet appears at ~ 165 ppm), we do not believe that species containing F - Sn - O - are intermediates in our reaction. 30,36 It is also clear that the Sn - F species observed during our reaction is not polymer ic tributyltin fluoride , which typically 129 appears far upfield (~ - 10 ppm in hexane solution) as a triplet with a coupling constant of ~1350 Hz. 37 Figure 3.9 119 Sn NMR spectrum of crude reaction after addition of PMHS before B(C 6 F 5 ) 3 Addition of B(C 6 F 5 ) 3 and PMHS not only results in the formation of the tributyltin hydride, there is evidence from the 19 F NMR spectral data that silicon bound fluorides are produced. Figure 3.10 shows an expansion region of change for the 19 F NMR spectrum prior to (top) and a fter (bottom) B(C 6 F 5 ) 3 and PMHS addition. The new resonances at - 146.0 and - 145.4 ppm are consistent with fluorine bound to silicon. 38 Therefore once the tributyltin hydride is produced, a Si - F species is also generated in the reaction mixture. Finally, w hen phenyl acetylene (0.04 mL, 0.375 mmol) was added to a solution of Intermediate mixture II , the tributyltin hydride and the tin doublet disappeared and the corresponding peak of the vi nylstannane species appeared at 5 5.4 ppm (Figure 3.11 ) ( 119 Sn NMR o f purified vinylstannane sh owed a sharp singlet at - 56 ppm) . 11 B NMR of the crude product showed two peaks at 0.13 and - 1.40 ppm (Figure 3.1 2 ). 39 130 Figure 3.10 Expansion of 19 F spectra prior to (top) and after (bottom) addition of B(C 6 F 5 ) 3 and PMHS . 131 F igure 3.11 119 Sn NMR spectra of crude product mixture with exponential multiplication set to 100 Hz (i.e. lb=100) (top). With lb=10 (bottom). 132 Figure 3.12 11 B NMR spectra of crude product mixture 39 After all this NMR analysis we proposed a mechanism descr ibed in Figure 3.13 that is supported by 119 Sn and 11 B NMR spectra after addition of each reagent. Furthermore , in order to eliminate the possibility of Bu 3 SnF involvement, reactions were performed with premade tributyltin fluoride for 3 h (exact same tim e as our typical hydrostannation step for phenyl acetylene in our optimized allylation - hydrostannation protocol). We obtained a different result using Bu 3 SnF ( 177 ), as ( Z ) - 152 and ( E ) - 176 vinylstannanes were produced in almost equal amounts with a combined 11% yield. Finally, from mass spectrometry experiments done in our lab , it was known that Bu 3 SnF can undergo a boron to tin ligand exchange reaction , thus this erosion of yield is not unexpected (Scheme 3.2 3 ) . Non - selective product formation and the low 133 y ield obtained in the reaction further indicates that it is unlikely for Bu 3 SnF to be involved in our allylation - hydrostannation reaction. Figure 3.13 Mechanistic rationale of one - pot all ylation hydrostannation reaction 134 Scheme 3.2 3 Hydrostannation of phenylacetylene by Bu 3 SnF 3.6 Conclusions We were able to develop a new one - pot allylation - hydrostannation sequence of alkynals where the tin byproduct, fro m the BF 3 2 promoted allylation step, was successfully recycled by the introduction of PMHS and catalytic B(C 6 F 5 ) 3 to form Bu 3 SnH in situ; that was used on the hydrostannation reaction. The step wise analysis of this methodology highlights that degradati on of the final product in the reaction mixture was consistent with the moderate yields observed in our one - pot protocol. O ur one - pot was more efficient than carrying out an allylation and hydrostannation of an alkynal in two separate steps. The latter ste pwise reaction gave us 42% yield of a 1.4 /1 mixture of (Z) - and (E) - stannanes, while the one - pot reaction yield 51% of only (Z) - stannane. Furthermore, we confirm that the presence of PMHS is crucial for the formation in situ of Bu 3 SnH, as without PMHS act ivated by B(C 6 F 5 ) 3 only allylic alcohol 169 was obtained. 135 In addition, our studies were the first BF 3 2 mediated allylation being followed by 119 Sn and 11 B NMR, although such studies have been described for SnCl 4 27f and solvent mediated 27g allylstannat ions. The only reports for BF 3 2 mediated allylation done by Denmark 27b were followed by 13 C NMR. Therefore, following the reaction by 119 Sn and 11 B NMR revealed that a Sn - F intermediate is formed during the BF 3 2 mediated reaction between the aldehy de and allyltributylstannane. Later the Sn - F intermediate is reduced to Bu 3 SnH by B(C 6 F 5 ) 3 activated PMHS. I n our one - pot protocol B(C 6 F 5 ) 3 also acts as a catalyst for the subsequent hydrostannation. 3. 7 Experimental s ection General Materials and Method s All r eactions were carried out in oven or flame - dried glassware under nitrogen in round bottom flasks or in sealed tubes unless otherwise noted. All commercial reagents were used without purification except benzaldehyde ( 148 ) and phenylacetylene ( 149 ) th at were purchased from Sigma - Aldrich and often freshly distilled before reactions. allylstannane ( 135 a ), polymethylhydrosiloxane, BF 3 2 and alkynes 153 , and 156 were purchased from Sigma - Aldrich and used as received. Tris(pentafluorophenyl)borane (B(C 6 F 5 ) 3 ) was purchased from Sigma - Aldrich and Strem chemicals. All solvents were reagent grade. Dichloromethane and toluene were freshly distilled from calcium hydride under nitrogen. T etrahydrofuran was distilled from sodium and benzophenone under nitrogen. Except as otherwise indicated, all reactions were magnetically stirred and monitored by thin - layer chromatography with 0.25 - mm pre - coated silica 136 gel plates and developed with uv or phosphomolybdic acid or potassium permanganate solutions. Flash chromatogra phy was performed with silica gel 60 Å (230 400 mesh ASTM). Yields refer to chromatographically and spectroscopically pure compounds unless otherwise mentioned. 1 H, 11 B, 13 C, 19 F, and 119 Sn NMR spectra were recorded on Varian spectrometers: Inova - 300 (300. 11 MHz for 1 H and 75.47 MHz for 13 C), Varian UnityPlus - 500 (499.74 MHz for 1 H, 470.169 MHz for 19 F, 186.357 MHz for 119 Sn, 160.335 MHz for 11 B, and 125.67 MHz for 13 C). Experimental Synthesis of ( Z ) - 1 - [4 - (2 - (tributylstannyl)vinyl)phenyl]but - 3 - en - 1 - ol (161 ) : 4 - Ethynylbenzaldehyde ( 153 ) (130 mg, 1 mmol) was dissolved in toluene (2 mL) in a round - bottom flask and the mixture was cooled to 35 C. Allylstannane ( 135a ) (0.31 mL, 1 mmol) was added followed by BF 3 OEt 2 (0.13 m L, 1.05 equiv). The reaction was monitored until complete (15 minutes). At this point, B(C 6 F 5 ) 3 (103 mg, 20 mol %) was added to the solution under N 2 (glove bag) and it was cooled to 35 C. PMHS (0.12 mL, 2 equiv) was added and the reaction was run for 1 h. NEt 3 was added to quench the reaction. The crude mixture was passed through a short silica plug (1´´), buffered with 1% NEt 3 , with 4:1 hexane/EtOAc solution (200 137 mL) The solution was concentrated and subjected to column chromatography [silica gel; 80:20 hexane:EtOAc, 1% Et 3 N] to afford 161 ( 232 mg, 50% ) as an oil. Data for 161 : IR (neat): 3386 cm - 1 . 1 H NMR (300 MHz, CDCl 3 ) (ppm) = 0.74 - 0.96 (m, 15H), 1.17 - 1.32 (m, 6H), 1.35 - 1.51 (m, 6H), 2.12 (br s, 1H), 2.46 - 2.52 (m, 2H), 4.70 - 4.75 (m, 1H), 5.10 - 5.1 8 (m, 2H), 5.71 - 5.84 (m, 1H), 6.18 (d, J = 13.7, 1H), 7.22 - 7.30 (m, 4H), 7.59 (d, J = 13.7, 1H). 13 C NMR (75 MHz, CDCl 3 ) (ppm) = 10.8, 13.6, 27.2, 29.0, 43.8, 73.1, 118.4, 125.6, 127.1, 132.8, 134.3, 141.0, 142.9, 146.9. HRMS (EI) m/z calcd for C 20 H 31 O 11 6 Sn [M - Bu] + , 403.1392; found: 403.1406. Control experiments: (a) Step - wise allylation and hydrostannation reaction of 4 - ethynylbenzaldehyde ( 153 ) 4 - Ethynylbenzaldehyde ( 153 ) (130 mg, 1 mmol) was dissolved in toluene (1 m L) in a round - bottom flask and the mixture was cooled to 35 C. Allylstannane ( 135a ) (0.31 mL, 1 mmol) was added followed by BF 3 OEt 2 (0.13 mL, 1.05 equiv). The reaction was monitored until complete (30 minutes). 2 mL of water were added to quench the rea ction. The organic phase was 138 separated and the aqueous phase was extracted with CH 2 Cl 2 (3 x 2 mL). Organic phase were combined, dried with MgSO 4 and evaporated using a rotavap. The crude product was subjected to column chromatography [silica gel; 80:20 hex ane/EtOAc, 1% Et 3 N] to afford 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol ( 169 ) (148.4 mg, 86%) as a clear oil. Data for 169 : 1 H - NMR (500 MHz, CDCl 3 ) (ppm) = 7.46 7.44 (d, J = 8.5 Hz, 2 H, Ar - H), 7.29 7.27 (d, J = 8.5 Hz, 2 H, Ar - H), 5.79 5.70 (m, 1 H, C H =CH 2 ), 5.15 5.11 (m, 2 H, CH=C H 2 ), 4.71 4.68 (dd, J = 5.0, 8.0 Hz, 1 H, C H H ), 2.49 2.41 (m, 2 H, CHC H 2 ), 2.20 (s, br, 1H, O H ). 13 C NMR (125 MHz, CDCl 3 ) (ppm) = 144.5, 133.9, 132.1, 125.7, 121.1, 118.7, 83.4, 77.1, 72.7, 43.6. 1 - (4 - Ethynylphenyl)but - 3 - en - 1 - ol ( 169 ) (107.1 mg, 0.62 mmol) was dissolved in toluene in a round - bottom flask. Then B(C 6 F 5 ) 3 (63 mg, 20 mol %) was added to the solution under N 2 (glove bag) and it was cooled to 35 C. Freshly prep ared tributyltin hydride (0.167 mL, 1 equiv) was added and the reaction was run for 1 h. NEt 3 was added to quench the reaction. The crude was passed through a short celite plug ( 1´´ ) buffered with 1% NEt 3 with hexanes (200 mL). The solution was concentrate d and subjected to column chromatography [silica gel; 90:10 hexane/EtOAc, 1% Et 3 N] to recover a mixture of Z ( 161 ) and E ( 170 ) ratio 1.4: 1 (121.4 mg, 139 42 %) as yellow oils. 36% of the starting 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol ( 169 ) was also recovered. (b) Stu dy of the stability of the allylation and allylation - hydrostannation product of 4 - ethynylbenzaldehyde (6) in the reaction media 1 - (4 - Ethynylphenyl)but - 3 - en - 1 - ol ( 169 ) (70 mg, 0.41 mmol) was dissolved in toluene in a roun d - bottom flask. Then B(C 6 F 5 ) 3 (42 mg, 20 mol %) was added to the solution under N 2 (glove bag) and it was cooled to 35 C. Then PMHS (0.04 mL, 2 equiv) was added dropwise. Finally the reaction was run for 1 h. NEt 3 was added to quench the reaction. The cr ude was passed through a short celite plug ( 1´´ ) buffered with 1% NEt 3 with hexanes (150 mL). The solution was concentrated and subjected to column chromatography [silica gel; 90:10 hexane/EtOAc, 1% Et 3 N] to recover the starting material 169 (50 mg, 71 %) a s a clear oil. ( Z ) - 1 - (4 - (2 - (tributylstannyl)vinyl)phenyl)but - 3 - en - 1 - ol ( 161 ) , 100 mg, 0.22 mmol) was dissolved in toluene in a round - bottom flask and the mixture was cooled to 35 C. 140 Allylstannane ( 135a ) (0.07 mL, 1 eq uiv) was added followed by BF 3 OEt 2 (0.03 mL, 1.05 equiv). After 15 min B(C 6 F 5 ) 3 (22 mg, 20 mol %) was added to the solution under N 2 (glove bag) and it was cooled to 35 C. PMHS (0.03 mL, 2 equiv) was added and the reaction was run for 1 h. NEt 3 was adde d to quench the reaction. The crude was passed through a short celite plug ( 1´´ ) buffered with 1% NEt 3 with 4:1 hexane/EtOAc solution (200 mL) The solution was concentrated and subjected to column chromatography [silica gel; 80:20 hexane/EtOAc, 1% Et 3 N] to afford the starting material 161 (40 mg, 40%) as clear oil. (c) B(C 6 F 5 ) 3 - catalyzed hydrostannation of 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol ( 169 ) with tributyltin hydride in presence of PMHS 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol ( 169 ) (52 mg, 0.30 mmol) was dissolved in toluene in a round - bottom flask. Then B(C 6 F 5 ) 3 (31 mg, 20 mol %) was added to the solution under N 2 (glove bag) and it was cooled to 35 C. Freshly prepared tributyltin hydride (0.08 mL, 1 equiv) was added followe d by addition of PMHS (0.04 mL, 2 equiv) dropwise. Finally the reaction was run for 1 h. NEt 3 was added to quench the reaction. The crude was passed through a short celite plug ( 1´´ ) buffered with 1% NEt 3 with hexanes (150 mL). The solution was concentrate d and subjected to 141 column chromatography [silica gel; 90:10 hexane/EtOAc, 1% Et 3 N] to recover the starting material 169 (41 mg, 7 9 %) and trace amount of Z - stannane as clear oil s . (d) One - pot allylation - hydrostannation of 4 - ethynylbenzaldehyde without PMHS 4 - ethynylbenzaldehyde ( 153 ) (130 mg, 1 mmol) was dissolved in toluene in a round - bottom flask and the mixture was cooled to 35 C. Allylstannane ( 135a ) (0.31 mL, 1 mmol) was added followed by BF 3 2 (0.13 mL, 1.05 equiv) . The reaction was monitored until complete (15 minutes). At this point, B(C 6 F 5 ) 3 (102 mg, 20 mol %) was added to the solution under N 2 (glove bag) and it was cooled to 35 C. The reaction was run for 1 h. NEt 3 was added to quench the reaction. The crude was passed through a short celite plug ( 1´´ ) buffered with 1% NEt 3 with 4:1 hexane/EtOAc solution (200 mL) The solution was concentrated and subjected to column chromatography [silica gel; 80:20 hexane/EtOAc, 1% Et 3 N] to afford 1 - (4 - ethynylphenyl)but - 3 - en - 1 - ol ( 169 ) (160.5 mg, 93%) as a clear oil. 142 NMR Studies Experimental 119 Sn NMR, 19 F NMR and 11 B NMR study of one - pot allylation/hydrostannation protocol : It should be noted that monitoring this reaction mixture using NMR proved to be very challenging d ue to the viscosity, heterogeneity, and difficulties in transferring reaction mixtures from reaction flasks to NMR tubes. Performing the entire experiment in an NMR tube without transfer was also problematic most likely due to inefficient mixing. With eit her method, thorough mixing, careful temperature control, and accurate reagent addition were essential to success. In all cases, if the Sn - F species was not observed, the reaction would not produce the desired product. Temperature of a reaction bath was maintained at 35 C by dry ice and a mixture of ethanol (30%) and ethylene glycol (70%). All 119 Sn and 11 B NMR spectra were acquired with a 500 MHz NMR instrument kept at 35 C. To an NMR tube under nitrogen, in the reaction bath, containing toluene - d 8 , were dissolved benzaldehyde ( 148 ) (0.04 mL, 0.375 mmol) and allyltributylstannane ( 135 a ) (0.12 mL, 0.375 mmol) and vortexed. The NMR tube containing the reaction mixture was transferred to the spectrometer, at - 35 C, and 119 Sn NMR was recorded. The NMR tu be was returned to the cold bath, BF 3 2 (0.05 mL, 0.393 mmol) was added, the tube returned to the instrument, and 119 Sn NMR was observed again. B(C 6 F 5 ) 3 (38 mg, 20%) was added in a glove bag under N 2 followed by addition of PMHS (0.05 mL) and 119 Sn NMR was recorded again. 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E., Jr.; Ghosh, B.; Gallagher, W. P.; Baker, A. J.; Muchnij, J. A.; Szymanski, A. L. Tet rahedron 2013 , 69 , 4000 4008. (29) Asao, N.; Yamamoto, Y . Bull. Chem. Soc. Jpn . 2000 , 73 , 1071 1087. (30) Davies, A. G; Organotin Chemistry , 2 nd ed.; Wiley - VCH: Weinheim, Germany, 2004: Chapter 2. (31) Dakternieks, D.; Zhu,H.; Organometallics , 1992 , 11 , 3820 3825. b) Al - Juaid, S. S.; Dhaher, S. M.; Eaborn, C.; Hitchcock, P. B.; Smith, J. D. J. Organomet. Chem . 1987 , 325 , 117 127. c) Plass, W.; Verkade, J. G. Inorg. Chem. 1993 , 32 , 5153 5159. d) Dean, P.A.W.; Evans, D.F. J. Chem. Soc. (A) 1968 , 1154 1166 . (32) a) Carbillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A. Org. Lett. 2001 , 3 , 1165 1167 . b) Wrackmeyer, B. Nuclear Magnetic Resonance Spectroscopy of Boron Compounds Containing Two - , Three - , and Four - Coordinate Boron . In Annual Reports on NMR S pectroscopy; Webb, G.A., Ed.; Academic Press: London, 1988 ; Vol. 20; p 61. (33) Chandrasekhar, S.; Reddy, C. R.; Babu, B. N. J. Org. Chem . 2002 , 67 , 9080 9082. (34) The coupling is ~1450 Hz. Accurate measurement of these couplings is difficult due to the broadness of the peaks. (35) Note: In fact, (Bu 3 Sn) 2 O, an oxygen bound tin species, reacts with PMHS at 35 C to form tributyltin hydride, albeit, at a much slower rate compared to that observed at room temperature. The rate at which (Bu 3 Sn) 2 O forms tri butyltin hydride at 35 C increases a great deal when B(C 6 F 5 ) 3 was added. (36) Lawrence, N. J.; Drew, M. D. Bushell, S. M. J. Chem. Soc., Perkin Trans . 1 , 1999 , 3381 3391. (37) Kim, Y. W.; Labouriau, A.; Taylor, C. M.; Earl, W. L.; Weberlow, L. G . J. P hys. Chem. 1994 , 98 , 4919 4922. (38) a) Feher, F.J.; Soulivong, D.; Lewis, G.T. J. Am. Chem. Soc. 1997 , 119 , 11323 11324. b) For a bridging fluoride, see Panisch, R.; Bolte, M.; Müller, T. J. Am. Chem. Soc. 2006 , 128 , 9676 9682. (39) This last 11 B NMR w as obtained from a kinetic experiment perform by Dr. Ghosh. 147 CHAPTER 4: CARBON - TO - CARBON [1,2] - SILYL MIGRATION IN ALPHA SILYL ALLYLIC ALCOHOLS T R IGGERED BY EPOXIDATION 4.1 Introduction Bond reorganization of - metalated ethers are known as Wittig rear rangements. 1 These reactions can take place via different pathways depending on the nature of the substrate (e.g. symmetrical vs. unsymmetrical ethers, neighboring - systems, etc). Wittig rearrangements can proceed through a concerted, orbital - symmetry all owed [2,3] - sigmatropic pathway ( S cheme 4.1, route A), 2,3 or a stepwise radical/radical - anion pair [1,2] - migration (route B). 4 Deprotonation at the allylic position followed by rearrangement would provide the [1,2] and [1,4] product ( 18 6 and 18 7 ), whereas m etalation at the benzylic position (if R = Ph in 179 ) would lead to the [2,3] product 181 . Therefore, regioselectivity in the deprotonation step is an important factor in charting the synthetic course of Wittig rearrangements. Preparation of substrates capable of efficient [1,2] - migration are limited perhaps by the required radical - stabilization groups (R in 183 ) for facile C O bond homolysis. Another problem is the regioselectivity issue after the radical formation of 183 species from 182 (scheme 4.1), where a mixture of products can be obtained for the competition between the [1,4] - migration and the [1,2] - shift. 5,6 This problem is not observed for the [2,3] - W ittig rearrangement , which has found more synthetic application s due to their remarkable featur es of regioselective carbon - carbon bond formation, generation of specific olefin geometries and transfer of chirality. 2 The last two routes C and D ( S cheme 4. 1) highlight the [1,4] - wittig rearrangement as a unique pathway in the formation of stereodefine d enolates. 7 - 9 There is evidence supporting a 148 stepwise mechanishm (route C), 9.10 however if the orbitals are aligned on a cisoid conformation a concerted process is allowed in some substrates (route D). 1b T he critical factors that favor the [1,4] over the [1,2] pathways or vice versa, are not totally clear. 8,11 - 13 It is known that the [1,4] - shift is favored at lower temperatures, furthermore the nature of the base and base counterion also affect the final product distribution. 9 Conversely, the major influen tial factor seems to be the substrate type that can direct th e rearrangement to one particular pathwa y preferentially over the other. 9,14 But, f ew studies have been done in order to fully address this substrate dependence . 9 Scheme 4.1 Possible Wittig rearrangement pathways of 178 In the quest for a better understanding of the selectivities in [ 1,4] vs [1,2] Wittig rearrangements from earlier studies done in our labs, we explored these rearrangements on small cyclic et hers ( S cheme 4.2). We demonstrated that the transformation of the s e diastereomeric 2 - 149 silyl - 6 - aryl - 5,6 - dihydro - (2 H ) - pyrans ( 1 89 ) was directed by electronic and steric factors. 15 The remark able work done by Dr. Mori showed that the p roper choice of the silyl group or selective olefin substitution, as well the appropriate electron - donating or electron - withdrawing group on the aromatic moiety allow one to direct this ring contractions toward the - cyclopropyl acylsilanes 190 (via [1,4] - Wittig) or - silyl cyclop entenols (via [1,2] - Wittig) 191 with excellent diastereselectivities and in a stereoconvergent fashion. Scheme 4.2 Known Wittig rearrangements of dihydropyrans Even though, the ring contraction of macrocyclic ethers vi a [1,2] - and [2,3] - Wittig rearrangements have been reported by Marshall 16 - 18 and Takahashi, 19 - 21 - ,22,23 the st udy of smaller cyclic ethers is limited to few examples. 8,24 - 28 In particular, the [1,4] - Wittig rearrangement of cyclic allylic ethers was limite d to two examples reported by Rautenstrauch, 8 150 this study showed that isomerization of dihydropyran ( 192 ) and nerol oxide ( 193 ) occur to give the corresponding - cyclopropyl acetaldehydes 194 and 195 (scheme 4.2). The work done by Dr. Mori not only gives us access to novel structures like 190 and 191 , it also shows us that it may be possible to tune this reaction towards the [1,4] or the [1,2] pathway and is what make s this research stand out . Further stereochemical experiments showed that both the [1,4] - an d [1,2] - Wittig rearrangements of such cyclic ethers proceed with high retention of stereochemistry at the migrating center. Final ly deuterium trapping experiments indicated the presence of a common intermediate, leading to the observed stereoconvergence of both isomeri za tion pathways (S cheme 4.3). 15 It was concluded that the primary mechanism of the [1,4] - Wittig reaction in these substrates involves a stepwise process similar to the [1,2] - pathway. Scheme 4.3 [1,4] - and [1 ,2] - Wittig rearrangements of model 2 - silyldihydropyrans As part of our studies on organosilicon compounds we decided to study a series of - silyl allylic alcohols ( 191 ) of the type obtained from the [1,2] - Wittig rearrangements of allyl benzyl 151 ethers ( 18 9 ) with a silyl group at the - allylic position 29 under epoxidizing conditions. Upon treatment of alcohol 20 0 with m - CPBA in the presence of sodium bicarbonate, an interesting rearrangement that involve s a carbon - to - carbon [1,2] - silyl migration was trigger ed ( S cheme 4.4). This novel migration generates - silyl ketone 20 1 via a simple protocol. Scheme 4.4 Novel [1,2] - silyl migration in - silyl allylic alcohols 4.2 Carbon - to - carbon [1,2] - silyl migration The most common 1, 2 - shift of silicon it is the one involving the migration from C to O of the so called Brook rearrangement (see Chapter 1 page 7). A less common and often unexplored transformation is the 1,2 - silyl migration from C to C. The literature examples of such 1,2 - silyl migration are typically triggered by protic acids. 30 Other examples of 1,2 - silyl migrations involve alkynyl silanes or silyl propagylic systems and are catalyzed by Lewis acids 31 and/or transitions metals. 32 However, to the best of our knowlegde 1,2 - silyl migration of - sil yl allylic alcohols to generate - silyl ketones 20 1 has not been reported. Therefore all the structures presented in this study are new organosilicon containing molecules. Al though the substrates employed in this novel protocol ar e racemic alcohols, it seems that the migration of the silyl group occurs in a syn fashion without epimerization of the benzylic 152 position. The s tereoselective epoxidation of the double bond by m - CPBA could be guided by the intramolecular hydrogen bonding i nteraction with the tertiary alcohol (Scheme 4.5). Then t he epoxide opening could be due to ring strain for the formation of an epoxide group next to the cyclopentane framework. This silyl migration appears to be triggered by the release of unfavorable rin g strain and also by steric interactions between the bulky phenyl and trimethylsilyl groups that are syn to one another. Scheme 4.5 Proposed mechanism for carbon - to - carbon [1,2] - silyl migration At this point it is unk nown if this protocol proceed s though a concerted process (epoxide ring opening/silyl migration) or stepwise (epoxide ring opening to give a tertiary carbocation, then silyl migration). A concerted mechanism would involve an intramolecular S N 2 reaction at a quaternary center by a bulky silyl group, which seems unlikely. Therefore a stepwise process is more probable. A s mention ed before previous reports on 1,2 - silyl migration indicate the formation of a carbocation followed by 1,2 - sillyl migration is usually triggered by protic acids. 30 153 4.2.1 S ynthesis of starting materials The preparation of the selected - silyl allylic alcohols [1,2] - Wittig products , was developed and optimiz ed by Dr. Mori. 15 T his route was employed again for the preparation of our st arting materials (Scheme 4.6). The synthesis of the cyclic ethers started with the addition of homoallylic alcohols to trichloroacetonitrile under basic conditions ( 20 4 20 5 ). L ewis acid - catalyzed etherification of - silyl alcohols ( 20 6 ) with the homoally lic trichloroacetimidate ( 20 5 ) yield the bisallylic precursors 20 7 . The - hydroxysilanes 20 6 were prepared by a retro - Brook rearrangement of the in situ generated O - silylated allylic alcohols. The dienes 20 7 were submitted to ring - closing metathesis using the Grubbs 2 nd generation catalyst to afford the cyclic ethers cis 2 08 and trans 2 09 ( S cheme 4.6) . The cyclic ethers were obtained as mixtures of cis/trans diastereomers from diastereomeric 20 7 or as a single d iastereomer from either syn or anti - 20 7 via r ing closing metathesis. The cis/trans cyclic ethers were completely separable by column chromatography. Finally the isolated cis 2 08 and trans 209 were subjected to the Wittig rearrangement conditions to yield the [1,4] ( 2 10 ) and [1,2] ( 21 1 ) products ( S che me 4.7). As with previous examples 15 the trans cyclic ethers rearrange d more quickly and efficiently than the cis. Also electron - donating groups on the aromatic moiety favor ed the [1,4] - shift ( E ntry 1, T able 4.1) while electron - withdrawing groups favor ed the [1,2] - pathway. Therefore all the substrates selected for these studies on silyl migration were those w h ere the [1,2] - Wittig products were major ( E ntry 2 to 4, T able 4.1). 154 Scheme 4.6 Synthesis of cyclic ethers 208 an d 209 Scheme 4.7 Synthesis of [1,4] and [1,2] - Wittig rearrangement products 155 Table 4.1 Wittig rearrangement of t rans - disubstituted pyrans for selected substrates 15 P lacing an alkyl subs tituent on the double bond proximal to the silicon group afforded exclusively the [1,2] - Wittig products, even when para positioned electron - donating groups on the Ar moeity were present ( E ntries 3 - 6, T able 4.2). 15 This is in contrast to previous observatio n s where R 2 = H, in which [1,4] - Wittig were favored in the presence of para electron - donating substituents. 15 Once again the trans diastereomers were more reactive and higher yielding than the cis isomers in these reactions. T hus some of these trans substr ates were selected for the 1,2 silyl migrations studies. 156 Table 4.2 Effect of substitution at the double bond 15 Finally the following starting materials were selected to undergo the 1,2 - silyl migration (Scheme 4.8). A s mention before they were obtained as the major product of the Wittig rearrangements and most of these compound were isolated as white solids . During the preparation of these substrates a crystal structure of the 2 - napthyl derivative ( 222 ) was obtained, c onfirming our relative stereochemical assignment. 15 157 Scheme 4.8 Selected starting materials for 1,2 - silyl migration 4. 3 Results and discussion S cheme 4.9 shows the product s obtained by this novel carbon - to - carbon [1, 2] - silyl migration. Upon treatment of the selected [1,2] - Wittig products with m - CPBA in the presence of sodium bicarbonate , the cyclopentanone derivatives were obtained. The reactions were run for up to 30 min at room temperature using dichloromethane as a solvent. The yields ranged from moderated to high (70% to 92%) and in some cases purification by column chromatography w as not necessary. 158 Scheme 4.9. Carbon - to - carbon [1,2] - silyl migration Even though the cyclopentanon e products contain a hydroxyl group and R 3 Si unit next to each other on the cyclopentanone framework ( - hydroxysilanes), an expected loss of th e silicon group via a Peterson o lefination 33 was not observed. Usually under diluted acid conditions or Lewis aci d these type of substrates undergo a stereospecific anti - elimination (E2) to afford an alkene. When the hydroxyl group and silyl moiety are syn to each other , basic conditions are required for a syn - elimination via the formation of an oxasiletadine interme diate. 33 The latter scenario is not possible for our substrates because the hydroxyl group and the R 3 Si unit are anti to each other. In our hands the cyclopentanone compounds were stable during purification and isolation. However several months after stor age under freezing conditions, a 1 H NMR was 159 retaken in order to check the stability o f the cyclopentanones products. U nfortunately loss of the SiR 3 was observed in all the products, and the NMR show complicated mixtures. A notable case was the rearran gement of a cyclopentanol substrate where the silyl group was trans to the phenyl group ( 223 ). Even though the yield was lower than other examples, the substrate under went the [1,2] - silyl migration and no epimerization was observed (scheme 4.10). This resu lt suggested that the position of the phenyl group does not determine the stereochemistry of this reaction, instead the position of the tertiary allylic alcohol dominates this transformation promoting a stereoselective epoxidation presumably guided by inte rmolecular hydrogen bonding interaction. Scheme 4.10 [1,2] - silyl migration of 223 as a single diastereomer 4.4 Conclusions A novel carbon - to - carbon [1,2] - silyl migration was discovered. This migration was triggered by epoxidation of the olefin present in the [1,2] - Wittig product (1 - silylcyclopent - 2 - en - 1 - ol structures). The new cyclopentanones obtained feature a silyl group located at the position of the carbonyl. There are no reports of similar cyclic stru c tures . F urthermore, substitution at the double bond leads to more stable materials, threfore the purification process of those products in some cases does not require column chromatography. 160 Finally this migration was not affected by the different SiR 3 groups e mployed (R = Me, Et or Me 2 Ph) or by the aryl group being cis or trans to the silyl group. We believe that the stereochemistry of this reaction is determine by the position of the terti ary allyli c alcohol, thus promoting a sterereoselective epoxidation guid ed by intermolecular hydrogen bonding interaction s . 4.5 Experimental section All reactions were run under a positive atmosphere of nitrogen in oven - dried or flame - dried round bottom flasks or disposable drum vials capped with rubber septa. Solvents were removed by rotary evaporation at temperatures lower than 45 ºC. Column chromatography was run on silica gel 60 Å ( 230 400 mesh ASTM) . Tetrahydrofuran and diethyl e ther were distilled from sodium and benzophenone under nitrogen ; dichloromethane, benzene, di isopropylamine, triethylamine and trimethylsilyl chloride were distilled from calcium hydride. Hexane and cyclohexane were used as r eceived. Triethylsilyl chloride and dimethylphenylsilyl chloride, were used as received. Methyllithium (1.4 M in diethyl eth er), n - butyllithum (1.6 M in hexanes), sec - butyllithium (1.4 M in cyclohexane) were titrated with diphenylacetic acid (average of three runs). 1 H NMR spectra was collected in 500 MHz and 600 MHz instruments using CDCl 3 as solvent, which was referenced at 7 .24 ppm (residual chloroform proton) and 13 C NMR spectra was collected in CDCl 3 at 126 MHz or 151 MHz and referenced at 77 ppm. Yield refer to chromatographically and spectroscopically pure compounds unless otherwise mentioned. 161 General conditions for [ 1,2] - silyl migration To a solution of the corresponding - silyl allylic alcohol (0.2 mmol) in dichloromethane ( 2 mL) was added NaHCO 3 ( 1.2 equiv) followed by m - CPBA ( 77% w/w, 1.1 equiv) . The reaction mixture was stir for 30 min at room temperature. The re action was followed by TLC (typically 5% EtOAc in hexanes) using triethylamine pre - washed plates. After completion (typically 30 min), the reaction was diluted with CH 2 Cl 2 (5 mL) and extracted twice with NaHCO 3 (2 x 5 mL). The aqueous phase was extracted w ith CH 2 Cl 2 (3 mL). Combined organic extracts were washed with Brine, dried over MgSO 4 , filtered and concentrated by rotary evaporation . Finally the residue was purified by silica gel column chromatography (typically 5% EtOAc in hexanes) buffered with ~1% t riethylamine. Experimental details and spectroscopic data: Following the general procedure to the - silyl allylic alcohol 200 (15.7 mg, 0.064 mmol, 1 equiv), m - CPBA (77% w/w, 15.72 mg, 0.0701, 1.1 equiv) and NaHCO 3 (6. 43 mg, 1.2 equiv) afforded after column chromatography (10% EtOAc in hexanes) 14 mg (83%) of 201 as a white solid. 1 H NMR (500 MHz, CDCl 3 ) 7.27 (m, 4 H), 7.21 (m, 1 H), 4.5 6 (m, 1 H), 3.76 (dd, J = 8.5 , 12. 5 Hz, 1 H), 2. 50 (ddd, J = 1.2 , 8.4, 13.8 H z, 1 H), 2.40 (ddd, J = 4.2, 12.6, 13.8 Hz, 1 162 H), 1.73 (s, 1 H), 1.28 (s, 3 H), 0.04 (s, 9 H). 13 C NMR ( 125 MHz, CDCl 3 (2 C), 127.8 (2 C), 126.7, 72.5, 50.7, 50.1, 36.7, 13.8, - 2.3. Following the general procedure to the - silyl allylic alcohol 22 0 ( 40 mg, 0.150 mmol, 1 equiv), m - CPBA (77% w/w, 36.97 mg, 0. 165 mmol , 1.1 equiv) and NaHCO 3 ( 15 . 12 mg, 1.2 equiv) afforded after column chromatography (20% EtOAc in hexanes) 35.3 mg ( 83 %) of 22 6 as a whit e solid . 1 H NMR (500 MHz, CDCl 3 31 ( d , J = 8.5 Hz 2 H), 7. 17 ( d , J = 8.5 Hz, 1 H), 4.71 (d, J = 4.0 Hz, 1 H), 3.8 1 (dd, J = 8.5 , 12. 2 Hz, 1 H), 2.51 (m, 1 H), 2.3 2 (m, 1 H), 2. 28 (dt, J = 4.0, 13.5 Hz, 1 H), 1. 26 (s, 1 H), 0.1 3 (s, 9 H). Follow ing the general procedure to the - silyl allylic alcohol 221 (26.5 mg, 0.0 86 mmol, 1 equiv), m - CPBA (77% w/w, 21.18 mg, 0.0 94 , 1.1 equiv) and NaHCO 3 ( 8.66 mg, 1.2 equiv) afforded after column chromatography ( 2 0% EtOAc in hexanes) 25 mg ( 90 %) of 2 27 as a wh ite solid. 1 H NMR ( 5 00 MHz, CDCl 3 5 H), 7.41 (t, J = 7.8 Hz, 2 H), 7. 28 (m 2 H), 4.71 163 (d, J = 4.2 Hz, 1 H), 3.86 (dd, J = 8.4, 12.6 Hz, 1 H), 2.53 (m, 1 H), 2.36 (dt, J = 4.2, 13.2 Hz, 1 H), 2.31 (m, 1 H), 1.25 (s, 1 H), 0.15 (s, 9 H). 13 C NMR (1 25 MHz, CDCl 3 139.8, 136.3, 128.7 (2C), 128.4 (2 C), 127.3 (2 C), 127.1, 127.0 (2 C), 70.5, 54.0, 51.0, 39.2, - 1.5. Following the general procedure to the - silyl allylic alcohol 222 (25 mg, 0.077 mmol, 1 equiv), m - CPBA (77% w/w, 18. 98 mg, 0.084 mmol, 1.1 equiv) and NaHCO 3 (7.76 mg, 1.2 equiv) afforded after column chromatography (20% EtOAc in hexanes) 20.7 mg (79%) of 228 as a white solid. 1 H NMR (500 MHz, CDCl 3 - 7.82 (m, 3 H), 7.65 (s, 1 H), 7.5 - 7.40 (m, 3 H), 4.80 (m, 1 H), 3.80 (m, 1 H), 3. 49 (m, 1 H), 2. 62 (m, 1 H), 2. 50 (m, 1 H), 1.80 (s. 1 H), 0.89 (t, J = 8.0 Hz, 9 H), 0.70 (dq, J = 1.5, 8.0 Hz, 6 H). Following th e general procedure to the - silyl allylic alcohol 224 (15 mg, 0.046 mmol, 1 equiv), m - CPBA (77% w/w, 11.25 mg, 0.05 mmol, 1.1 equiv) and NaHCO 3 (4.60 mg, 1.2 equiv) afforded after column chromatography (20% EtOAc in hexanes) 11 mg (70%) of 229 as a white 164 solid. 1 H NMR ( 5 00 MHz, CDCl 3 7.44 (m, 3 H), 7. 36 (m, 2 H), 7. 18 ( d , J = 8.0 , 2 H), 6.75 (d, J = 8.0 Hz , 2 H), 4.70 (d, J = 3.5 Hz, 1 H), 3.71 (ddd, J = 1.8, 3.0, 6.5 Hz, 1 H), 3.50 (ddd, J = 1.2, 2.4, 6.5 Hz, 1 H), 2.4 9 ( m , 1 H), 2.31 (m, 1 H), 1.96 (d t, J = 4.0 , 13.5 Hz, 1 H), 1. 56 (s, 1 H), 0.50 (s, 3 H), 0. 46 (s, 3 H). Following the general procedure to the - silyl allylic alcohol 22 5 ( 50 mg, 0. 181 mmol, 1 equiv), m - CPBA (77% w/w, 44.62 mg, 0. 199 mmol , 1.1 equiv) and NaHCO 3 ( 1 8. 25 mg, 1.2 equi v) afforded after column chromatography (20% EtOAc in hexanes) 48.6 mg ( 92 %) of 2 30 as a white solid. 1 H NMR (500 MHz, CDCl 3 22 (d , J = 8.5 Hz, 2 H), 6 . 88 ( d , J = 8.5 Hz, 2 H), 4. 56 (d, J = 4. 0 Hz, 1 H), 3.80 (s, 3H), 3. 72 (dd, J = 8.5 , 13 Hz, 1 H), 2. 50 (d dd , J = 1.5, 8.9 , 13. 5 Hz, 1 H), 2.3 8 ( ddd , J = 4.5, 10.5, 13 Hz 1 H), 1.30 (s, 3 H), 1.27 (s, 1H) 0. 07 (s, 9 H). Following the general procedure to the - silyl allylic alcohol 223 (40 mg, 0.163 mmol, 1 equiv), m - CPBA (77% w/w, 40.12 mg, 0.1790 mmol , 1.1 equiv) and NaHCO 3 (16.37 mg, 1.2 equiv) afforded after column chromatography (20% EtOAc in hexanes) 22.1 mg (52%) of 231 as a white solid. 1H NMR ( 5 00 (m, 1 H), 3.42 165 (dd, J = 8.5 , 9.7 Hz, 1 H), 2.7 9 (ddd, J = 5.4, 9.7, 13.8 Hz, 1 H), 2.23 (ddd, J = 5.0, 8.5 , 13. 8 Hz, 1 H), 1.6 0 (s, 1 H), 1.27 (s, 3H), 0.17 (s, 9 H). 13 C NMR (151 MHz, CDCl 3 , 128.6 (2 C), 128.5 (2 C), 126.7, 72.8, 53.9, 51.2 , 38.6, 12.2, - 3.6. 166 REFERENCES 167 REFERENCES (1) (a) Mikami, H.; Nakai, T. Org. React. 1994 , 46 , 105 209. (b) Marshall, J. A. In Comprehensive Organic Synthesis ; Patte nden, G., Ed.; Pergamon: London, 1991 ; Vol. 3, pp 975 1014. (2) Nakai, T.; Mikami, K. Chem. Rev. 1986 , 86 , 885 - 902. (3) Nakai, T.; Tomooka, K. Pure Appl. Chem. 1997 , 69 , 595 - 600. . (4) Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. Recl. 1997 , 1275 - 12 81. 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