To the Graduate Council: I am submitting herewith a dissertation written by Michael Patrick Quinn entitled “Boron and Titanium(IV) Halide Mediated Reactions.” I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Organic Chemistry. George W. Kabalka, Major Professor We have read this dissertation and recommend its acceptance: __Shane Foister __Ziling (Ben) Xue __Paul Dalhaimer Accepted for the Council: _ Carolyn R. Hodges _ Vice Provost and Dean of the Graduate School BORON AND TITANIUM(IV) HALIDE MEDIATED REACTIONS A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Michael Patrick Quinn August 2010 DEDICATION To my best friend and wife, Amber, Thank you for all the support during this process, You have been a tremendous source of strength and advice, I could not have done this without your help. ACKNOWLEDGMENTS I would first like to acknowledge my advisor, Dr. George W. Kabalka. Thank you for all the support you have shown me over the past several years. Working with you has been a privilege and there are not enough words to express my gratitude. I would also like to acknowledge Dr. Min-Liang Yao. Thank you for your insight and help over the past years, again, there are not enough words to express my gratitude. I would also like to thank my committee members; Dr. Shane Foister, Dr. Ziling (Ben) Xue, and Dr. Paul Dalhaimer. Great teachers do more than convey subject matter; they inspire us with enthusiasm, motivate with optimism, offer true support when needed, and provide us with the right questions. Therefore, I would like to express my gratitude to the Faculty of the Chemistry Department at the University of Tennessee. It has been a pleasure to work and learn with you. I would also like to specifically thank Dr. Ron Magid and Dr. George Schweitzer who were not only instrumental in developing my interest in pursuing a career in chemistry but provided the recommendations to do so. I would also like to express my sincerest thanks to the Kabalka Group. There is not enough paper nor time for me to truly express my how truly great it has been, thank you Kelly Hall, Li Yong, Travis Quick, Adam Pippin, Coltuclu Vitali, Thomas Moore, and David Blevins. I would also like to thank Brad Miller and Josh Abbott for all their help in making ACGS a better organization and for all the fun we had while doing it. To all my other friends who made this one of the best experiences of my life thus far, thank you. Finally, I am deeply grateful to my wife and family. Without your support, this goal might not have been realized. I would also like to express my sincerest gratitude to God. Thank you. ABSTRACT This dissertation summarizes research efforts focused on the use of boron and transition metal halides to form new carbon-carbon and carbon-halide bonds. The boron halide mediated alkyne-aldehyde coupling reaction to generate 1,3,5-triaryl-1,5-dihalo-1,4-dienes was reinvestigated in an attempt to explain the stereochemistry observed during changing of both the mode of addition and the reaction temperature. Either (Z,Z)-1,4-dienes or (Z,E)-1,4-dienes can be the predominant product depending on reaction conditions used. This mechanistic investigation also led to the discovery of several novel reactions. These include the stereoselective preparation of (Z)-3-chloroallylic ethers from the reaction of alkenylboron dichlorides with aryl aldehydes in the presence of an amine; the titanium(IV) halide coupling of alkoxides and alkynes; the haloallylation of aryl aldehydes with boron trihalide using different allylmetals; and the base induced elimination of the haloallylated products to form 1,3-dienes. The results of these studies strongly imply a cationic mechanism. The new reactions described herein can be characterized as atom-efficient, environmentally friendly, and capable of generating the desired products in good to excellent yields. TABLE OF CONTENTS 1Chapter 1. Lewis Acids in Organic Synthesis 1.1 Scope of this Dissertation 1 1.1.1 Historical Aspects of Boron and Transition Metal Halides in Organic Synthesis 1 1.1.2 Reactions of Boron Trihalides in Organic Chemistry 2 1.1.3 Reactions of Titanium(IV) Halides in Organic Chemistry 5 1.2 Alcohol Functional Group Conversion 7 1.3 Synthesis of Alkenyl Halides and Alkenylation of Carbonyl Groups 7 1.4 Allylation of Carbonyl Compounds 10 1.5 Boron Trihalide Haloboration of Alkynes 11 1.6 Statement of Problem 13 Chapter 2. Reaction Pathways Involved in Boron Trichloride Mediated Alkyne-Aldehyde Coupling under Varying Reaction Conditions 14 2.1 Introduction 14 2.2 Results and Discussion 16 2.3 Conclusions 22 2.4 Experimental 22 2.4.1 General Methods 22 2.4.2 Typical Reaction Procedure 23 2.4.3 Characterization of Compound 3 23 Chapter 3. Stereoselective Preparation of (Z)-3-Chloroallylic Ethers: The reaction of Alkenylboron Dichlorides with Aryl Aldehydes in the Presence of Amine 24 3.1 Introduction 24 3.2 Results and Discussion 25 3.2.1 Generation of (Z)-3-Chloroallylic Alcohols 25 3.2.2 Allyltrimethysilane 28 3.2.3 (Z)-3-Chloroallylic Ethers 29 3.3 Conclusions 31 3.4 Experimental 32 3.4.1 General Methods 32 3.4.2 Typical Reaction Procedure for (Z)-3-Chloroallylic Alcohol 32 3.4.3 Typical Reaction Procedure for (Z)-3-Chloroallylic Ether 33 3.4.4 Characterization of Compounds 34 3.4.5 Representative NMR Spectra of 3and 4a-4g 36 Chapter 4. Titanium(IV) Halide Mediated Coupling of Alkoxides and Alkynes: An Efficient and Stereoselective Route to Trisubstituted (E)-Alkenyl Halides 52 4.1 Introduction 52 4.2 Results and Discussion 53 4.3 Conclusions 58 4.4 Experimental 58 4.4.1 General Methods 58 4.4.2 Representative Procedure for the Synthesis of (E)-Alkenyl Chlorides (1a -1l) 59 4.4.3 Representative procedure for the syntheses of (E)-Alkenyl Bromides (2a-2g) 59 4.4.4 Characterization of Compounds 1a-1l and 2a-2g 60 4.4.5 Representative NMR Spectra of 1a-1l and 2a-2g 65 Chapter 5. Boron Trihalide Mediated Haloallylation of Aryl Aldehydes using Allylsilane Compounds 103 5.1 Introduction 103 5.2 Results and Discussion 106 5.3 Conclusions 112 5.4 Experimental 113 5.4.1 General Methods 113 5.4.2 Typical Reaction Procedure 113 5.4.3 Reaction Procedure for Haloallylation of Aryl Aldehydes using (2-Bromoallyl)trimethylsilane 114 5.4.4 Characterization of Compounds 2a-2n 114 5.4.5 Representative NMR Spectra 118 Chapter 6. Boron Trihalide Mediated Haloallylation of Aryl Aldehydes using Allylmetal Compounds 138 6.1 Introduction 138 6.2 Results and Discussion 140 6.3 Conclusions 144 6.4 Experimental 144 6.4.1 General Methods 144 6.4.2 Typical Reaction Procedure for Haloallylation of Aryl Aldehydes using Allyltriethylgermane 145 6.4.3 Typical Reaction Procedure for Haloallylation of Aryl Aldehydes using Allyltriphenylstannane 145 6.4.4 Characterization of Compounds 1a - 1l and 2a - 2k . 146 6.4.5 Representative NMR Spectra of 1a - 1m and 2a - 2k 151 Chapter 7. A Two-pot Reaction Sequence to Aryl Dienes Based on a Boron Halide Mediated Haloallylation Followed by an Elimination using 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) 161 7.1 Introduction 161 7.2 Results and Discussion 162 7.2.1 Generation of Aryl Dienes from Haloallylation of Aryl Aldehydes 162 7.2.2 Generation of Aryl Trienes from Haloallylation of Aryl Aldehydes 166 7.3 Conclusions 168 7.4 Experimental 169 7.4.1 General Methods 169 7.4.2 Typical Reaction Procedure for Aryl Dienes and Trienes 169 7.4.3 Procedure for One Pot Formation of (E)-4-(buta-1,3-dien-1-yl)-N,N- dimethylaniline 170 7.4.4 Characterization of Compounds 1a - 1j, 2, and 5a - 5b. 171 7.4.5 Representative NMR Spectra of 1a - 1j, 2, and 5a-5b 174 LIST OF REFERENCES 190 Appendix A 206 Appendix B 212 VITA....... 217 LIST OF TABLES 20Table 2-1 The influence of reaction temperature on the ratio of isomers.a Table 2-2 Chemical Shift and Coupling Constants for Vinyl, Benzylic Proton and Benzylic Carbon. 21 Table 3-1 Efficiency of Addition of Triethylamine in Controlling (Z)- 3-Chloroallylic Alcohol Formation.a 26 Table 3-2 Generation of (Z)-3-chloroallylic Ethers.a 30 Table 4-1 Titanium (IV) Mediated Coupling of Alkoxides with Alkynes.a 56 Table 4-2 Titanium(IV) Bromide Mediated Coupling of Alkoxides with Alkynes.a 57 Table 5-1 Haloallylation of Aryl Aldehydes.a 107 Table 5-2 Haloallylation of Aryl Aldehydes using 2-Bromoallyltrimethylsilane Resulting in 1,3-Dihaloallylated Products.a 112 Table 6-1 Haloallylation of Aryl Aldehydes with Allyltriethylgermane.a 141 Table 6-2 Haloallylation of Aryl Aldehydes with Allyltriphenylstannane.a 143 Table 7-1 A Two-pot Reaction Sequence to Gernerate Aryl Diene.a 165 Table 7-2 Synthesis of Trienes.a 168 LIST OF FIGURES 19Figure 2-1 Chromatogram of isomers resulting from the addition of boron trichloride to a mixture of two equivalents of phenylacetylene and one equivalent of p-bromobenzaldehyde at 21Figure 2-2 X-Ray Crystallography of 3 (see Appendix A for crystal data). 27Figure 3-1 Time Elapsed Rearrangement of (Z)-1-(4-bromophenyl)-3-chloro-3-phenylprop-2-en-1-ol; Spectrum 1 is of the isolated (Z)-1-(4-bromophenyl)-3-chloro-3-phenylprop-2-en-1-ol, Spectrum 2 is the spectrum of the rearranged, and Spectrum 3 is the spectrum of the rearranged product after addition of deuterium oxide. 55Figure 4-1 X-Ray Crystallography of 1d (see Appendix B for crystal data). LIST OF SCHEMES 3Scheme 1-1 Boron Halide Induced Reactions of Aldehydes: (1) Dihalogenation, (2) Haloalkylation, (3) 1,3-Dihalo-1,3-diarylpropanes, (4) 3-Chloro-1,3-diarylpropanols, (5) Dialkenylation, and (6) Haloallylation. Scheme 1-2 Dihalogenation of Aromatic Aldehydes. 4 Scheme 1-3 TiCl4 Mediated Reactions forming Carbon-Carbon Bonds. 5 Scheme 1-4 TiCl4 Assisted Reaction of Oxyaldehydes with Allylsilanes. 6 Scheme 1-5 Transition Metal Halide Reactions. 7 Scheme 1-6 Reaction of β-Oxido Phosphonium Ylides with Electrophilic Halogen to Generate E-Halogen Substituted Alkenes. 8 Scheme 1-7 Modified Julia Olefination between α-Halomethyl Sulfones and Aldehydes to Yield Alkenyl Halides with High E/Z Stereoselectivities. 8 Scheme 1-8 Modified Nozaki-Hiyama-Kishi Reaction. 9 Scheme 1-9 Lewis-acid Assisted Allylation of Carbonyl Compounds to form Homoallylic Alcohols. 10 Scheme 1-10 [2,3] Wittig Rearrangement 11 Scheme 1-11 Haloboration of Alkynes. 12 Scheme 1-12 Bromoboration of Acetylene. 12 Scheme 2-1 Formation of (Z,Z)-1,5-Dichloro-1,4-pentadiene vs Grignard-like Addition. 14 Scheme 2-2 Reaction of Aldehyde with (Z,Z)-Di(chlorovinyl)boron Chloride. 16 Scheme 2-3 Reaction of an Aldehyde with Two Equivalents of Z-Chlorovinylboron Dichloride. 17 Scheme 2-4 BCl3-Mediated Coupling of Aryl Aldehydes and Alkynes. 18 Scheme 2-5 Lewis Acid Boron Trichloride Initiated Alkyne-Aldehyde Coupling. 20 Scheme 3-1 Formation of (Z)-2-Chloro-1-alkenylboron Dichloride. 25 Scheme 3-2 Plausible Mechanism for (Z)-3-chloroallylic Alcohol Rearrangement. 28 Scheme 3-3 Allylation of Alkenylboroloxy Dichloride Amine Intermediate. 29 Scheme 4-1 Stereochemical Modification via Modificaton of Reagent Addition Sequence. 52 Scheme 4-2 Lewis Acid Induced Coupling Reaction. 54 Scheme 4-3 Proposed Reaction Mechanism. 58 Scheme 5-1 Process of Lewis Acid Addition to Allyltrimethylsilane and an Aldehyde. 103 Scheme 5-2 Direct Substitution of Hydroxyl Groups with Stereodefined Alkenyl and Alkynyl Moieties using Boron Dihalides. 104 Scheme 5-3 Allyltrimethylsilane Addition to a Propargyloxyboron Dihalide. 105 Scheme 5-4 Formation of Dichloro- and Chloroallylated Compounds from Aryl Aldehydes. 105 Scheme 5-5 Chemoselective Bromoallylation of p-Chlorobenzaldehyde in the Presence of Equimolar Amounts of Boron Trihalide. 106 Scheme 5-6 Determination of Catalytic Nature of Reaction by Addition of Substoichiometric Amount of BX3. 109 Scheme 5-7 Experimental Illustration of Me3SiCl Removal. 109 Scheme 5-8 Proposed Mechanistic Pathway for Formation of Haloallylated Product (2) from Intermediate 3. 110 Scheme 5-9 Haloallylation of Aryl Aldehydes with 2-Bromoallyltrimethylsilane. 111 Scheme 5-10 Proposed Mechanistic Pathway for (1,3-Dichlorobut-3-en-1-yl)benzene Compounds. 111 Scheme 6-1 Stereochemistry of the Electrophilic Addition of Allyl Metals. 139 Scheme 6-2 Regioselective Allylation of Electrophiles with Allylmetals: Generation of Carbenium Ion. 139 Scheme 7-1 Haloallylation of 4-Chlorobenzaldehyde. 162 Scheme 7-2 One Pot Formation of Diene. 166 Scheme 7-3 Haloallylation of α-Halocinnamaldehydes. 166 LIST OF SYMBOLS AND ABBREVIATIONS OAc Acetate ( Alpha Anal. Calcd Analytical Calculated Å Angstrom Bn Benzyl ( Beta 9-BBN 9-Borabicyclo[3.3.1]nonane n-BuLi Butyl lithium Cat. Catalyst C Celsius DCM Dichloromethane J Coupling constant ( degrees CDCl3 Deuterochloroform d doublet dd doublet of doublets dt doublet of triplets Equiv. Equivalents Et Ethyl Et2O Diethyl ether OTf Trifluoromethanesulfonate g grams Hz Hertz h hours THF Tetrahydrofuran MHz Megahertz Me Methyl OTs 4-Methylbenzenesulfonate TMS Tetramethylsilane (m micrometer mg milligram mL milliliter mmol millimole min minutes M Molar m multiplet NMR Nuclear Magnetic Resonance Ph Phenyl PhLi Phenyl lithium n-Pr Propyl q quartet s singlet t triplet Chapter 1. Lewis Acids in Organic Synthesis 1.1 Scope of this Dissertation This dissertation focuses on Lewis acid (boron trihalide and titanium(IV) halide) mediated reactions involving alcohols, alcoholates, alkynes, and aldehydes. Several novel reactions have been developed. These include: (1) alkyne-aldehyde coupling reactions induced by boron trihalides; (2) titanium (IV) mediated coupling of alkoxides with alkynes; and (3) haloallylation of aryl aldehydes induced by boron trihalides in the presence of different allylmetals. Numerous applications of these novel reactions have been developed. These include the base mediated elimination of the haloallylated products to yield (E)-1,3-dienes and the preparation of (Z)-3-chloroallylic ethers resulting from the coupling of alkynes and aryl aldehydes. The discussion in the present chapter includes historical developments involving the use of the Lewis acids boron trihalide and titanium(IV) halide in organic synthesis as well as reactions pertaining to alkenylation and allylation of carbonyl compounds. Subsequent chapters contain discussions of the significance of these novel reactions as they relate to the literature and will provide mechanistic insights into these newly discovered reactions. 1.1.1 Historical Aspects of Boron and Transition Metal Halides in Organic Synthesis A Lewis acid is a chemical substance that can accept a pair of electrons from an electron pair donor (Lewis base), a concept named for American physical chemist Gilbert Norton Lewis.1 In valence bond formalism, trivalent boron reagents are Lewis acids because their valence shell is electron deficient, whereas, a Lewis base is electron rich. Chemistry occurs between the two because the acceptance of electrons by the Lewis acid completes a full octet of electrons in the outer valence shell, resulting in the formation of a new bond. The Lewis acidic strength of boron trihalides increases as the halide becomes larger and less electronegative,2-3 counterintuitive on the basis of the relative (-donor strengths of the halide ions. This discrepancy is explained by the overlap of a filled p-orbital on the halogen with the empty p-orbital on the boron that will be used to form a σ-bond.4 The p-orbital overlap between B-F is large and strong, whereas, p-orbital overall in a B-I bond is negligible. This explains the increased Lewis acidity of BI3. In transition metal Lewis acids, the more electron deficient or smaller dn configurations are stronger Lewis acids than those with higher dn configurations. Since titanium(IV) chloride and bromide form d0 complexes, they are strong Lewis acids as compared to copper(II) chloride, a d9 complex. 1.1.2 Reactions of Boron Trihalides in Organic Chemistry The synthetic applications of the boron trihalides have been known for over half a century.5-6 Ether cleavage by boron trihalides is a well-known reaction and widely used since reaction conditions are mild and the reactions proceed with high regio- and chemoselectivity.7-8 Other applications include the cleavage of acetals and esters,9-10 stereoselective glycosidation of glycols under mild conditions,11 Aldol reactions,12-13 Friedel-Crafts alkylation and acylation reactions, 14-15 ADDIN EN.CITE Diels-Alder reactions, ADDIN EN.CITE 16-17 and other acid-induced reactions including rearrangements18 and cyclizations.19 In recent years, the Kabalka group has developed several novel reactions using boron halide Lewis acids as depicted in Scheme 1-1. ADDIN EN.CITE 20-26 These reactions serve as the background for the research presented in this dissertation. O Cl Cl R Cl X OH X X X Cl X BCl 3 ,Hex, BX 3 , BX 3 ,2equiv RBCl 2 ,O 2 BX 3 , PhBCl 2 , Ar Ar Ar TMS (1) (6) (5) (2) (3) (4) X=Cl(E,Z) X=Br(Z,Z) Z Z Z Z Z Z Z Z Y Y Scheme 1-1 Boron Halide Induced Reactions of Aldehydes: (1) Dihalogenation, (2) Haloalkylation, (3) 1,3-Dihalo-1,3-diarylpropanes, (4) 3-Chloro-1,3-diarylpropanols, (5) Dialkenylation, and (6) Haloallylation. At elevated reaction temperatures, the dihalogenation of aromatic aldehydes with BCl3 occurs to form aryl dichloromethanes (Eq (1), Scheme 1-1). Based on a NMR study, the reaction proceeds through a benzyloxyboron dichloride intermediate that was the first indication that C-O bond cleavage occurs when boron trihalides coordinate with carbonyl groups as shown in Scheme 1-2.27 CHO Cl OBCl 2 Cl Cl Z Z Z BCl 3 Hexanes 9examples 76-99% Scheme 1-2 Dihalogenation of Aromatic Aldehydes. The reaction of dialkylboron chloride with aryl aldehydes in the presence of oxygen was found to produce excellent yields of alkylarylmethanols.28 To increase atom economy, the use of monoalkylboron dichlorides was investigated and the reaction produced chloroalkylation products exclusively at room temperature (Eq (2), Scheme 1-1).29 The Grignard-like alkylation of aldehydes and ketones using organoborane reagents offers several synthetic advantages that include mild reaction conditions normally not associated with more commonly used organometallic reagents including a tolerance of functional groups. The haloboration of styrenes using boron trihalides regioselectively produces diastereomeric mixtures of 1,3-dihalo-1,3-diaryl-propanes from aryl aldehydes (Eq. (3), Scheme 1-1). During examination of this reaction, the detection of chloroalcohols prompted an investigation into their synthesis. It was determined that if phenylboron dichloride was used instead of boron trichloride, anti-β-chloroalcohols were regioselectively produced in good to excellent yields (Eq (4), Scheme 1-1).22 The dialkenylation and haloallylation of aryl aldehydes (Eq (5) and (6), Scheme 1-1) will be discussed in further detail in subsequent chapters, however, a brief review of alkenylation and allylation reactions is presented in this chapter. 1.1.3 Reactions of Titanium(IV) Halides in Organic Chemistry The titanium(IV) halides have been extensively studied and are useful reagents in organic synthesis. 30-32 ADDIN EN.CITE The use of titanium(IV) halides to selectively form new carbon-carbon bonds has been demonstrated in a multitude of reactions, including Aldol condensations, 33-36 ADDIN EN.CITE Claisen condensations, 37-39 ADDIN EN.CITE and alkynylations of carbonyl compounds.40 A few select examples of these reactions are provided in Scheme 1-3. Ph O SiMe 3 O Ph O OH CO 2 Me CO 2 Me O CO 2 Me TiCl 4 70-74% TiCl 4 ,NEt 3 Me 3 SiOTf 91% AldolCondensation ClaisenCondensation Alkynylation Et CHO Me Ph SnBu 3 TiCl 4 Et Me OH Ph Et Me OH Ph 71 : 29 70% Scheme 1-3 TiCl4 Mediated Reactions forming Carbon-Carbon Bonds. The reaction of titanium(IV) chloride with an allylmetal was first reported by Hosomi and Sakurai41 to yield homoallylic alcohols from aldehydes. The versatility of homoallylic compounds has generated tremendous interest in organic synthesis.  Their preparation from aldehydes, ketones, mixed acetals ,and α-keto esters have been investigated using titanium(IV) chloride assisted allylation. 42-52 ADDIN EN.CITE Perhaps more important is the diastereoselective allylation of carbonyl and related compounds with allylsilanes mediated by TiCl4. A fundamental method used for the construction of stereogenic centers is the allyl addition to α- or β-oxyaldehydes in the presence of TiCl4.53-54 Examples are provided in Scheme 1-4. CHO OBn SiMe 3 TiCl 4 OH OBn 98-99%de OBn CHO Me SiMe 3 TiCl 4 OBn Me OH OBn Me OH 15 : 1 58-74% Scheme 1-4 TiCl4 Assisted Reaction of Oxyaldehydes with Allylsilanes. Titanium(IV) chloride is also used in Claisen rearrangements,55 Baylis-Hillman, 56-63 ADDIN EN.CITE and Friedel-Crafts 64-66 ADDIN EN.CITE reactions as well as organic functional group transformations. Some of the more common conversions include ethers to alcohols, 67-68 ADDIN EN.CITE ketals to carbonyl compounds,69 and carbonyl compounds to acetals.70 In recent years, the Kabalka group has developed several novel reactions using transition titanium halide 71-72 ADDIN EN.CITE as Lewis acid (Scheme 1-5). These reactions serve as the background for the research presented in this dissertation. R R 1 R 2 O R 3 R 2 R 3 R 1 R R 1 X X R R 1 R 1 TiCl 4 RCHO TiX 4 X=Cl,Br Scheme 1-5 Transition Metal Halide Reactions. 1.2 Alcohol Functional Group Conversion In the context of this dissertation, alcohols are converted into alkoxides and allowed to react with stereodefined haloalkenyl moieties in what can generally be considered the first transition-metal free nucleophilic substitution of hydroxyl groups. This will be discussed further in Chapter 3. Although the chemistry of alcohols is substantial, few results have been achieved involving the direct substitution of hydroxyl groups. Most substitution reactions require activation of the hydroxyl group which involve not only additional steps in the synthesis but the formation of large amounts of byproduct. Side reactions can also lead to unwanted byproducts during these conversions, decreasing atom efficiency and generating waste that creates environmental concerns. Encouraging results for the direct substitution of hydroxyl groups by nucleophiles have been achieved, 73-77 ADDIN EN.CITE but further developments remain a challenge. 1.3 Synthesis of Alkenyl Halides and Alkenylation of Carbonyl Groups Developing efficient synthetic routes to stereodefined alkenyl halides is an important goal in synthetic organic chemistry due to their importance in transition-metal catalyzed cross-coupling reactions. To this end, several reactions have been developed to facilitate the formation of stereodefined alkenyl halides from aldehydes and ketones. Recent advances in the formation of Wittig reagents, specifically β-oxido phopohonium ylides prepared in situ from aldehydes and Wittig reagents, include their reaction with electrophilic halogen sources to form predominantly E-bromo or iodosubstituted alkenes from aldehydes (Scheme 1-6).78 R 1 O Ph 3 P R 2 LiBr,PhLi E (E=I 2 or Br(CF 2 ) 2 Br) R 1 X R 2 X=I,Br Scheme 1-6 Reaction of β-Oxido Phosphonium Ylides with Electrophilic Halogen to Generate E-Halogen Substituted Alkenes. The use of (PhO)3P-halogen based reagents in Horner-Wadsworth-Emmons type reactions also allows the preparation of stereodefined vinyl halides and several modifications have been reported.79-80 The necessity to form either phosphonium ylides or phosphanate carbanion may be viewed as a limitation, especially considering the required use of strong base which limits application to reagents bearing labile functional groups. An interesting route to alkenyl halides was recently reported using α-halomethyl sulfones in a an extension of the modified Julia olefination reaction (Scheme 1-7).81 Ar O N N N N Ph S X O O 2eq.HMPA 2eq.LiHMDS Ar X H H X=Br,Cl THF/hexanes(2:1) 25  C,0.5hr Scheme 1-7 Modified Julia Olefination between α-Halomethyl Sulfones and Aldehydes to Yield Alkenyl Halides with High E/Z Stereoselectivities. The necessary preparation of sulfones prior to olefination may prove inhibitory in selection of this method to obtaining the desired alkenyl halides two or three steps are required. The general alkenylation of carbonyl compounds using alkenylmetal reagents such as alkenyllithium, -magnesium, -copper, or -chromium yields allylic alcohols.82-83 The alkenylation of carbonyl compounds promoted with Cr(II)/cat. Ni(II), known as the Nozaki-Hiyama-Kishi reaction, proceeds chemoselectively under very mild conditions and has been used in the synthesis of complex natural products.84 Issues of toxicity have been addressed in more recent applications of this reaction using aluminum and catalytic amounts of chromium and nickel wherein aluminum acts as an electron source and CrC12 and NiBr2 function as the electron-transfer catalysts (Scheme 1-8).85 O H R 3 Br R 1 R 2 OR R 3 R 1 R 2 cat.CrCl 2 orCrCl 3 -Zn,cat.NiBr 2 Al,Me 3 SiCl,DMF roomtemp.,24h Z Z R=HorMe 3 Si Scheme 1-8 Modified Nozaki-Hiyama-Kishi Reaction. The Nozaki-Hiyama-Kishi reaction provides a method for alkenylation of aldehydes to yield allylic alcohols and exemplifies the importance of vinyl halides as important synthetic targets. The utility of allylic systems has been demonstrated in Claisen, Ireland-Claisen, and Alder-Ene rearrangements. The Prins reaction is another method for synthesizing allylic alcohols, however, the majority of methodology developed for allylation can be considered extensions of the Hosomi-Sakurai Reaction for the formation of homoallylic systems as discussed in the next section. 1.4 Allylation of Carbonyl Compounds The Lewis acid mediated allylation of carbonyl compounds leading to homoallylic alcohols constitutes one of the most important synthetic reactions (Scheme 1-9).86 Numerous allylic organometallic reagents and Lewis acids have been investigated and have proven to be enormously useful in the synthesis of open-chain systems bearing sequences of stereocenters. ADDIN EN.CITE 87-90 High degrees of diastereo- and enantioselectivity are observed for these reactions depending on allylmetal reagent selection. Furthermore, the products of these reactions offer substantial functionality in terms of alcohols and alkenes. R O TMS LewisAcid R 1 OH R 1 R Scheme 1-9 Lewis-acid Assisted Allylation of Carbonyl Compounds to form Homoallylic Alcohols. Asymmetric syntheses of homoallylic alcohols have been accomplished by incorporating chiral modifiers in allylic organometallic reagents such as the modified allylic borane91 or allylic titanium92 reagents. Considerable progress has been made in this area by Brown,93 Roush,94 Corey,95 and Hafner and Duthaler,96 among others. ADDIN EN.CITE 97-98 The use of other allylmetals has been extended to include allylic silanes and stannanes ADDIN EN.CITE 99-101 and the reactions include low temperature boron halide mediated allylation of cyclic ketones using allylstannane to give homoallylic alcohols.102 The Lewis acid-catalyzed allylation of acetals has been well documented as a synthetic route to homoallylic ethers. ADDIN EN.CITE 103-106 Many of these methods require a two-step conversion of aldehydes into acetals and subsequent allylation of acetals to form the homoallylic ethers.107 Various extensions of the Sakurai reaction to form homoallylic ethers from aldehydes in one-pot have also been reported.108 The interest in generating homoallylic ethers indirectly stems from the preparation of optically active homoallylic alcohols, an area of continuing synthetic interest. ADDIN EN.CITE 109-112 The synthesis of chiral homoallylic ethers has also been used for the asymmetric synthesis of natural products like the immunosuppressant rapamycin.113 Furthermore, allylic ethers are also very interesting synthons because of base induced [2,3] Wittig rearrangements (Scheme 1-10).114-115 O R O R O R HO R [2,3] base workup allylether homoallylic alcohol Scheme 1-10 [2,3] Wittig Rearrangement Several applications in asymmetric syntheses have been reported utilizing the [2.3]-Wittig rearrangement as a critical step including the synthesis of Stork’s prostaglandin intermediate and the total synthesis of the alkaloid, (+)-astrophylline. ADDIN EN.CITE 116-117 1.5 Boron Trihalide Haloboration of Alkynes The haloboration of terminal alkynes using boron trihalides generates halovinylboron halides in a highly stereo- and regioselective manner.118 Depending on the quantity of alkyne used, selective haloboration of one equivalent of alkyne generates (Z)-halovinylboron dihalide whereas the (Z,Z)-di(halovinyl)boron halide results when two equivalents of the alkyne are used (Scheme 1-11).119 The reactions leading to (Z)-halovinylboron dihalides occur rapidly at -78 ˚C and provide the desired products in high purity (>98 %). Haloboration of internal alkynes is also possible with boron tribromide. BX 3 R R X R BX 2 R B R X X X X=Cl,Br BBr 3 R R 1 X R BX 2 R 1 Scheme 1-11 Haloboration of Alkynes. Interestingly, the bromoboration of acetylene generates the unexpected (E)-2-bromethenylboron dibromide.120 A spontaneous rearrangement from the cis to the trans isomer occurs immediately after the syn addition of the boron tribromide to the acetylene (Scheme 1-12). H H BBr 3 DCM -78 o C Br H H BBr 2 H Br H BBr 2 Scheme 1-12 Bromoboration of Acetylene. The halovinylboron halides are air and water- sensitive and are somewhat difficult to handle, but these shortcomings may be overlooked when considering their synthetic versatility resulting from the presence of vinylboron, vinyl halide, and alkene functional groups within the reagent. 1.6 Statement of Problem Lewis acids such as the boron trihalides and titanium(IV) halides can mediate reactions involving alkynes, aldehydes, and alcohols to generate compounds containing new carbon-carbon and carbon-halogen bonds. This dissertation is focused on a study of the reactions of boron halides and transition metal halides with carbonyl and hydroxy compounds. The boron halide mediated alkyne-aldehyde coupling reaction to generate 1,3,5-triaryl-1,5-dihalo-1,4-dienes was reinvestigated in an attempt to explain the stereochemistry observed during the changing of mode of addition and the reaction temperature. A mechanistic investigation was carried out in an effort to explain the observation that boron tribromide produces the (Z,Z)-1,4-diene isomer exclusively, while boron trichloride produces the (Z,E)-1,4-diene isomer (Chapter 2). The stereoselective preparation of (Z)-3-chloroallylic ethers from the reaction of alkenylboron dichlorides with aryl aldehydes in the presence of amine was investigated as a result of initial observations during the dialkenylation of aldehydes with vinylboron halides (Chapter 3). The alkenylation of allylic, benzylic, and propargylic alcohols using phenylacetylenes and titanium (IV) halides to afford high (E,Z) ratios of alkenylated products was investigated (Chapter 4). The previously unknown capture of a carbocation by alkynes generated from an unprecedented alkoxide C-O bond cleavage was investigated. The haloallylation of aryl aldehydes using boron trihalides further validates carbocation formation and is discussed in Chapter 5. The use of other allylmetals to facilitate haloallylation of aryl aldehydes was also previously not known and was investigated (Chapter 6). Synthesis of (E)-1,3-dienes from bromoallylated products using the haloallylation of aryl aldehydes was previously unknown (Chapter 7). Chapter 2. Reaction Pathways Involved in Boron Trichloride Mediated Alkyne-Aldehyde Coupling under Varying Reaction Conditions 2.1 Introduction Our research group has focused on the chemistry of organoboron halide derivatives for many years and the studies resulted in the first report of a Grignard-like alkylation of aryl aldehydes using dialkylboron chlorides28 and alkylboron dichlorides29. In a continuation of this study, we investigated the feasibility of expanding the reaction to the addition of vinylboron dichloride reagents to aryl aldehydes.21, 121 Surprisingly, the reaction afforded (Z,E)-1,5-dichloro-1,4-pentadienes as major products instead of the expected Grignard-like addition products, if preformed (Z)-vinylphenylboron dichloride reagents were used (Scheme 2-1).21 . Cl BCl 2 O Z ExpectedGrigard-likeAddition OH Z Cl Cl Ph Z Unexpected(Z,E)-1,5-Dichloro-1,4-pentadiene Cl Ph Scheme 2-1 Formation of (Z,Z)-1,5-Dichloro-1,4-pentadiene vs Grignard-like Addition. Since it has been reported that boron trichloride adds to terminal alkynes readily to generate (Z)-vinylboron dichloride,118 we decided to explore a one-pot reaction employing boron trichloride, phenylacetylene, and benzaldehyde at 0 oC. We found that a diene product formed but, unexpectedly, (Z,E)-1,5-dichloro-1,4-pentadiene was isolated as the major product instead of the expected (Z,Z)-1,5-dichloro-1,4-pentadiene. (None of the (E,E)-1,5-dichloro-1,4-pentadiene isomer was detected.) Several novel reactions were then designed to probe the reaction mechanism. ADDIN EN.CITE 122-130 During these studies, we discovered novel reactions involving an unprecedented C-O bond cleavage in R1R2CH-O-BXnR3-n intermediates; they included a transition-metal-free, formal Suzuki-coupling of alkoxides with vinylboron dichlorides,122 the boron trichloride mediated coupling of alkoxides with allylsilane,123 and the boron trihalide mediated haloallylation of aryl aldehydes using allylmetal compounds.131 In addition, we found that, at low temperature the reaction of boron chloride with two equivalents of terminal alkynes, yields only vinylboron dichloride instead of the reported divinylboron chloride. Although the methodology required for the stereoselective boron trihalide mediated alkyne-aldehyde coupling reactions has been reported, the dramatic influence of reactant addition order and reaction temperature on the stereochemistry of the products had not been investigated in details. To fully explore these parameters, we chose the reaction of phenylacetylene with p-bromobenzaldehyde as a model system for probing these parameters. 2.2 Results and Discussion (Z,Z)-1,5-Dichloro-1,4-pentadiene (1) and (Z,E)-1,5-dichloro-1,4-pentadiene (2) were synthesized according to reported procedures.21, 121 In the reaction of (Z,Z)-di(chlorovinyl)boron chloride with p-bromobenzaldehyde (Scheme 2-2), the halovinyl group migrates from boron to carbon with retention of stereochemistry.122 Interestingly, racemization in chiral benzyloxide derivatives in the coupling reaction of benzyloxides and vinylboron dihalides suggest that a cationic mechanism is involved in this migration.123 D C M 0 ° C t o r t P h C l P h C l C H O C l B P h C l + B r B r P h C l B r O B C l P h C l P h C l 1 ( Z , Z ) - d i e n e Scheme 2-2 Reaction of Aldehyde with (Z,Z)-Di(chlorovinyl)boron Chloride. Alternatively, compound 1 can also be prepared by the reaction of p-bromobenzaldehyde with two equivalents of preformed (Z)-chlorovinylboron dichloride (Scheme 2-3). The Grignard-like addition of (Z)-halovinylboron dichloride to the aldehyde followed by a carbon-oxygen bond cleavage affords a carbocation intermediate. Then the cation adds to a second equivalent of the monovinylboron dichloride to generate the observed Z,Z-diene product. It has been demonstrated that electrophiles can add to vinylboron reagents stereoselectively with retention of configuration of the vinyl group. ADDIN EN.CITE 132-136 1 O B C l 2 P h C l P h C l P h C l C H O C l B C l P h C l + B r B r B r P h C l B r C l B C l P h C l D C M 0 o C t o r t Scheme 2-3 Reaction of an Aldehyde with Two Equivalents of Z-Chlorovinylboron Dichloride. (Z,E)-1,5-Dichloro-1,4-pentadiene (2) was prepared by adding boron trichloride to a mixture of the aldehyde and phenylacetylene at 0 ˚C (Scheme 2-4). Reaction of boron trichloride with the alkyne generates the (Z)-chlorovinylboron dichloride. Addition of (Z)-halovinylboron dichloride to the aldehyde followed by carbon-oxygen bond cleavage affords the carbocation intermediate which then adds to the second alkyne to generate the more thermodynamically stable (Z,E)-diene 2 as the major product.129 The reactions outlined in Scheme 2-4 presumably compete with those shown in Scheme 2-3. This assumption is strongly supported by two observations: the quantity of (Z,Z)-diene 1 increases when aldehyde is added to a mixture of phenylacetylene and boron trichloride which favors the formation of the vinylboron dichloride (Scheme 2-3), whereas adding boron trichloride to a mixture of aldehyde and excess phenylacetylene (3.0 equivalents) at 0 ˚C results in a higher ratio of 2 to 1. Since (Z,Z)-di(chlorovinyl)boron chloride only forms at elevated temperature (refluxing dichloromethane),125 the reaction pathway shown in Scheme 2-2 should not be important in this investigation. P h B C l 3 C l B C l P h C l O B C l 2 P h C l C H O P h + 2 B C l 3 , D C M 0 ° C t o r t C H O P h C l - O B C l 2 P h + C l B r B r B r B r C l P h P h C l P h C l P h C l + 2 1 M a j o r M i n o r B r B r + 1 + 2 Scheme 2-4 BCl3-Mediated Coupling of Aryl Aldehydes and Alkynes. After establishing the analytical GCMS conditions for analyzing stereoisomers 1 and 2 (see Experimental), we examined the addition of boron trichloride to a mixture of two equivalents of phenylacetylene and one equivalent of p-bromobenzaldehyde at various temperature (Table 2-1). The reaction mixtures were subjected to GCMS analyses after a simple workup (see Experimental). As illustrated in Table 2-1, (Z,E)-1,5-dichloro-1,4-pentadiene (2) was always the major product, indicating that the reaction pathway shown in Scheme 2-4 played a predominant role. As the temperature was decreased from 0 ˚C to –42 ˚C, the ratio of the (Z,E) to (Z,Z) isomer increased due to the thermodynamic stability of the (Z,E)-1,5-dichloro-1,4-pentadiene product 2. The reaction pathway shown in Scheme 2-3 is also presumably involved but it would be expected to be minimal at temperatures approaching –60 ˚C, because the haloboration reaction would be less effective at very low temperatures. As a consequence of slow haloboration, the concentration of (Z)-chlorovinylboron dichloride remains low compared to that of phenylacetylene. Therefore, the reaction pathway (Scheme 2-3) leading to (Z,Z)-1,5-dichloro-1,4-pentadiene 1 is suppressed. A representative chromatogram for the reaction at -60 ˚C is provided in Figure 2-1. Figure 2-1 Chromatogram of isomers resulting from the addition of boron trichloride to a mixture of two equivalents of phenylacetylene and one equivalent of p-bromobenzaldehyde at -60 ˚C. Retention times are 36.4, 38.8, and 42.4 minutes for the E,E, E,Z, and Z,Z isomers, respectively. Interestingly, reactions run at or below –60 ˚C produce an additional isomer (molecular weight 444, Rt = 42.4 min) which was later confirmed to be the (E,E)-1,5-dichloro-1,4-pentadiene 3. At these low temperatures, the unreacted boron trichloride acts as a Lewis acid and initiates a competing reaction to generate (E,E)-1,5-dichloro-1,4-pentadiene 3 (Scheme 2-5). Addition of the alkyne to the boron trichloride activated carbonyl group, followed by C-O bond cleavage, to form a carbocation bearing a thermodynamically stable (E)-vinyl moiety. Addition of this cation to the second alkyne then generates the more thermodynamically stable (E,E)-diene product 3. Table 2-1 The influence of reaction temperature on the ratio of isomers.a Reaction temperature Ratio of (Z,Z)-: (Z,E)-: (E;E)- b 0 ˚C ~ 1 : 6 : 0 - 20 ˚C ~ 1 : 24 : 0 - 42 ˚C ~ 1 : 27 : 0 - 60 ˚C ~ 2 : 43 : 1 - 78 ˚C ~ trace : 9 : 1 a See Experimental for reaction procedure. b The ratios shown in table are the average of multiple experiments. C H O P h + B r - 7 8 ° C B C l 3 C l B O P h A r C l C l O B C l 2 C l P h C l P h - O B C l 2 P h + C l B r B r C l P h C l P h + 3 B r 2 ( E , E ) - d i e n e * A r = p - b r o m o b e n z y l Scheme 2-5 Lewis Acid Boron Trichloride Initiated Alkyne-Aldehyde Coupling. To confirm the formation of 3, it was isolated by column chromatography; the 1H spectrum of the compound exhibited only one set of vinyl resonances which supports the formation of the symmetrical (E,E)-1,5-dichloride-1,4-pentadiene isomer. The structure was further confirmed by X-ray crystallography (Figure 2-1). Figure 2-2 X-Ray Crystallography of 3 (see Appendix A for crystal data). The specific chemical shifts and coupling constants for vinyl and benzylic protons, as well as the and benzylic carbons, for the (Z,Z)-, (Z,E)-, (E;E)-isomers are tabulated in Table 2-2. Table 2-2 Chemical Shift and Coupling Constants for Vinyl, Benzylic Proton and Benzylic Carbon. Isomer 1H NMR 13C NMR Vinyl proton Benzylic proton Benzylic carbon (Z,Z)-diene 6.30 (d, 2H, J = 8.97 Hz) 5.39 (t, 1H, J = 8.97 Hz) 45.3 (Z,E)-diene 6.21 (d, 1H, J = 9.1 Hz), 6.13 (d, 1H, J = 10.5 Hz) 4.81 (dd, 1H, J = 10.5 and 9.1 Hz) 45.0 (E,E)-diene 6.05 (d, 2H, J = 10.7 Hz) 4.34 (t, 1H, J = 10.7 Hz) 44.8 As summarized in Table 2-2, both the vinyl and benzylic protons in the (E,E)-diene are upfield when compared to those in (Z,Z)-diene. Interestingly, the chemical shift difference in shifts of the benzylic proton in (E,E)-diene and (Z,Z)-diene approaches 1 ppm. 2.3 Conclusions The reaction pathways involved in the reactions of phenylacetylene, p-bromobenzaldehyde and boron trichloride are discussed. Through the use of GC-MS, the ratios of (Z,Z)-, (Z,E)- and (E,E)-1,5-dichloro-1,4-diene isomers in the crude reaction mixtures obtained under different reaction conditions were determined. The investigation reveals that at temperatures greater than - 42 ˚C) the addition of boron trichloride to phenylacetylene occurs rapidly and boron trichloride functions as a reactant. While, at relative lower temperature, the addition of boron trichloride to phenylacetylene becomes sluggish and the unreacted boron trichloride acts as a Lewis acid and leads to the (E,E)-diene. 2.4 Experimental 2.4.1 General Methods All reagents were used as received. Column chromatography was performed using silica gel (60 Å, 230–400 mesh, ICN Biomedicals GmbH, Eschwege, Germany). Analytical thin-layer chromatography was performed using 250 μm silica plates (Analtech, Inc., Newark, DE). 1H NMR and 13C NMR spectra were recorded at 250.13 and 62.89 MHz, respectively. Chemical shifts for 1H NMR and 13C NMR spectra were referenced to TMS and measured with respect to the residual protons in the deuterated solvents. Atlantic Microlab, Inc., Norcross, Georgia, performed microanalysis. Gas Chromatography-Mass Spectroscopy studies were run on Hewlett Packard: HP 6890 series GC System with 5973 Mass Selective Detector; Column: Agilent 19091S-433E, 30.0mm X 0.25mm X 0.25 μm; Gas (He) flow rate: 0.8 mL/min; Initial temperature; 50 ˚C (hold 1 min); Ramp temperature rate: 7 ˚C/min to maximum 280 ˚C. 2.4.2 Typical Reaction Procedure Phenylacetylene (204 mg, 2.00 mmol) and p-bromobenzaldehyde (185 mg, 1.00 mmol) were placed in a dry argon-flushed, 50 mL round-bottomed flask equipped with a stirring bar and dissolved in 15 mL dry CH2Cl2. The solution was cooled to the desired temperature, and boron trichloride (1.1 mmol, 1.1 mL of a 1.0 M CH2Cl2 solution) was added via syringe. The solution was allowed to stir for one hour at that temperature. The resulting mixture was hydrolyzed with water (20 mL) and extracted with hexanes (2 x 30 mL). The organic layer was separated and passed through a short silica gel column to remove the trace of water and acidic by-product. 2.4.3 Characterization of Compound 3 (E,E)-1,5-dichloro-1,5-diphenyl-3-(4-bromophenyl)-penta-1,4-diene (3): 1H NMR (250 MHz, CDCl3): δ 7.47-7.01 (m, 14H), 6.05 (d, 2H, J = 10.7 Hz), 4.34 (t, 1 H, J = 10.7 Hz). 13C NMR (CDCl3): δ 140.6, 136.2, 132.9, 132.00, 128.8, 128.6, 128.2, 128.2, 121.0, 44.8. Confirmed by X-ray diffraction, refer to Appendix A. Chapter 3. Stereoselective Preparation of (Z)-3-Chloroallylic Ethers: The reaction of Alkenylboron Dichlorides with Aryl Aldehydes in the Presence of Amine 3.1 Introduction Allylic alcohol represents an important building block in synthetic organic chemistry. The synthesis of allylic alcohols can be achieved by α-cleavage of epoxides, allyl hydroxylation, and reduction of α,β-unsaturated carbonyl compounds.137 The alkenylation of carbonyl compounds (the Nozaki-Hiyami-Kishi83 reaction) can also be used to form allylic alcohols and has been used in the synthesis of complex natural products such as brefeldin138, ophiobolin C139, and polytoxin.140 However, to reach the corresponding allylic ethers, an additional step is normally required. One of the few direct routes to allylic ethers is the synthesis of (E)-allylic TBS ethers based upon a unique Kocienski-Julia olefination reaction as reported by Pospisil and Marko.141 The use of allylic ethers as protecting groups142 illustrates their importance to the synthetic community, but they are also useful synthons in base induced [2,3]-Wittig rearrangements.114-115 Herein, we report the synthesis of (Z)-3-chloroallylic ethers from aryl aldehydes via their reaction with alkenylboron dichlorides in the presence of triethylamine. These reactions are important not only because they represent a direct route to allylic ethers, but they also permit further synthetic manipulation of the vinyl chloride in chemistry such as metal-catalyzed coupling reactions (Heck, Kumada, Negishi, Stille, & Suzuki). 3.2 Results and Discussion 3.2.1 Generation of (Z)-3-Chloroallylic Alcohols As discussed in Chapter 2, we recently reinvestigated the boron trihalide mediated reaction between aryl acetylenes and aryl aldehydes.143 It was discovered that the reaction proceeded through different pathways depending on the reaction temperatures and order of reagent addition. For reactions below room temperature, the Grignard-like addition of stereodefined (Z)-2-halovinylboron dihalide to the aldehyde to form allyloxyboron halide was believed to be the first step. The subsequent C-O bond cleavage in the allyloxyboron halide intermediate then gives a carbocation which undergo further reaction with another equivalent of alkenylboron halide. The isolation of allylic alcohol (16% isolated yield from a reaction at 0 ˚C) from the reaction quenched prior to completion supported this mechanism. Considering the importance of the resultant multi-functionalized allylic alcohol, we decided to examine the feasibility of inhibiting the generation of carbocation from the allyloxyboron halide intermediate and thereby develop an efficient route to stereodefined haloallylic alcohols. It is well-known that the reaction of terminal alkynes with one equivalent of boron trichloride generates the stereodefined (Z)-2-chloro-1-alkenylboron dichloride, 1, in quantitative yields as shown in Scheme 3-1.144 BCl 3 ,0  Ctort DCM Cl Cl 2 B 1 Scheme 3-1 Formation of (Z)-2-Chloro-1-alkenylboron Dichloride. Triethylamine was used to decrease the Lewis-acidic strength (or reactivity) of 1 via complexation, meanwhile hoping the similar complexation would also increase the stability of allyloxyboron intermediate and, thus, greatly slow down the generation of a carbocation.145 Procedurally, after the formation of 1, triethylamine was added to the reaction mixture. Immediately, a white cloud was observed due to the coordination of Et3N and the alkenylboron dichloride. Even though the exact mechanism of the reaction is not clear, the results in Table 3-1 clearly indicate that addition of triethylamine does favor the formation of the desired (Z)-3-chloroallylic alcohol. Table 3-1 Efficiency of Addition of Triethylamine in Controlling (Z)- 3-Chloroallylic Alcohol Formation.a O DCM,0  Ctort OH Cl 1 2 3 Et 3 N Br Br Entry Et3N (equiv). Aldehyde 2 (equiv) Product Yield (%) 1 0.50 1.50 3 41 2 0.50 2.00 - - 3 0.50 1.50 3 53 4 0.75 2.00 3 22 5 1.00 1.50 3 51 6 1.50 1.50 - - a Certain amount of Triethylamine was added to 1. The resulted reaction mixture then was added dropwise at 0 ˚C to 1.3 equivalents of aldehyde in 2 mL DCM (see Experimental for details). . b Isolated yield based on phenylacetylene. Isolation difficulties lead to yield discrepancies when comparing entries of Table 3-1. It was discovered that addition of 1% triethylamine to the eluent (5 hexanes : 1 ethyl acetate) facilitates isolation of the alcohol. However, once compound 3 was isolated it rearranged as evident by a comparison of 1H NMR over time displayed in Figure 3-1. Figure 3-1 Time Elapsed Rearrangement of (Z)-1-(4-bromophenyl)-3-chloro-3-phenylprop-2-en-1-ol; Spectrum 1 is of the isolated (Z)-1-(4-bromophenyl)-3-chloro-3-phenylprop-2-en-1-ol, Spectrum 2 is the spectrum of the rearranged, and Spectrum 3 is the spectrum of the rearranged product after addition of deuterium oxide. An acid catalyzed mechanism for this rearrangement during isolation is proposed since the addition of triethylamine to the eluent during separation hindered the rearrangement leading to an increased yield of the intended product (Scheme 3-2). Proton integration support rearrangement for the isolated (Z)-3-chloroallylic alcohol rather than product degradation since the rearranged product integrates to an equivalent number of protons and also contains an alcohol (Figure 3-1). Unfortunately, full characterization of both the (Z)-3-chloroallylic alcohol and subsequent product from rearrangement has been hindered perhaps because of resonance stabilized carbocation formation. Z Cl Ph Z Cl Ph OH Z Cl Ph HOH 2 O Z Cl Ph H H Z Cl Ph Z Cl Ph OH 2 OH 2 -H 2 O +H 2 O ~H + MixtureofProducts Scheme 3-2 Plausible Mechanism for (Z)-3-chloroallylic Alcohol Rearrangement. 3.2.2 Allyltrimethysilane Allyltrimethylsilane has been successfully used as a carbocation scavenger.146 Since the isolation of the (Z)-3-chloroallylic alcohol had proven difficult, capturing the carbocation with allyltrimethylsilane might produce the allylated product as shown in Scheme 3-3. This product would be less susceptible to acid-catalyzed carbocation formation during separation. O DCM,0  Ctort Z 1+Et 3 N Z Cl O Z Cl Cl 2 B B TMS NEt 3 Scheme 3-3 Allylation of Alkenylboroloxy Dichloride Amine Intermediate. Initially, the alkenylboron dichloride, 1, was added to a cooled solution of aryl aldehyde and allyltrimethylsilane. This procedure resulted in the predominant formation of the haloallylated product. As a result, triethylamine was added to 1 and this solution was added dropwise to the aryl aldehyde and allowed to form intermediate B shown in Scheme 3-3. At that time, allyltrimethylsilane was added to the reaction. A mixture of products was detected by both NMR and GC-MS. The homoallylic alcohol was detected as the major product but other products included the haloallylated product, the dialkenylated product, and the desired allylated compound in miniscule amounts. Further investigations are underway. 3.2.3 (Z)-3-Chloroallylic Ethers The discovery of (Z)-3-chloroallylic ethers occurred during attempts to isolate the (Z)-3-chloroallylic alcohols using chloroform as an eluent for silica gel chromatography. NMR analysis of the isolated products revealed the characteristic splitting pattern for the (Z)-3-chloroallylic alcohol in addition to the presence of an ethyl group. At first, it was thought that residual triethylamine had co-eluted and not efficiently removed. The sample was placed under high vacuum but the ethyl group remained, as evident by NMR analysis. IR analysis of the sample (4d, Table 3-2) validated the absence of an alcohol and confirmed the presence of an ethyl ether. After reading the literature, it was determined that trace amounts of ethanol used to stabilize the chloroform were reacting with the alkenylboroloxy dichloride amine intermediate B (Scheme 3-3) and capturing the resultant carbocation. The addition of ethanol to products during the tosylation of alcohols had been documented and occurred as a result of using chloroform stabilized with ethanol.147 Table 3-2 Generation of (Z)-3-chloroallylic Ethers.a O DCM,0  Ctort Z 1 Z Cl OEt +Et 3 N CHCl 3 (1%EtOH) Entry Z Time / hour Product Yieldb (%) Z : E ratioc 1 H 3 4a 77 99 : 1 2 4-Me 5 4b 49 99 : 1 3 4-Cl 3 4c 50 96 : 4 4 4-Br 9 4d 63 99 : 1 5 4-NO2 3 4e 37 98 : 2 6 3-Cl 4 4f 50 99 : 1 7 3-Br 11 4g 66 98 : 2 8 2-Br 12 4h - a 0.9 equivalent of triethylamine added to 1. Then this solution is added dropwise at 0 ˚C to 1.3 equivalents of aldehyde in 2 mL DCM. After two hours at 0 ˚C, 25 mL of CHCl3 (1% EtOH) is added at room temperature (see Experimental for details). b Isolated yield based on phenyl acetylene. c Determined by 1H NMR spectroscopy. Since the (Z)-3-chloroallylic ethers were stable when compared to the allylic alcohols, the procedure was modified to generate the ethyl ether products. After formation of B, chloroform with 1% ethanol was added and allowed to react, resulting in the formation of (Z)-3-chloroallylic ethers. The products were easily isolated using silica gel chromatography using chloroform as an eluent and the results are presented in Table 3-2. Based on the results provided in Table 3-2, the reaction is stereoselective for the formation of (Z)-3-chloroallylic ethers and tolerant of a variety of functional groups. Problems associated with the isolation of (Z)-3-chloroallylic alcohols are eliminated as a result of the conversion. Ortho-substituted aryl rings appear to sterically inhibit the reaction (entry 8 in Table 3-2). 3.3 Conclusions In conclusion, a stereoselective formation of (Z)-3-chloroallylic ethers has been developed using the reaction of alkenylboron dichlorides with aryl aldehydes. Triethylamine was found to greatly slow down the dialkenylation of the aryl aldehyde. Reaction conditions are mild and the reagents are readily available. The application of this reaction to include other nucleophiles is of genuine interest, especially in the context of [2,3]-Wittig rearrangements of allylic ethers. The ability to increase the organic functionality of the vinyl chloride enhances this new route to (Z)-3-chloroallylic ethers. 3.4 Experimental 3.4.1 General Methods All reagents were used as received. Column chromatography was performed using silica gel (60 Å, 230–400 mesh, ICN Biomedicals GmbH, Eschwege, Germany). Analytical thin-layer chromatography was performed using 250 μm silica plates (Analtech, Inc., Newark, DE). 1H NMR and 13C NMR spectra were recorded at 250.13 and 62.89 MHz, respectively. Chemical shifts for 1H NMR and 13C NMR spectra were referenced to TMS and measured with respect to the residual protons in the deuterated solvents. Atlantic Microlab, Inc., Norcross, Georgia, performed microanalysis. Gas Chromatography-Mass Spectroscopy studies were run on Hewlett Packard: HP 6890 series GC System with 5973 Mass Selective Detector; Column: Agilent 19091S-433E, 30.0mm X 0.25mm X 0.25 μm; Gas (He) flow rate: 0.8 mL/min; Initial temperature; 50 ˚C (hold 1 min); Ramp temperature rate: 7 ˚C/min to maximum 280 ˚C. 3.4.2 Typical Reaction Procedure for (Z)-3-Chloroallylic Alcohol Phenylacetylene (1.50 mmol, 153 mg) and dry dichloromethane (10 mL) are placed in a dry argon-flushed, 50 mL round-bottomed flask equipped with a magnetic stirring bar. The solution is cooled to 0 ˚C, and boron trichloride (1.65 mmol, 1.65 mL of a 1.00 M CH2Cl2) is added via syringe. After completion of the addition, the ice-bath is removed and the resulting solution is allowed to warm to room temperature for one hour. Triethylamine (1.35 mmol, 188 µL) is added to the solution and allowed to stir for an additional thirty minutes. In a separate flask, the aryl aldehyde (1.95 mmol) in dry dichloromethane (2 mL) is cooled to 0 ˚C. The first solution is then added dropwise to the aldehyde via syringe and allowed to react for two hours. Once the solution has warmed to room temperature, the reaction mixture is hydrolyzed with water and extracted into dichloromethane. The organic layer is washed three times with a saturated solution of aqueous sodium bicarbonate, once with brine, then separated, and dried over anhydrous MgSO4. The solvents are removed in vacuo and the product purified by silica gel column chromatography using hexanes : ethyl acetate : triethylamine = 5:1:0.01. 3.4.3 Typical Reaction Procedure for (Z)-3-Chloroallylic Ether Phenylacetylene (1.50 mmol, 153 mg) and dry dichloromethane (10 mL) are placed in a dry argon-flushed, 50 mL round-bottomed flask equipped with a magnetic stirring bar. The solution is cooled to 0 ˚C, and boron trichloride (1.65 mmol, 1.65 mL of a 1.00 M CH2Cl2) is added via syringe. After completion of the addition, the ice-bath is removed and the resulting solution is allowed to warm to room temperature for one hour. Triethylamine (1.35 mmol, 188 µL) is added to the solution and allowed to stir for an additional thirty minutes. In a separate flask, the aryl aldehyde (1.95 mmol) in dry dichloromethane (2 mL) is cooled to 0 ˚C. The first solution is then added dropwise to the aldehyde via syringe and allowed to react two hours. Once the solution has warmed to room temperature, 25 mL of chloroform stabilized with 1% ethanol is added to the reaction and the reaction allowed to proceed to completion. The solvents are removed in vacuo and the product purified by silica gel column chromatography using chloroform as an eluent. 3.4.4 Characterization of Compounds (Z)-1-(4-Bromophenyl)-3-chloro-3-phenylprop-2-en-1-ol (3): 1H NMR (250 MHz, CDCl3): δ 7.59 – 7.53 (m, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.37 – 7.30 (m, 5H), 6.29 (d, J = 8.1 Hz, 1H), 5.82 (d, J = 8.1 Hz, 1H), 2.61 (s, 1H). 13C NMR (63 MHz, CDCl3): δ 141.0, 136.9, 134.4, 131.7, 129.2, 128.7, 128.4, 127.7, 126.6, 121.7, 71.1. HRMS-ESI+ (m/z): [M - OH]+ calcd for C15H12BrClO, 306.970; found, 306.971. (Z)-(1-Chloro-3-ethoxyprop-1-ene-1,3-diyl)dibenzene (4a): 1H NMR (250 MHz, CDCl3): δ 7.60 – 7.51 (m, 2H), 7.46 (d, J = 7.2 Hz, 2H), 7.29 (ddd, J = 9.4, 7.2, 4.8 Hz, 6H), 6.31 (d, J = 8.3 Hz, 1H), 5.49 (d, J = 8.3 Hz, 1H), 3.69 – 3.46 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H). 13C NMR (63 MHz, CDCl3): δ 140.9, 137.3, 134.3, 129.0, 128.6, 128.6, 128.3, 127.8, 126.6, 78.9, 64.2, 15.4. Anal. Calcd for C17H17ClO: C, 74.86; H, 6.28. Found: C, 74.87; H, 6.10. (Z)-1-(3-Chloro-1-ethoxy-3-phenylallyl)-4-methylbenzene (4b): 1H NMR (250 MHz, CDCl3): δ 7.57 (dd, J = 7.5, 2.3 Hz, 2H), 7.38 – 7.26 (m, 5H), 7.16 (d, J = 8.1 Hz, 2H), 6.32 (d, J = 8.3 Hz, 1H), 5.44 (d, J = 8.3 Hz, 1H), 3.68 – 3.45 (m, 2H), 2.33 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H). 13C NMR (63 MHz, CDCl3): δ 137.8, 137.5, 137.4, 133.9, 129.2, 128.9, 128.7, 128.3, 126.6, 126.5, 78.7, 64.0, 21.2, 15.4. Anal. Calcd for C18H19ClO: C, 74.38; H, 6.68. Found: C, 75.67; H, 6.65. (Z)-1-Chloro-4-(3-chloro-1-ethoxy-3-phenylallyl)benzene (4c): 1H NMR (250 MHz, CDCl3): δ 7.61 – 7.53 (m, 2H), 7.42 – 7.30 (m, 7H), 6.26 (d, J = 8.3 Hz, 1H), 5.45 (d, J = 8.2 Hz, 1H), 3.70 – 3.45 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (63 MHz, CDCl3): δ 139.3, 137.1, 134.6, 133.4, 129.0, 128.7, 128.3, 128.1, 127.9, 126.5, 78.1, 64.2, 15.3. HRMS-ESI+ (m/z): [M - OEt]+ calcd for C17H16Cl2O, 261.023; found, 261.023. (Z)-1-Bromo-4-(3-chloro-1-ethoxy-3-phenylallyl)benzene (4d): 1H NMR (250 MHz, CDCl3): δ 7.60 – 7.54 (m, 2H), 7.50 – 7.45 (m, 2H), 7.33 (ddd, J = 6.1, 4.4, 2.1 Hz, 5H), 6.25 (d, J = 8.3 Hz, 1H), 5.44 (d, J = 8.2 Hz, 1H), 3.57 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (63 MHz, CDCl3): δ 139.9, 137.0, 134.6, 131.6, 129.1, 128.3, 128.2, 128.0, 126.5, 121.6, 78.2, 64.2, 15.3. IR (cm-1): 3058, 2974, 2918, 2872, 2849, 1633, 1591, 1486, 1445, 1397, 1330, 1244, 1220, 1134, 1105, 1086, 1073, 1011, 914, 866, 823, 759, 718, 692, 570, 514. [M - OEt]+ calcd for C17H16BrClO, 304.973; found, 304.972. (Z)-1-(3-Chloro-1-ethoxy-3-phenylallyl)-4-nitrobenzene (4e): 1H NMR (250 MHz, CDCl3): δ 8.21 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.9 Hz, 2H), 7.58 (dd, J = 6.8, 3.0 Hz, 2H), 7.37 – 7.32 (m, 3H), 6.21 (d, J = 8.3 Hz, 1H), 5.59 (d, J = 8.3 Hz, 1H), 3.77 – 3.48 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H). 13C NMR (63 MHz, CDCl3): δ 148.2, 147.4, 136.7, 135.7, 129.3, 128.4, 127.1, 126.5, 123.8, 77.9, 64.6, 15.3. HRMS-ESI+ (m/z): [M - OEt]+ calcd for C17H16ClNO3, 272.048; found, 272.047. (Z)-1-Chloro-3-(3-chloro-1-ethoxy-3-phenylallyl)benzene (4f): 1H NMR (250 MHz, CDCl3): δ 7.57 (dd, J = 6.6, 3.1 Hz, 2H), 7.47 (s, 1H), 7.35 – 7.24 (m, 6H), 6.25 (d, J = 8.3 Hz, 1H), 5.46 (d, J = 8.3 Hz, 1H), 3.58 (tdd, J = 9.2, 7.0, 2.2 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (63 MHz, CDCl3): δ 142.9, 137.0, 134.9, 134.5, 129.8, 129.1, 128.3, 127.9, 126.6, 126.6, 124.7, 78.1, 64.3, 15.3. Anal. Calcd for C17H16Cl2O: C, 66.46; H, 5.25. Found: C, 66.34; H, 5.13. (Z)-1-Bromo-3-(3-chloro-1-ethoxy-3-phenylallyl)benzene (4g): 1H NMR (250 MHz, CDCl3): δ 7.62 – 7.57 (m, 2H), 7.43 – 7.32 (m, 6H), 7.20 (d, J = 7.8 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 5.45 (d, J = 8.3 Hz, 1H), 3.70 – 3.47 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H). 13C NMR (63 MHz, CDCl3): δ 143.2, 137.0, 134.9, 130.8, 130.1, 129.5, 129.1, 128.3, 127.8, 126.6, 125.1, 122.7, 78.1, 64.3, 15.3. HRMS-ESI+ (m/z): [M - OEt]+ calcd for C17H16BrClO, 304.973; found, 304.972. 3.4.5 Representative NMR Spectra of 3and 4a-4g 1H spectrum of 3 SHAPE \* MERGEFORMAT 13C spectrum of 3 SHAPE \* MERGEFORMAT 1H spectrum of 4a SHAPE \* MERGEFORMAT 13C spectrum of 4a SHAPE \* MERGEFORMAT 1H spectrum of 4b SHAPE \* MERGEFORMAT 13C spectrum of 4b SHAPE \* MERGEFORMAT 1H spectrum of 4c SHAPE \* MERGEFORMAT 13C spectrum of 4c SHAPE \* MERGEFORMAT 1H spectrum of 4d SHAPE \* MERGEFORMAT 13C spectrum of 4d SHAPE \* MERGEFORMAT 1H spectrum of 4e SHAPE \* MERGEFORMAT 13C spectrum of 4e SHAPE \* MERGEFORMAT 1H spectrum of 4f SHAPE \* MERGEFORMAT 13C spectrum of 4f SHAPE \* MERGEFORMAT 1H spectrum of 4g SHAPE \* MERGEFORMAT 13C spectrum of 4g SHAPE \* MERGEFORMAT Chapter 4. Titanium(IV) Halide Mediated Coupling of Alkoxides and Alkynes: An Efficient and Stereoselective Route to Trisubstituted (E)-Alkenyl Halides 4.1 Introduction In 2005, we reported the first transition-metal-free nucleophilic substitution of hydroxyl groups, through the corresponding alkoxides, by stereodefined haloalkenyl moieties (Sequence 1, Scheme 4-1).123, 131 The reaction involves the unprecedented C−O bond cleavage of an alkoxide in the presence of (Z)-halovinylboron dihalide and provides a practical route to trisubstituted (Z)-alkenyl halides. The stereochemistry is dependent on the formation of the (Z)-halovinylboron dihalide prior to addition to the alkoxide. The reaction proceeds quite well with alkoxides generated in situ from reactions of aldehydes and alkyllithium reagents which further adds versatility to the method.131, 148 Ph BCl 3 CH 2 Cl 2 0  Ctort CH 2 Cl 2 0  Ctort Ar OLi R Ar R Ph Cl Zonly Sequence1 Sequence2 Ar OLi R Ph BCl 3 CH 2 Cl 2 0  Ctort Ar R Cl Ph E:Z=~2-19:1 Ar O R B Cl Ph Cl Ph Cl Cl 2 B Ar O R B Cl Cl Ph Ar R Cl + Scheme 4-1 Stereochemical Modification via Modificaton of Reagent Addition Sequence. During ongoing mechanistic studies of the aldehyde-alkyne coupling reaction,121 we discovered that changing the mode of reagent addition greatly affects the stereochemistry of the product formed. It was determined that boron trihalide, when added to a mixture of alkoxide and alkyne, resulted in the coupling of alkoxides with terminal alkynes to yield trisubstituted (E)-alkenyl halides as the major products with moderate stereoselectivities.149 In this case, we believe that carbocations are generated from alkoxides in the presence of boron trihalide and subsequently captured by the terminal alkynes (Sequence 2, Scheme 4-1). 4.2 Results and Discussion Our recent study of boron tribromide-mediated aryl propargyl ether cleavage130 suggests that the addition of boron trihalide to terminal alkynes is a very fast process. Methoxy groups (known to react with BBr3) were found to survive the reaction conditions because of the high reactivity of BBr3 toward the terminal alkynes. This observation led us to propose that the moderate stereoselectivity for the reaction shown in Sequence 2 (Scheme 4-1) resulted from a competitive reaction involving the facile formation of (Z)-vinylboron dihalide (giving the Z-isomer after coupling with the alkoxide). To minimize this undesired competitive reaction, we felt that replacement of boron trihalide with Lewis acids that do not undergo facile addition to alkynes might enhance the stereoselectivity of the overall coupling reaction. Previous studies from our group, 71-72, 150 ADDIN EN.CITE as well as other groups, ADDIN EN.CITE 151-153 have demonstrated that C−O bond cleavage in alkoxide-type RC−OMXn (M = Ti, Fe) intermediates can occur smoothly at room temperature. In 2008, Fuchter and Levy reported a one-pot method for the conversion of carbonyl electrophiles to allylic chlorides by activating the in situ generated magnesium alkoxides using TiCl4.154 Related work by Murai and co-workers documented successful C−S bond cleavage. ADDIN EN.CITE 155-156 Herein, we report our preliminary results focused on the stereoselective synthesis of trisubstituted (E)-alkenyl halides. The reaction of lithium diphenylmethanoxide with phenylacetylene was chosen as the model system (Scheme 4-2). Due to its low cost, FeCl3 was initially used to test the feasibility of the coupling reaction. Ph OLi Ph Ph Lewisacid 0  Ctort Ph Ph Cl Ph Majorisomer Lewisacid:FeCl 3 ,TiCl 4 ,ZnCl 2 ,NiCl 2 Scheme 4-2 Lewis Acid Induced Coupling Reaction. Several solvents were surveyed but the poor solubility of FeCl3 led to modest yield even after twenty four hours at room temperature. Elevating the reaction temperature did increase the yield but led to decreased stereoselectivity. These results are consistent with a recent publication concerning the FeCl3 mediated coupling of benzyl alcohols and aryl alkynes in refluxing CH2Cl2 which reports the formation of trisubstituted (E)-alkenyl halides as the major products but with only moderate stereoselectivities (E/Z = 8:1).157 Notably, in 2008 Jana et al. reported that a FeCl3 mediated reaction in nitromethane at 80 °C gives aryl ketones, rather than trisubstituted (E)-alkenyl halides.158 Due to the poor solubility of FeCl3 in organic solvents at room temperature, we decided to screen other metal halides. Fortunately, the desired reaction occurred smoothly at room temperature using TiCl4; product 1a was isolated in 78% yield and with excellent stereoselectivity (E/Z = 96:4). ZnCl2 and NiCl2 proved to be ineffective. The product’s E stereochemistry was confirmed by X-ray analysis of compound 1d shown in Figure 4-1. Figure 4-1 X-Ray Crystallography of 1d (see Appendix B for crystal data). To evaluate the scope and limitations of the reaction, a variety of benzylic, allylic, and propargylic alcohols were prepared and subjected to the new reaction conditions (Table 4-1). Several examples illustrate that ether moieties, double bonds, and triple bonds all tolerate the reaction conditions. The E products are produced in excellent stereochemical yields. Even lithium di(4-fluorobenzyl)methanoxide gives excellent stereoselectivity (entry 5, Table 4-1) using TiCl4. In our previous work, this reaction afforded very poor stereoselectivity (E/Z = 60:40) when BCl3 was used.126 Successful coupling using an aliphatic alkyne is notable, though the stereoselectivity is rather poor (E/Z = 70:30, entry 7). In recent reports, ADDIN EN.CITE 157-158 it was noted that the FeCl3 mediated coupling reaction of benzylic alcohols with alkynes is only successful for aryl alkynes. The lower E/Z stereoselectivity for aliphatic alkynes is most likely due to the lack of steric bulk of the n-butyl group. Table 4-1 Titanium (IV) Mediated Coupling of Alkoxides with Alkynes.a R R 2 R 1 OLi TiCl 4 CH 2 Cl 2 0  Ctort R 2 R 1 R Cl Entry R1 R2 R prod. E:Z b Yield (%)c 1 Ph Ph Ph 1a 96:4 (90:10)d 78 (84)d 2 2-MeC6H4 Ph Ph 1b 99:1 58 3 4-FC6H4 4-FC6H4 Ph 1c 98:2 (60:40)d 81 (80)d 4 4-ClC6H4 Ph 4-MeC6H4 1d 96:4 76 5 4-FC6H4 4-FC6H4 4-MeC6H4 1e 98:2 76 6 4-MeOC6H4 4-MeOC6H4 Ph 1f 92:8 43 7 Ph Ph n-Bu 1g 70:30 62 8 (E)-PhCH=CH Ph Ph 1h 99:1 68 9 n-Bu 4-ClC6H4 Ph 1i 99:1 68 10 n-Bu 4-MeC6H4 Ph 1j 99:1 67 11 Ph Ph Ph 1k 98:2 75 12 Ph n-Pr Ph 1l 96:4 71 a Reaction carried out at 0 ˚C for 10 min, then maintained at room temperature (see experimental section for details). b E:Z ratio determined by NMR. c Isolated yield based on alcohol. d E:Z stereoselectivity and yield using BCl3 instead of TiCl4. Because of the synthetic potential of alkenyl bromides in transition metal catalyzed coupling reactions, we examined the use of TiBr4 (Table 4-2). Again, the reaction proceeds readily at room temperature and good yields are obtained. We then examined the reactions of in situ generated lithium propargyloxides (from aryl aldehydes and lithium acetylide) with phenylacetylene (entries 4 and 5). High stereoselectivity and good yields were obtained in both cases. Table 4-2 Titanium(IV) Bromide Mediated Coupling of Alkoxides with Alkynes.a R R 2 R 1 OLi TiBr 4 CH 2 Cl 2 0  Ctort R 2 R 1 R Br Entry R1 R2 R prod. E:Z b Yield (%)c 1 4-MeOC6H4 4-MeOC6H4 4-MeC6H4 2a 96:4 59 2 4-MeOC6H4 4-MeOC6H4 Ph 2b 96:4 64 3 Ph Ph 4-MeC6H4 2c 98:2 79 4d Ph Ph Ph 2d 99:1 74 5d n-Bu Ph Ph 2e 99:1 76 6 n-Bu Ph 4-MeC6H4 2f 99:1 66 7 n-Bu 4-ClC6H4 Ph 2g 98:2 66 a Reaction carried out at 0 ˚C for 10 min, then maintained at room temperature (see experimental for details). b E:Z ratio determined by NMR. c Isolated yield based on alcohol used. d Lithium alkoxide generated in situ from the reaction of benzaldehyde and lithium acetylide. In view of the previously reported results ADDIN EN.CITE 121, 149 along with the dark purple color of reaction mixture, we postulate that the reactions proceed through a carbocation mechanism (Scheme 4-3). The reaction of the lithium alkoxide with TiX4 first forms intermediate 3 [R1R2CHO−TiCl3]. Carbocation 4 is then generated from either intermediate R1R2CHO−TiCl3 or an oxonium ion intermediate [R1R2CHO−(TiCl4)TiCl3]. ADDIN EN.CITE 128, 159-161 At present, there is insufficient data available to distinguish between these two pathways. Capture of carbocation 4 by the alkyne affords final product 1 or 2. The carbocation nature of the reaction is supported by compounds 1 and 2 possessing the same stereochemistry as compounds that were obtained in a previously reported reaction of benzylic carbocations with alkynes.162 Scheme 4-3 Proposed Reaction Mechanism. 4.3 Conclusions In summary, a method for preparing trisubstituted (E)-alkenyl halide derivatives with high stereoselectivity is described. Both trisubstituted (E)-alkenyl halide and (Z)-alkenyl halide derivatives can now be prepared from readily available alkoxides and acetylenes. The feasibility of generating carbocations from alkoxides under Brønsted acid-free reaction conditions was further confirmed. Application of this new synthetic method is currently underway. 4.4 Experimental 4.4.1 General Methods All glassware was dried in an oven at 120 °C and flushed with dry argon. All reactions were carried out under an argon atmosphere. CH2Cl2 was distilled over CaH2. All alcohols and alkynes were purchased from commercial sources and used as received or synthesized following literature procedures. Titanium(IV) chloride and titanium(IV) bromide were diluted to 1.0 M in CH2Cl2. Products were purified by flash chromatography using silica gel (60 D, 230-400 mesh). 1H NMR and 13C NMR were recorded in CDCl3 at 250 MHz or 300 MHz with chemical shifts reported relative to TMS. 4.4.2 Representative Procedure for the Synthesis of (E)-Alkenyl Chlorides (1a -1l) Diphenylmethanol (276 mg, 1.50 mmol) and dichloromethane (15 mL) were placed in a dry, argon-flushed, 100 mL round-bottomed flask equipped with a magnetic stirring bar. The solution was cooled to 0 ˚C in an ice bath and n-butyllithium (1.0 mL, 1.6 mmol of a 1.0 M hexanes solution) was added via syringe. The solution was allowed to stir for 10 minutes at 0 ˚C and then for 30 minutes at room temperature. Phenylacetylene (0.16 mL, 1.5 mmol) was added via syringe, followed by titanium(IV) chloride (1.65 mL g, 1.65 mmol of a 1.0 M dichloromethane solution). The reaction solution gradually turned dark purple and was allowed to react overnight. The resulting mixture was hydrolyzed with water (15 mL) and extracted into dichloromethane (3 x 15 mL). The organic layer was separated and dried over anhydrous MgSO4. Product 1a (356 mg, E/Z (96:4), 78% yield) was isolated by flash column chromatography using hexanes as eluent. 4.4.3 Representative procedure for the syntheses of (E)-Alkenyl Bromides (2a-2g) Bis(4-methoxyphenyl)methanol (0.37 g, 1.5 mmol) and dichloromethane (15 mL) were placed in a dry, argon-flushed, 100 mL round-bottomed flask equipped with a magnetic stirring bar. The solution was cooled to 0 ˚C in an ice bath and n-butyllithium (1.0 mL, 1.6 mmol of a 1.0 M hexane solution) was added via syringe. The solution was allowed to stir for 10 minutes at 0 ˚C and then for 30 minutes at room temperature. (Note: for 2d and 2e, lithium alkoxides were generated in situ from the reaction of benzaldehyde with lithium acetylide3). 1-Ethynyl-4-methylbenzene (0.19 mL, 1.5 mmol) was added via syringe, followed by titanium(IV) bromide (1.65 mL, 1.65 mmol of a 1.0 M dichloromethane solution). The reaction solution gradually turned dark purple and was allowed to react overnight. The resulting mixture was hydrolyzed with water (15 mL) and extracted with dichloromethane (3 x 15 mL). The organic layer was separated and dried over anhydrous MgSO4. Product 2a (0.31 g, 96:4 (E/Z), 59% yield) was isolated by flash column chromatography, using hexanes as eluent. 4.4.4 Characterization of Compounds 1a-1l and 2a-2g (E)-1-Chloro-1,3,3-triphenylprop-1-ene (1a)162: 1H NMR (250 MHz, CDCl3): δ 7.08-7.36 (m, 15H); 6.45 (d, 1H, J = 11.0 Hz); 4.78 (d, 1H, J = 11.0 Hz). 13C NMR (CDCl3): δ 143.3, 136.9, 131.5, 131.4, 128.9, 128.6, 128.3, 128.1, 126.6, 50.7. Anal. Calcd. for C21H17Cl: C, 82.75; H, 5.62. Found: C, 82.68; H, 5.63. (E)-1-Chloro-1,3-diphenyl-3-(o-tolyl)prop-1-ene (1b): 1H NMR (250 MHz, CDCl3): δ 7.05-7.30 (m, 14H); 6.41 (d, 1H, J = 10.7 Hz); 4.94 (d, 1H, J = 10.7 Hz); 1.91 (s, 3H). 13C NMR (CDCl3): δ 143.2, 141.5, 136.9, 135.9, 131.4, 131.2, 130.7, 128.8, 128.6, 128.5, 128.3, 127.9, 126.7, 126.5, 126.4, 47.5, 20.5. Anal. Calcd. for C22H19Cl: C, 82.87; H, 6.01. Found: C, 83.17; H, 6.13. (E)-1-Chloro-1-phenyl-3,3-di(p-fluorophenyl)prop-1-ene (1c)126: 1H NMR (250 MHz, CDCl3): δ 7.28-7.32 (m, 5H); 6.96-7.10 (m, 8H); 6.36 (d, 1H, J = 9.0 Hz); 4.74 (d, 1H, J = 9.0 Hz). 13C NMR (CDCl3): δ 159.9, 138.9, 136.6, 130.9, 129.6, 129.5, 129.1, 128.5, 115.7, 115.4, 49.2. Anal. Calcd. for C21H15ClF2: C, 74.01; H, 4.44. Found: C, 74.47; H, 4.45. (E)-1-Chloro-1-(p-tolyl)-3-phenyl-3-(p-chlorophenyl)prop-1-ene (1d): 1H NMR (250 MHz, CDCl3): δ 7.00-7.30 (m, 13H); 6.35 (d, 1H, J = 10.7 Hz); 4.75 (d, 1H, J = 10.7 Hz); 2.33 (s, 3H). 13C NMR (CDCl3): δ 142.9, 141.9, 138.9, 133.8, 132.4, 130.4, 129.4, 129.1, 128.7, 128.4, 128.0, 126.8, 50.1, 21.3. Anal. Calcd. for C22H18Cl2: C, 74.79; H, 5.14. Found: C, 74.66; H, 5.32. (E)-1-Chloro-1-(p-tolyl)-3,3-di(p-fluorophenyl)prop-1-ene (1e)131: 1H NMR (250 MHz, CDCl3): δ 6.94-7.24 (m, 12H); 6.31 (d, 1H, J = 9.0 Hz); 4.74 (d, 1H, J = 9.0 Hz); 2.35 (s, 3H). 13C NMR (CDCl3): δ 159.9, 139.1, 138.9, 133.7, 132.1, 130.5, 129.5, 129.1, 128.4, 115.6, 49.2, 21.3. (E)-1-Chloro-1-phenyl-3,3-di(p-methoxyphenyl)prop-1-ene (1f)131: 1H NMR (250 MHz, CDCl3): δ 7.28-7.37 (m, 5H); 7.00-7.05 (m, 4H); 6.79-6.85 (m, 4H); 6.39 (d, 1H, J = 11.0 Hz); 4.68 (d, 1H, J = 11.0 Hz); 3.74 (s, 6H). 13C NMR (CDCl3): δ 158.2, 135.7, 131.9, 129.6, 128.7, 128.6, 128.3, 128.0, 126.6, 113.9, 55.1, 49.0. (E)-1-Chloro-1-(n-butyl)-3,3-diphenylprop-1-ene (1g)162: 1H NMR (250 MHz, CDCl3): δ 7.02- 7.32 (m, 20H); 6.09 (d, 1H, J = 10.2 Hz); 5.96 (d, 1H, J = 9.4 Hz); 5.22 (d, 1H, J = 9.4 Hz); 4.86 (d, 1H, J = 10.1 Hz); 2.36-2.47 (m, 4H); 1.47-1.62 (m, 4H); 1.10-1.41 (m, 4H); 0.80-0.98 (m, 6H). 13C NMR (CDCl3): δ 143.5, 135.5, 129.9, 128.5, 128.2, 126.5, 126.3, 49.8, 39.3, 33.7, 29.4, 21.9, 13.9. (E,E)-1-Chloro-1,3,5-triphenyl-1,4-pentadiene (1h): 1H NMR (250 MHz, CDCl3): δ 7.12-7.45 (m, 15H); 6.20-6.47 (m, 3H); 4.29-4.35 (m, 1H). 13C NMR (CDCl3): δ 142.2, 136.9, 131.6, 131.2, 130.7, 128.8, 128.7, 128.5, 128.3, 127.6, 127.5, 126.8, 126.3, 48.4. Anal. Calcd For C23H19Cl: C, 83.50; H, 5.79. Found: C, 83.61; H, 5.97. (E)-1-Chloro-1-phenyl-3-(p-chlorophenyl)non-1-en-4-yne (1i): 1H NMR (250 MHz, CDCl3): δ 7.19-7.52 (m, 9H); 5.97 (d, 1H, J = 10.4 Hz); 4.41 (d, 1H, J = 10.4 Hz); 2.23-2.30 (m, 2H); 1.39-1.57 (m, 4H); 0.90-0.96 (m, 3H). 13C NMR (CDCl3): δ 138.6, 136.4, 132.6, 131.9, 129.4, 129.1, 128.7, 128.6, 128.5, 85.2, 78.3, 36.9, 30.9, 21.9, 18.6, 13.6. Anal. Calcd. for C21H20Cl2: C, 73.47; H, 5.88. Found: C, 73.88; H, 6.02. (E)-1-Chloro-1-phenyl-3-(p-tolyl)non-1-en-4-yne (1j)122: 1H NMR (250 MHz, CDCl3): δ 7.09-7.54 (m, 9H); 6.01 (d, 1H, J = 10.5 Hz); 4.39 (d, 1H, J = 10.5 Hz); 2.31 (s, 3H); 2.21-2.35 (m, 2H); 1.32-1.59 (m, 4H); 0.88-0.96 (m, 3H). 13C NMR (CDCl3): δ 137.2, 136.6, 131.3, 130.1, 129.4, 129.2, 128.9, 128.8, 128.4, 128.2, 127.1, 84.5, 79.0, 37.1, 30.9, 21.9, 20.9, 18.6 (E)-1-Chloro-1,3,5-triphenylpenta-1-en-4-yne (1k): 1H NMR (250 MHz, CDCl3): δ 7.15-7.54 (m, 15H); 6.09 (d, 1H, J = 10.4 Hz); 4.65 (d, 1H, J = 10.4 Hz). 13C NMR (CDCl3): δ 137.9, 136.3, 133.1, 132.8, 131.7, 129.2, 128.8, 128.6, 128.3, 126.5, 122.9, 87.8, 84.8, 37.4. Anal. Calcd. for C23H17Cl: C, 84.01; H, 5.22. Found: C, 84.12; H, 4.87. (E)-1-Chloro-1,5-diphenyl-3-(n-propyl)penta-1-en-4-yne (1l)122: 1H NMR (250 MHz, CDCl3): δ 7.27-7.50 (m, 10H); 5.95 (d, 1H, J = 10.4 Hz); 3.33 (dt, 1H, J = 10.4 Hz); 1.37-1.65 (m, 4H); 0.82-0.88 (m, 3H). 13C NMR (CDCl3): δ 131.9, 131.6, 129.7, 128.8, 128.7, 128.3, 128.2, 127.8, 126.6, 123.5, 90.3, 82.3, 37.9, 32.4, 20.1, 13.7. (E)-1-Bromo-1-(p-tolyl)-3,3-di(p-methoxyphenyl)prop-1-ene (2a)131: 1H NMR (250 MHz, CDCl3): δ 7.23 (d, 2H, J = 8.2 Hz); 7.13 (d, 2H, J = 8.0 Hz); 7.02 (d, 4H, J = 8.5 Hz); 6.82 (d, 4H, J = 8.5 Hz); 6.58 (d, 1H, J = 10.7 Hz); 4.62 (d, 1H, J = 10.7 Hz); 3.76 (s, 6H); 2.34 (s, 3H). 13C NMR (CDCl3): δ 158.2, 138.6, 135.7, 135.5, 129.1, 128.9, 128.6, 127.6, 120.9, 113.9, 55.2, 50.0, 21.3. HRMS. for C24H24BrO2 (M+1 peak): 423.0786. Found: 423.0806. (E)-1-Bromo-1-phenyl-3,3-di(p-methoxyphenyl)prop-1-ene (2b): 1H NMR (250 MHz, CDCl3): δ 7.32 (s, 5H); 7.02 (d, 4H, J = 8.6 Hz); 6.82 (d, 4H, J = 8.9 Hz); 6.61 (d, 1H, J = 11.0 Hz); 4.62 (d, 1H, J = 11.0 Hz); 3.75 (s, 6H). 13C NMR (CDCl3): δ 158.2, 136.0, 135.4, 129.2, 128.7, 128.5, 128.2, 127.7, 120.6, 113.9, 55.2, 49.9. HRMS. for C23H22BrO2 (M+1 peak): 409.0629. Found: 409.0643. (E)-1-Bromo-1-(p-tolyl)-3,3-diphenylprop-1-ene (2c)131: 1H NMR (250 MHz, CDCl3): δ 7.08-7.27 (m, 14H); 6.65 (d, 1H, J = 11.0 Hz); 4.73 (d, 1H, J = 11.0 Hz); 2.30, (s, 3H). 13C NMR (CDCl3): δ 143.0, 138.7, 135.4, 135.1, 128.9, 128.6, 128.5, 128.3, 128.1, 126.5, 121.5, 51.6, 21.3. (E)-1-Bromo-1,3,5-triphenylpenta-1-en-4-yne (2d)131: 1H NMR (250 MHz, CDCl3): δ 7.21-7.53 (m, 15H); 6.37 (d, 1H, J = 10.3 Hz); 4.62 (d, 1H, J = 10.3 Hz). 13C NMR (CDCl3): δ 139.2, 137.9, 132.9, 131.7, 129.0, 128.9, 128.7, 128.5, 128.3, 128.2, 127.3, 123.1, 122.0, 88.0, 84.5, 38.9. (E)-1-Bromo-1,3-diphenylnon-1-en-4-yne (2e)122: 1H NMR (250 MHz, CDCl3): δ 7.17-7.50 (m, 10H); 6.26 (d, 1H, J = 10.4 Hz); 4.37 (d, 1H, J = 10.4 Hz); 2.23-2.28 (m, 2H); 1.36-1.59 (m, 4H); 0.89-0.95 (m, 3H). 13C NMR (CDCl3): δ 139.8, 137.9, 133.8, 128.9, 128.5, 128.4, 127.2, 126.9, 121.2, 84.9, 78.5, 38.4, 30.9, 21.9, 18.6, 13.6. (E)-1-Bromo-1-(p-tolyl)-3-phenylnon-1-en-4-yne (2f): 1H NMR (250 MHz, CDCl3): δ 7.13-7.40 (m, 9H); 6.22 (d, 1H, J = 10.3 Hz); 4.39 (d, 1H, J = 10.3 Hz); 2.34 (s, 3H); 2.22-2.30 (m, 2H); 1.38-1.58 (m, 4H); 0.89-0.95 (m, 3H). 13C NMR (CDCl3): δ 139.9, 138.8, 135.1, 133.5, 129.0, 128.8, 128.5, 127.2, 126.9, 121.5, 84.8, 78.6, 38.4, 30.9, 21.9, 21.2, 18.6, 13.6. Anal. Calcd. for C22H23Br: C, 71.94; H, 6.31. Found: C, 72.08; H, 6.45. (E)-1-Bromo-1-phenyl-3-(p-chlorophenyl)non-1-en-4-yne (2g)122: 1H NMR (250 MHz, CDCl3): δ 7.19-7.49 (m, 9H); 6.20 (d, 1H, J = 10.4 Hz); 4.33 (d, 1H, J = 10.4 Hz); 2.23-2.29 (m, 2H); 1.36-1.59 (m, 4H); 0.90-0.96 (m, 3H). 13C NMR (CDCl3): δ 138.4, 137.8, 133.3, 132.8, 129.0, 128.8, 128.6, 128.5, 128.4, 121.7, 85.3, 78.1, 37.9, 30.9, 21.9, 18.6, 13.6. HRMS. for C21H21BrO2 (M+1 peak): 389.0494. Found: 389.0485. 4.4.5 Representative NMR Spectra of 1a-1l and 2a-2g 1H spectrum of 1a 13C spectrum of 1a 1H spectrum of 1b 13C spectrum of 1b 1H spectrum of 1c 13C spectrum of 1c 1H spectrum of 1d 13C spectrum of 1d 1H spectrum of 1e 13C spectrum of 1e 1H spectrum of 1f 13C spectrum of 1f 1H spectrum of 1g 13C spectrum of 1g 1H spectrum of 1h 13C spectrum of 1h 1H spectrum of 1i 13C spectrum of 1i 1H spectrum of 1j 13C spectrum of 1j 1H spectrum of 1k 13C spectrum of 1k 1H spectrum of 1l 13C spectrum of 1l 1H spectrum of 2a 13C spectrum of 2a 1H spectrum of 2b 13C spectrum of 2b 1H spectrum of 2c 13C spectrum of 2c 1H spectrum of 2d 13C spectrum of 2d 1H spectrum of 2e 13C spectrum of 2e 1H spectrum of 2f 13C spectrum of 2f 1H spectrum of 2g 13C spectrum of 2g Chapter 5. Boron Trihalide Mediated Haloallylation of Aryl Aldehydes using Allylsilane Compounds 5.1 Introduction The Lewis acid mediated allylation of carbonyl compounds leading to homoallylic alcohols constitutes one of the most important synthetic reactions.163 Numerous allylic organometallic reagents and Lewis acids have been investigated. In recent years, asymmetric allylation reactions have also been studied extensively due to their importance in medicinal and natural product chemistry. Lewis acid mediated allylations have been shown to be stepwise processes, as shown in Scheme 5-1. R O H SiMe 3 MX n R O MX n-1 SiMe 3 R O MX n-1 XSiMe 3 A X MX n R O SiMe 3 B RegenerateMX n Silylcationcatalyzed reaction Lewisacidcatalyzed pathway Scheme 5-1 Process of Lewis Acid Addition to Allyltrimethylsilane and an Aldehyde. The addition of allylsilane to an activated aldehyde forms intermediate A. The silyl electrofuge cleavage then produces the metal homoallyloxide B and Me3SiX. If the metal exchange between B and Me3SiX occurs, Lewis acid MXn is regenerated and the reaction is catalytic in nature. However, if the metal exchange does not occur, Me3SiX could also induce further allylations (silyl cation catalyzed pathway). To achieve high enantioselectivity in chiral Lewis acid catalyzed allylations, minimizing the contribution from the silyl cation catalyzed pathway is required. In the last decade, our group has developed a number of novel reactions using the chemistry of boron halide derivatives. These include, for example, the dialkenylation of aryl aldehydes by divinylboron halides,164 a reaction that appears to occur via an unprecedented process: C—O bond cleavage in the alkoxyboron monohalide intermediate. This discovery led us to develop reactions in which the hydroxyl groups were substituted with stereodefined alkenyl ADDIN EN.CITE 24, 124, 165 and alkynyl166 moieties using boron dihalides as represented in Scheme 5-2. R 2 R 1 OLi CH 2 Cl 2 0  Ctort R 2 R 1 X Ar R 2 R 1 OH n-BuLi CH 2 Cl 2 rt X Ar BX 2 R 2 R 1 O B X X Ar R 1 =aryl R 2 =aryl,propargyl,allyl,alkyl X=Cl,Br alkoxyboronmonohalide intermediate R 2 R 1 R 2 R 1 O B Cl BCl 2 R R R R=aryl,alkyl Scheme 5-2 Direct Substitution of Hydroxyl Groups with Stereodefined Alkenyl and Alkynyl Moieties using Boron Dihalides. Very recently we found that C—O bond cleavage also occurs smoothly (Scheme 5-3) in propargyloxyboron dihalide C, an intermediate which is generated from alternative route (by reaction of alkoxide with BCl3). ADDIN EN.CITE 149-150 OH R Z OBCl 2 R Z R Z 1.n-BuLi 2.BCl 3 C SiMe 3 Scheme 5-3 Allyltrimethylsilane Addition to a Propargyloxyboron Dihalide. In an earlier study, we reported a novel method for dihalogenating aryl aldehydes (Scheme 5-4).167 NMR study revealed that the reaction proceeds through the alkoxyboron dihalide intermediate 1. The similarity between intermediates C and 1 led us to investigate the feasibility of capturing intermediate 1 with allyltrimethylsilane. CHO Z Z Cl OBCl 2 Z Cl Cl Z Cl BCl 3 Hexanes 1 2 SiMe 3 /BCl 3 Thiswork Scheme 5-4 Formation of Dichloro- and Chloroallylated Compounds from Aryl Aldehydes. The mechanism shown in Scheme 5-4 led us to postulate that the reaction of aryl aldehydes with allylsilane in the presence of a stoichiometric quantity of a boron halide would lead to haloallylated product 2 rather than the homoallylic alcohol. In fact, during a kinetic study of the reaction between a carbocation and allylsilane, Mayr and Gorath noted chloroallylation of aryl aldehydes in the presence of 2—4 equivalents of BCl3.168 The sentence, “In the BCl3-promoted reaction of aldehydes with allyltrimethylsilanes, further halogeneration by excess BCl3 took place, and consecutive products were isolated instead of the corresponding alcohols” was used to describe the reaction mechanism. Herein are reported the results of a detailed study of this reaction, including a mechanistic discussion. 5.2 Results and Discussion Due to its air and moisture sensitivity, 1.1 equivalents of BCl3 were utilized for the reaction of benzaldehyde with allyltrimethylsilane. We found that the reaction proceeded readily in hexanes and gave the expected haloallylated product 2a in 85% yield. A series of aryl aldehydes were subjected to the reaction, shown in Table 5-1. Essentially all of the aryl aldehydes investigated were successfully converted to the haloallylated products with the exception of p-anisaldehyde (the cleavage of the methoxy ether by BCl3 and BBr3 is well known).7 Generally, reactions with BBr3 are faster than those using BCl3. Bromoallylated product 2i formed exclusively when a mixture of BBr3 and BCl3 (1.1 equivalents each) was added to the p-chlorobenzaldehyde reaction, demonstrating a high chemoselectivity (Scheme 5-5). CHO Cl 1.1equivBCl 3 1.1equivBBr 3 Allylsilane Hexanes Cl Br 2i Nochloroproduct Scheme 5-5 Chemoselective Bromoallylation of p-Chlorobenzaldehyde in the Presence of Equimolar Amounts of Boron Trihalide. Table 5-1 Haloallylation of Aryl Aldehydes.a CHO R SiMe 3 BX 3 (1.1Equiv.) Hexanes X R Z Z 2 Entry Z R X Time/min Product Yieldb (%) 1 H H Cl 30 2a 85 2 4-F H Cl 30 2b 62 3 4-Cl H Cl 20 2c 90 4 4-Br H Cl 30 2d 87 5 2-Me H Cl 20 2e 73 6 2-Br H Cl 180 2f 62 7 3,5-Br2 H Cl 120 2g 61 8 4-F Me Cl 60 2h 94 9 4-Cl Me Cl 60 2i 92 10 3-Br Me Cl 60 2j 94 11 2-Me Me Cl 60 2k 69 12 2,3,4,5,6-F5 Me Cl 180 2lc 67 13 4-CF3 Me Cl 120 2m 89 14 4-Cl H Br 10 2n 81 15 4-Cl Me Br 10 2o 72 16 4-Br Me Br 10 2p 78 17 3-Cl Me Br 20 2q 63 a Boron halide was added at 0 ˚C and reaction mixture was warmed to room temperature until complete. b Isolated yield based on aldehyde. c Refluxing is required for completion. Several control experiments were performed to probe the reaction mechanism. First, the reaction of allyltrimethylsilane with p-chlorobenzaldehyde using a substoichiometric amount of boron trihalide (0.8 equivalent) was carried out to determine whether the reaction was catalytic (Scheme 5-6). p-Chlorobenzaldehyde was not completely consumed after 24 hours, clearly indicating that the reaction is not catalytic. Remarkably, the Me3SiX (X = Cl, Br) generated in the reaction did not initiate a silyl cation catalyzed allylation. The discovery that Me3SiX (X = Cl, Br) was not a catalyst in the non-polar solvent hexane could be significant for allylation reactions involving chiral Lewis acid catalysts. Hydrolysis of the reaction mixture at this stage revealed products 4 and 2. Homoallylic alcohol 4 was isolated as the major product (70% yield) along with chloroallylated product 2c (8% yield) when BCl3 was employed. In contrast, bromoallylated product 2i was the main product if boron tribromide was used; the yields of 4 and 2i were 26% and 41%, respectively. In a separate experiment, an additional 0.3 equivalents of boron trihalide was added to the substoichiometric (0.8 equivalents) mediated reactions after they had been allowed to react for 24 hours. Both intermediate 3 and the unreacted p-chlorobenzaldehyde disappeared (no homoallylic alcohol 4 detected). Clearly the conversion of intermediate 3 to haloallylated product 2 occurred. CHO Cl BX 3 (0.8Equiv) Allylsilane Hexanes Cl X 2 BO Cl X CHO Cl (unreacted) Me 3 SiX Cl HO Cl X H 2 O BX 3 (0.3Equiv) 3 2c,2i 4 2 Scheme 5-6 Determination of Catalytic Nature of Reaction by Addition of Substoichiometric Amount of BX3. The complete conversion of intermediate 3 and unreacted p-chlorobenzaldehyde to haloallylated product 2 using only an additional 0.3 equivalent of boron trihalide (Scheme 5-6) was somewhat surprising. The isolation of homoallylic alcohol 4 in 53% yield from a modified reaction (Scheme 5-7) helps explain the earlier observation. Removal of the Me3SiCl prior to addition of the extra BCl3 inhibits the conversion of intermediate 3 to product 2c. CHO Cl Cl Cl BCl 3 (0.8Equiv) Allylsilane; Hexanes 30min 1.Vacuum 2.BCl 3 (0.4Equiv); Allylsilane; Hexanes HO Cl 4 2c Scheme 5-7 Experimental Illustration of Me3SiCl Removal. Based on these experiments, a tentative mechanism was proposed to explain the boron trihalide catalyzed transformation of 3 to 2 (Scheme 5-8). Boron trihalide coordinates with the oxygen in intermediate 3 to form 5. Rearrangement of 5 generates the desired product 2 along with X2B—O—BX2 (6). Exchange between 6 and Me3SiX regenerates boron trihalide and mixed anhydride 7. X 2 BO Z O Z X 3 B BX 2 X Z BX 3 O BX 2 X 2 B O SiMe 3 X 2 B Me 3 SiX 3 5 2 6 7 Scheme 5-8 Proposed Mechanistic Pathway for Formation of Haloallylated Product (2) from Intermediate 3. Interestingly, the haloallylation of aryl aldehydes using 2-bromoallyltrimethylsilane generated a mixture of (3-bromo-1-chlorobut-3-en-1-yl)benzene derivatives along with unexpected (3-chloro-1-chlorobut-3-en-1-yl)benzene derivatives (Scheme 5-9), which are proved by GC-MS spectrum. Cl Br Z O Z SiMe 3 Br BCl 3 Cl Cl Z Scheme 5-9 Haloallylation of Aryl Aldehydes with 2-Bromoallyltrimethylsilane. A mechanistic route to these unintended products is provided in Scheme 5-10. Similar to intermediate A (Scheme 5-1), intermediate D (Scheme 5-8) is generated by Lewis acid activation of aryl aldehydes with boron trichloride in the presence of 2-bromoallyltrimethylsilane. The subsequent chlorination of the carbocation of the metal homoalloxide intermediate D by chlorine forms intermediate E. Elimination of the more reactive bromine during silyl electrofuge cleavage produces intermediate F, resulting in the unintended (1,3-dichlorobut-3-en-1-yl)benzene compounds. Consequently, the haloallylation of aryl aldehydes using 2-bromoallyltrimethylsilane produces a mixture of inseparable 1,3-dihaloallylated products. R O Cl 2 B Br SiMe 3 Cl R O Cl 2 B Br SiMe 3 Cl Cl R O Cl 2 B Cl D E F Scheme 5-10 Proposed Mechanistic Pathway for (1,3-Dichlorobut-3-en-1-yl)benzene Compounds. Table 5-2 Haloallylation of Aryl Aldehydes using 2-Bromoallyltrimethylsilane Resulting in 1,3-Dihaloallylated Products.a Cl Br Z O Z SiMe 3 Br BCl 3 (1.1Equiv.) Cl Cl Z 8 9 Entry Z Time (min) Product Yieldb of 8 (%) Yieldb of 9 (%) Ratio of 8 : 9c 1 napthyl 60 8a + 9a 38 32 1.2 : 1 2 2-Me 60 8b + 9b 78 16 5.8 : 1 3 3-Br 60 8c + 9c 40 21 2.2 : 1 4 4-Cl 60 8d + 9d 69 29 2.8 : 1 5 4-Br 60 8e + 9e 48 25 2.2 : 1 6 4-NO2 120c 8f + 9f 37 33 1.4 : 1 a Boron trichloride was added at 0 ˚C and then the reaction mixture was warmed to room temperature until complete (see Experimental for details). b Yield based on aldehyde. c Ratio determined by 1H NMR. d Refluxing required for completion. The yields and product ratio for haloallylation of aryl aldehydes using 2-bromoallyltrimethylsilane are shown in Table 5-2. The percent of compound 8b in Table 5-2 suggests that steric hindrance slows the formation of the unintended chlorinated side product, 9b. 5.3 Conclusions In summary, a facile haloallylation of aryl aldehydes using boron trihalide is reported. A mechanistic study revealed the reaction involves two-steps: i) conversion of aldehydes to homoallyloxide borates in the presence of a stoichiometric amount of boron trihalides; ii) a boron trihalide catalyzed conversion of homoallyloxide borates into halogenated products in the presence of Me3SiX (X = Cl, Br). The use of 2-bromoallyltrimethylsilane in the haloallylation of aryl aldehydes results in a mixture of 1,3-dihaloallylated products. 5.4 Experimental 5.4.1 General Methods All reagents were used as received. Column chromatography was performed using silica gel (60 Å, 230–400 mesh, ICN Biomedicals GmbH, Eschwege, Germany). Analytical thin-layer chromatography was performed using 250 μm silica plates (Analtech, Inc., Newark, DE). 1H NMR and 13C NMR spectra were recorded at 250.13 and 62.89 MHz, respectively. Chemical shifts for 1H NMR and 13C NMR spectra were referenced to TMS and measured with respect to the residual protons in the deuterated solvents. Atlantic Microlab, Inc., Norcross, Georgia, performed microanalysis. Gas Chromatography-Mass Spectroscopy studies were run on Hewlett Packard: HP 6890 series GC System with 5973 Mass Selective Detector; Column: Agilent 19091S-433E, 30.0mm X 0.25mm X 0.25 μm; Gas (He) flow rate: 0.8 mL/min; Initial temperature; 50 ˚C (hold 1 min); Ramp temperature rate: 7 ˚C /min to maximum 280 ˚C. 5.4.2 Typical Reaction Procedure Finely ground 4-chlorobenzaldehyde (210 mg, 1.5 mmol), allyltrimethylsilane (256 mg, 2.25 mmol) and dry hexanes (16 mL) were placed in a dry argon-flushed, 50 mL round-bottomed flask equipped with a magnetic stirring bar. The solution was cooled to 0 ˚C, and boron trichloride (1.65 mmol, 1.65 mL of a 1.0 M CH2Cl2 solution) was added via syringe. After completion of the addition, the ice-bath was removed and the resulting solution was allowed to warm to room temperature. The reaction mixture was hydrolyzed with water and extracted with hexanes. The organic layer was separated, dried over anhydrous MgSO4, the solvent removed under reduced pressure, and the product isolated by flash column chromatography. 5.4.3 Reaction Procedure for Haloallylation of Aryl Aldehydes using (2-Bromoallyl)trimethylsilane Finely ground 4-chlorobenzaldehyde (70 mg, 0.50 mmol), (2-bromoallyl)trimethylsilane (116 mg, 0.60 mmol) and dry hexanes (10 mL) were placed in a dry argon-flushed, 50 mL round-bottomed flask equipped with a magnetic stirring bar. The solution was cooled to 0 ˚C, and boron trichloride (0.55 mmol, 0.55 mL of a 1.0 M CH2Cl2 solution) was added via syringe. After completion of the addition, the ice-bath was removed and the resulting solution was allowed to warm to room temperature. The reaction mixture was hydrolyzed with water and extracted with hexanes. The organic layer was separated, dried over anhydrous MgSO4, the solvent removed under reduced pressure, and the product isolated by flash column chromatography. 5.4.4 Characterization of Compounds 2a-2n (1-Chlorobut-3-enyl)benzene (2a)168: 1H NMR (250 MHz, CDCl3): δ 7.25-7.38 (m, 2H), 7.00–7.08 (m, 2H), 5.62-5.77 (m, 1H), 5.06-5.16 (m, 2H), 4.82 (t, J = 7.22 Hz, 1H), 2.72-2.85 (m, 2H). 13C NMR (CDCl3): δ 138.1, 134.4, 129.0, 128.8, 128.6, 116.3, 56.7, 43.2. 1-(1-Chlorobut-3-enyl)-4-fluorobenzene (2b): 1H NMR (250 MHz, CDCl3): δ 7.25-7.38 (m, 2H), 7.00–7.08 (m, 2H), 5.65-5.79 (m, 1H), 5.08-5.15 (m, 2H), 4.83 (t, J = 7.27 Hz, 1H), 2.73-2.86 (m, 2H). 13C NMR (CDCl3): δ 162.5, (1JCF= 246.5 Hz), 160.5, 137.4, 133.6, 128.8, (3JCF= 7.7 Hz), 118.4, 115.5, (2JCF= 21.2 Hz), 61.3, 44.2. Anal. Calcd for C10H10ClF: C, 65.05; H, 5.46. Found: C, 65.48; H, 5.61. 1-(1-Chlorobut-3-enyl)-4-chlorobenzene (2c)168: 1H NMR (250 MHz, CDCl3): δ 7.29-7.33 (m, 4H), 5.63-5.77 (m, 1H), 5.06-5.14 (m, 2H), 4.86 (t, J = 7.33 Hz, 1H), 2.71-2.86 (m, 2H). 13C NMR (CDCl3): δ 139.7, 134.0, 133.5, 128.7, 128.4, 116.5, 61.7, 44.0. 1-(1-Chlorobut-3-enyl)-4-bromobenzene (2d)169: 1H NMR (250 MHz, CDCl3): δ 7.44-7.47 (m, 2H), 7.21–7.25 (m, 2H), 5.63-5.76 (m, 1H), 5.06-5.13 (m, 2H), 4.81 (t, J = 7.21 Hz, 1H), 2.70-2.85 (m, 2H). 13C NMR (CDCl3): δ 140.1, 133.4, 131.7, 128.7, 118.5, 61.6, 43.9. 1-(1-Chlorobut-3-enyl)-2-methylbenzene (2e): 1H NMR (250 MHz, CDCl3): δ 7.14-7.50 (m, 4H), 5.74-5.80 (m, 1H), 5.07-5.17 (m, 3H), 2.81-2.91 (m, 2H), 2.38 (s, 3H). 13C NMR (CDCl3): δ 139.1, 135.3, 134.2, 130.5, 128.1, 126.5, 118.1, 58.7, 43.0, 19.1. Anal. Calcd for C11H13Cl: C, 73.12; H, 7.25. Found: C, 73.54; H, 7.37. 1-Bromo-2-(1-chlorobut-3-en-1-yl)benzene (2f)170: 1H NMR (250 MHz, CDCl3): δ 7.58 (ddd, J = 15.7, 7.9, 1.3 Hz, 1H), 7.42 – 7.29 (m, 1H), 7.15 (td, J = 8.0, 1.7 Hz, 1H), 5.82 (ddt, J = 23.3, 10.4, 6.9 Hz, 1H), 5.42 (t, J = 7.0 Hz, 1H), 5.22 – 5.05 (m, 1H), 2.87 – 2.70 (m, 1H). 13C NMR (CDCl3): δ 133.3, 132.7, 129.5, 128.7, 127.9, 122.9,