* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Methodology for the olefination of aldehydes and ketones via the Meyer-Schuster reaction
Bottromycin wikipedia , lookup
Woodward–Hoffmann rules wikipedia , lookup
Marcus theory wikipedia , lookup
Fischer–Tropsch process wikipedia , lookup
Kinetic resolution wikipedia , lookup
Elias James Corey wikipedia , lookup
Enantioselective synthesis wikipedia , lookup
George S. Hammond wikipedia , lookup
Physical organic chemistry wikipedia , lookup
Discodermolide wikipedia , lookup
Diels–Alder reaction wikipedia , lookup
Stille reaction wikipedia , lookup
Tiffeneau–Demjanov rearrangement wikipedia , lookup
Aza-Cope rearrangement wikipedia , lookup
Hofmann–Löffler reaction wikipedia , lookup
Aldol reaction wikipedia , lookup
1,3-Dipolar cycloaddition wikipedia , lookup
Asymmetric induction wikipedia , lookup
Ring-closing metathesis wikipedia , lookup
Baylis–Hillman reaction wikipedia , lookup
Wolff–Kishner reduction wikipedia , lookup
Ene reaction wikipedia , lookup
Wolff rearrangement wikipedia , lookup
Petasis reaction wikipedia , lookup
Hydroformylation wikipedia , lookup
FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES METHODOLOGY FOR THE OLEFINATION OF ALDEHYDES AND KETONES VIA THE MEYER-SCHUSTER REACTION By SUSANA SORINA LÓPEZ A Thesis submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Master of Science Degree Awarded: Spring Semester, 2009 Copyright © 2009 Florida State University All Rights Reserved The members of the Committee approve the Thesis of Susana Sorina López defended on April 2nd, 2009. __________________________________ Gregory B. Dudley Professor Directing Thesis ___________________________________ Igor Alabugin Committee Member __________________________________ Lei Zhu Committee Member __________________________________ Michael Shatruk Committee Member Approved: _____________________________________ Joseph Schlenoff, Chair, Arts and Sciences The Graduate School has verified and approved the above named committee members. ii Quiero dedicar esta tesis a mis padres, Oscar y Susana Mercedes López por todos los sacrificios que han hecho a lo largo de los años para ayudarme a convertirme en la mujer que soy hoy. Sin su amor y apoyo esto no habría sido posible. I would also like to dedicate this to Dr. Paul I. Higgs, who has provided me with the encouragement and guidance that has allowed me to never give up on myself. Lastly, I dedicate this to Brian Ray Jacobs, who has shown me that love can provide strength in times of weakness. With all my all love and appreciation, (Con todo mi amor y aprecio), Susana iii ACKNOWLEDGEMENTS I would like to express my gratitude to my major professor, Dr. Gregory B. Dudley, for his support and guidance during these first three years of my graduate studies. I would also like to thank the past and present members of the Dudley group for their friendship and support: Dr. Mariya V. Kozytska, David M. Jones, Jingyue Yang, Sami Tlais, Daniella Barker, Jumreang Tummatorn, post-docs: Dr. Philip Albiniak and Dr. Jeannie Jeong for their guidance during their time in our lab and Douglas A. Engel for the work and direction during our collaboration on the Meyer-Schuster chemistry. The members of my committee: Dr, Igor Alabugin, Dr. Lei Zhu and Dr. Michael Shatruk for their assistance and patience during the preparation of this thesis. Lastly, I would like to acknowledge Dr. George Fisher and Mara Tsesarskaja for exposing me to chemistry research for the first time as an undergraduate at Barry University. ii TABLE OF CONTENTS List of Tables ............................................................................................. List of Figures ............................................................................................ List of Symbols .......................................................................................... Abstract .................................................................................... vi vii ix xiv 1. Introduction............................................................................................ 1 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5 1.1.6 1.1.7 Olefination Strategies for the Synthesis of α,β-Unsaturated Esters.. Wittig Reaction ................................................................................. Horner-Wadsworth-Emmons............................................................ Meyer-Schuster Rearrangement of Propargyl Alcohols ................... Mechanism .................................................................................... Earlier Work in the Dudley Lab........................................................ Conclusion ..................................................................................... 1 3 5 6 8 9 11 2. Results and Discussion .......................................................................... 12 2.2.1 Lewis-acid Catalyzed Rearrangement of Ethoxyalkynyl Carbinols 2.2.2 Gold –catalyzed Meyer-Schuster Reaction of Secondary Ethoxyalkynyl Carbinols…… .................................................. 2.2.3 Substrate Scope and Stereoselectivity ....................................... 2.2.4 Conclusion ................................................................................. 2.2.5 Alternative Catalysts for the Meyer-Schuster Reaction of Secondary and Tertiary Ethoxyalkynyl Carbinols ...................................... 2.2.6 Screening of Alternative Catalysts ............................................. 2.2.7 Effects of Additives ................................................................... 2.2.8 Optimization of Reaction Conditions and Stereoselectivity ...... 2.2.9 Two-stage Olefination of Aldehydes and Ketones .................... 2.3.1 Mechanistic Hypothesis of the Lewis-acid Catalyzed iii 12 13 17 18 20 21 23 24 25 2.3.2 Meyer-Schuster Reaction ........................................................... 2.3.3 Conclusion ................................................................................. 3. Experimental 28 31 ……... ........................................................................ 32 REFERENCES .......................................................................................... 38 BIOGRAPHICAL SKETCH ...................................................................... 41 iv LIST OF TABLES Table1: Catalyst screenings .................................................................................... 14 Table 2: Solvent screenings .................................................................................... 15 Table 3: Additive screenings .................................................................................. 16 Table 4: Series of representative secondary alcohol substrates .............................. 17 Table 5: Catalytic screenings of alternative Lewis-acid catalysts .......................... 21 Table 6: Effect of additives on top three Lewis-acid catalysts ............................... 22 Table 7: Ethanol as an additive vs. ethanol as a co-solvent.................................... 24 Table 8: Scandium (III) triflate catalyzed homologation of hindered ketones ....... 26 Table 9: Statiscal incorporation of n-propanol ....................................................... 30 v LIST OF FIGURES Figure 1: Aldol condensation.................................................................................. 1 Figure 2: Acid-catalyzed aldol condensation.......................................................... 2 Figure 3: Base-catalyzed aldol condensation.......................................................... 2 Figure 4: Peterson olefination................................................................................. 3 Figure 5: Wittig reaction......................................................................................... 3 Figure 6: Examples of three different ylide categories........................................... 4 Figure 7: Horner-Wadsworth-Emmons reaction .................................................... 5 Figure 8: HWE stereoselectivity............................................................................. 6 Figure 9: Two possible reaction pathways of propargyl alcohols .......................... 7 Figure 10: Acetylide addition/Meyer-Schuster reaction......................................... 8 Figure 11: Lewis-acid catalyzed mechanism for activating propargyl alcohols..... 9 Figure 12: Gold-catalyzed Meyer-Schuster reactions of tertiary ethoxyalkynyl carbinols ................................................................................................ 10 Figure 13: Activation of Lewis basic sites of electronically neutral propargyl alcohols.................................................................................................. 12 Figure 14: Single step formation of α,β-unsaturated ketones ................................. 12 Figure 15: Gold(I) and silver (I) hexafluoroantimonate Meyer-Schuster rearrangement ............................................................. 13 Figure 16: Conditions for catalytic screenings ....................................................... 14 Figure 17: Conditions for solvent screenings ......................................................... 15 Figure 18: Conditions used for additive screenings................................................ 16 Figure 19: Optimized conditions for the gold (I) silver hexafluoroantimonate Meyer-Schuster rearrangement ............................................................ 17 vi Figure 20: Lewis-basic sites of propargyl alcohols ................................................ 23 Figure 21: Optimized conditions for Cu(I) and Sc(I) Meyer-Schuster rearrangement ....................................................................................... 25 Figure 22: Compatibility of the Meyer-Schuster reaction ...................................... 27 Figure 23.Hypothesized gold catalyzed Meyer-Schuster rearrangement ............... 28 Figure 24: Ratio of ethyl to n-propyl esters ............................................................ 28 Figure 25: .Reaction of α,β-unsaturated ester in Meyer-Schuster conditions......... 29 Figure 26: Hypothesized Meyer-Schuster rearrangement with n-propanol............ 30 Figure 27: Conditions for the Meyer-Schuster rearrangement with n-propanol..... 30 vii LIST OF SYMBOLS Ac acetyl acac acetylacetonate AIBN 2,2’-azobisisobutyronitrile anhyd anhydrous Ar aryl atm atmosphere(s) 9-BBN 9-borabicyclo[3.3.1]nonyl Bn benzyl BOC tert-butoxycarbonyl bp boiling point br broad (spectral) Bu butyl i-Bu iso-butyl s-Bu sec-butyl t-Bu tert-butyl °C degrees Celsius calcd calculated Cbz benzyloxycarbonyl CI chemical ionization (in mass spectrometry) cm centimeter(s) concd concentrated COSY correlation spectroscopy COT cyclooctatetraene Cp cyclopentadienyl Cy-hexyl cyclohexyl δ chemical shift in parts per million downfield from tetramethylsilane d day(s); doublet (spectral) DABCO 1,4-diazabicyclo[2.2.2]octane DBN 1,5-diazabicyclo[4.3.0]non-5-ene viii DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCB 2,6-dichlorobenzyl DCC N,N-dicyclohexylcarbodiimide DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4,benzoquinone DEAD diethyl azodicarboxylate DEPT distortionless enhancement by polarization transfer DIBALH diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMF dimethylformamide DMPU dimethylpropylene urea DMSO dimethyl sulfoxide E1 unimolecular elimination E2 bimolecular elimination ee enantiomeric excess EI electron impact (in mass spectrometry) Et ethyl FAB fast action bombardment (in mass spectrometry) FT Fourier transform g gram(s) GC gas chromatography H hours(s) HMO Hückel molecular orbital HMPA hexamethylphosphoric triamide HOMO highest occupied molecular orbital HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry Hz hertz IP ionization potential IR infrared ix J coupling constant (in NMR) k kilo KOH potassium hydroxide L liter(s) LAH lithium aluminum hydride LDA lithium diisopropylamide LHMDS lithium hexamethyldisilazane LTMP lithium 2,2,6,6-tetramethylpiperidide LUMO lowest occupied molecular orbital μ micro m multiplet (spectral), meter(s), milli M moles per liter MBH Morita-Baylis-Hillman m-CPBA m-chloroperoxybenzoic acid m/e mass to charge ratio (in mass spectrometry) Me methyl MEM (2-methoxyethoxy)methyl Mes mesityl, 2,4,6-trimethylphenyl MHz megahertz min minute(s) mM millimoles per liter MO molecular orbital mol mole(s) MOM methoxymethyl mp melting point Ms Methanesulfonyl (mesyl) MS mass spectrometry MVK methyl vinyl ketone m/z mass to charge ratio (in mass spectrometry) NBS N-bromosuccinimide NCS N-chlorosuccinimide x NMO N-methylmorpholine-N-oxide NMR nuclear magnetic resonance NOE nuclear Overhauser effect Nu nucleophile OD optical density ORD optical rotary dispersion PCC pyridinium chlorochromate PDC pyridinium dichromate PEG polyethylene glycol Ph phenyl PMB p-methoxybenzyl PPA polyphosphoric acid ppm parts per million (in NMR) PPTS pyridinium p-toluenesulfonate Pr propyl i-Pr isopropyl q quartet (spectral) re rectus (stereochemistry) Rf retention factor (in chromatography) rt room temperature s singlet (spectral); second(s) si sinister (stereochemistry) SN1 unimolecular nucleophilic substitution SN2 bimolecular nucleophilic substitution SN’ nucleophilic substitution with allylic rearrangement t triplet (spectral) TBAB tetrabutylammonium bromide TBDMS tert-butyldimethylsilyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride xi THF tetrahydrofuran THP tetrahydropyran TIPS triisopropylsilyl TLC thin layer chromatography TMEDA N,N,N’,N’-tetramethyl-1,2-ethylenediamine TMS trimethysilyl, tetramethylsilane Tr triphenylmethyl (trityl) Ts tosyl, p-toluenesulfonyl TS transition state tR retention time (in chromatography) UV ultraviolet xii ABSTRACT Our lab was faced with a synthetic challenge during studies towards the total synthesis of the anti-malaria drug, artemisinin. Known methods such as the Aldol condensation, the HornerWadsworth-Emmons and the Wittig reactions were ineffective for the olefination of hindered ketones. We were required to find an alternative approach of olefination that would not be restricted by steric constraints. In 2006, reported on a two-step strategy for the HWE-type olefination of hindered ketones: (1) addition of ethoxyacetylide, then (2) Au3+ catalyzed Meyer– Schuster rearrangement. Alkyne addition to carbonyl groups is relatively insensitive to sterics, whereas the resulting congested tertiary ethoxyalkynyl carbinols are sterically and electronically primed for rearrangement. Having identified this important two-stage synthetic application, we focused our attention on step two; the Meyer–Schuster rearrangement. The Meyer-Schuster reaction is a little-known but potentially powerful rearrangement that converts propargyl alcohols into α, βunsaturated carbonyl compounds. In our earlier study, which featured highly reactive tertiary propargyl alcohol substrates, rearrangement occurred immediately upon addition of the gold catalyst. In 2007, we expanded our scope and reported a new reaction protocol and important observations with respect to the rearrangement of secondary alcohol substrates. We found that secondary ethoxyalkynyl carbinols could be converted into the corresponding ethyl trans-α, β-unsaturated esters with moderate to good stereocontrol using a mixed catalyst system of gold (I) chloride and silver (I) hexafluoroantimonate. Recent advances in our methodology for the olefination of aldehydes and ketones using the Meyer–Schuster reaction of ethoxyacetylenes focused on four key points: (1) seeking alternative catalysts that are more economical and widely available than gold or silver salts, (2) lowering the catalyst loadings more than our previously reported methods using gold and silver salts, (3) obtain excellent stereoselectivity in the formation of the E-alkene isomer for most disubstituted alkenes, and (4) examine new mechanistic data suggesting that the higher stereoselectivity associated with the new catalysts may stem from a subtle alteration of the reaction mechanism. xiii CHAPTER I INTRODUCTION 1.1.1 Olefination Strategies for the Synthesis of α, β-Unsaturated Esters O O O + H O R O + H2 O R Figure 1. Aldol reaction The homologation of aldehydes and ketones to α,β-unsaturated esters (Fig. 1), an indispensable tool for generating carbon–carbon bonds, is typically achieved using aldol condensation1, Wittig, Horner–Wadsworth–Emmons (HWE), or other olefination methods2,3. Of these, the aldol condensation is most attractive from an atom economy4 standpoint in that water is the only by-product of the reaction. In the presence of dilute sodium hydroxide at room temperature, acetaldehyde undergoes an basecatalyzed dimerization reaction to produce 3-hydroxybutanal. Reactions of this nature are commonly referred to as aldol additions because that 3hydroxybutanal is both an alcohol and an aldehyde. The initial protocol involved the use of a Brønsted acid or base as the catalyst; however, this caused problematic and undesirable side reactions. Although the reaction was efficient, there was room for improvement to the methodology. The classical acid catalyzed aldol reaction (Fig. 2) is a reversible reaction in which the electrophile is activated via protonation and under goes nucleophilic attack by an enol. In contrast, the base catalyzed reaction (Fig. 3) involves the formation of an enolate via deprotonation, which then adds to the carbonyl forming the addition product. 1 Figure 2. Acid-catalyzed aldol dehydration Figure 3. Base-catalyzed aldol dehydration Dehydration of the aldol addition product gives rise to an α,β-unsaturated carbonyl compound. Thus, one can achieve the two-step homologation of aldehydes to α,β-unsaturated esters by aldol addition of the ester enolate, followed by elimination. This two-step condensation is an important transformation in organic synthesis, but it has key limitations in scope, stereoselectivity, and functional group tolerance. Consequently, alternative protocols for achieving the homologation of aldehydes and ketones to α, β-unsaturated esters have emerged over the years. The aldol addition of a α-silyl ester to an aldehyde can be followed by facile elimination of the silanol in a variant of the Peterson olefination (Fig. 4). The Peterson olefination uses α-trimethylsilylsubstituted organometallic compounds which convert carbonyl compounds to alkenes via a βsilylcarbinol. 2 R1 R2 OH R R3 R3Si R1 R1 R1 Si R2 R2 R4 R1 R3 R2 R3 R1 R4 acid O + R3 M base 4 R4 R1 R2 R3Si OH base 3 R R4 R1= alkyl, aryl; R2=alkyl, aryl, CO2R, CN, CONR2, CH=NR, SR, SOR, SO2R, SeR, SiR3, OR, BO2R2; R3, R4=alkyl, aryl, H Figure 4. Peterson olefination The α-silyl carbanions can be prepared by various methods but the subsequent addition to the carbonyl compound gives a diastereomeric mixture of β-silylcarbinols which depending on R2 substituent may or may not be easily separated. 1.1.2 Wittig Reaction The Wittig reaction1 (Fig. 5) between aldehydes or ketones with phosphoranes is a valuable method for the synthesis of olefins. This method provides for the synthesis of alkenes from carbonyl compounds by replacing the oxygen of a carbonyl with an alkylidene group. The phosphorus ylides that serve as the active reagents are prepared combining triphenylphosphine first with a primary or secondary alkyl halide and subsequently with an appropriate base. Although a strong base is typically used (eg. alkyllithium), if the salt is sufficiently acidic, then a mild base, such as sodium bicarbonate may be used for the deprotonation step. O O PPh3 O + H O R O Figure 5. Wittig reaction 3 R + Ph3P O Phosphorus ylides are prepared before the reaction or in-situ and precautions must be taken due to their sensitivity to moisture and air. The carbanion of the ylide is the characteristic component that allows for nucleophilic attack on the carbonyl carbon. The ylides have been found to demonstrate faster reaction rates with aldehydes than they do with ketone substrates. The reactivity of the ylide is dependent on its substituents. Ylides are classified into three different categories (Fig 6). The first category is the stabilized ylides. These ylides possess at least one strong electron withdrawing group which stabilizes the negative charge on the carbanion. In regards to the stereoselectivity when reacted with aldehydes, these stabilized ylides will yield the (E)-alkene. It is noteworthy to mention that ester and ketone stabilized ylides react with aldehydes to give aldol condensation type products. Ester-stabilized ylides are employed for homologation of aldehydes to α,βunsaturated esters. The reaction of ester stabilized ylides with ketones is rare. O R 3 1 (R )3P X R3 1 (R )3P X X= Cl, Br, I, R2 R2 OTs alkyl halide phsophonium salt 3 3 base R (R1)3P R5 R4 R2 -(R1)3P O R5 R3 4 R R (R1)3P R2 R2 phosphorus ylide (phosphorane) R4, R5= alkyl, aryl, alkynyl, H olefin “non-stabilized” ylide R1= aryl and R2,R3= alkyl, H “semi-stabilized” ylide R1= aryl and R2,R3= alkyl, alkenyl, benzyl, allyl, H “stabilized” ylide R1= aryl and R2,R3= -CO2R, -SO2R, -CN, -COR Figure 6. Examples of three different ylide categories On the other extreme there are the non-stabilized ylides which contain only alkyl substituents which do not stabilized the negative charge on the carbon. When a base is used in the absence of lithium halides (salt-free conditions) and polar, aprotic solvents these ylides provide a high selectivity for the (Z)-alkene. 4 The third category is semi-stabilized ylides. These ylides contain at least one aryl or alkenyl group which is less stabilizing when compared to the structure of the stabilized ylide. In contrast to the stabilized and non stabilized ylides, the semi stabilized ylides have poor stereo selectivity. Some other considerations that influence the stereochemical outcome of the reactions are the type of carbonyl compound which is used, the solvent and the counter ion that is used for formation of the ylide. 1.1.3 Horner-Wadsworth-Emmons The Horner-Wadsworth-Emmons (HWE) reaction1 is a variant of the Wittig designed specifically to overcome limitations in the reactivity of stabilized phosphorus ylides. The reaction (Fig. 7) takes place when an aldehyde or ketone reacts with a phosphonate as opposed to a phosphorane. The HWE is an improvement over the Wittig ylides since phosphonate anions are more reactive than the phosphorus ylides. These alkylphosphonates are easier to prepare and less costly than the phosphonium salts. O O O O + P H R OEt OEt O O R + O HO P OEt OEt Figure 7. Horner-Wadsworth-Emmons reaction A significant advantage of HWE reagents over phosphoranes is that HWE phosphonates can react with ketone substrates, whereas phosphoranes do not. Another feature that makes the HWE advantageous is that it can give desired stereoselectivity depending on the substituent that is placed in the R’ position. Bulkier groups, such as tert-butyl, will favor the (E)-olefin and smaller groups such as methyl will give rise to the (Z)-olefin as the product (Fig. 8). 5 Figure 8. HWE stereoselectivity The Wittig and HWE reaction both use stoichiometric phosphines, phosphine oxides, or phosphonates to provide α, β-unsaturated ester products. However, these reactions produce phosphorus by-products that can interfere with the isolation of the desired products. Whether using designer olefination reagents or a traditional aldol condensation protocol, these homologation reactions are sensitive to steric congestion around the carbonyl, such that olefination of hindered ketones can be problematic. In fact, homologation reactions of hindered ketones to α, β-unsaturated esters were a largely unsolved problem at the onset of this work. 1.1.4 Meyer-Schuster Rearrangement of Propargyl Alcohols Propargyl alcohols are readily available, versatile tools in organic synthesis, providing access through different reaction pathways to desirous products such as alkenes, allenes, alkynes, ketones, etc.5,6 For example, hydrometalation (syn or anti), substitution (at the α- or γ-centers), hydration, oxidation, hydrogenation, and deoxygenation all may be accomplished through selective activation of propargyl alcohol substrates. One such pathway is the Meyer-Schuster rearrangement. This reaction converts propargyl alcohols into α, β-unsaturated carbonyls. The Meyer-Schuster rearrangement involves the acid catalyzed isomerization of secondary and tertiary propargyl alcohols. A formal [1, 3] shift of the hydroxyl group and tautomerization gives α, βunsaturated carbonyl, probably via a propargyl cation. The reaction may be catalyzed with Lewis or protic acids and is not sensitive to moisture in that it may be conducted in either aqueous or anhydrous 6 conditions. However, the Meyer-Schuster rearrangement is but one possible fate of the propargyl cation and selecting for the Meyer-Schuster pathway has been a long lasting challenge. The most significant competing pathway is the Rupe rearrangement 7 (Fig 9). Figure 9. Two possible reaction pathways of propargyl alcohols Under the original Meyer-Schuster conditions, most propargyl alcohols in fact show a preference for reacting along the Rupe pathway. The Rupe and Meyer-Schuster rearrangements (Fig. 9) are not often used in chemical synthesis due to harsh conditions and poor selectivity. The Meyer-Schuster products (path b) are especially rare because the dehydration that leads into the Rupe pathway (path a) generally takes precedence under traditional modes of activation that target the substrate through the alcohol moiety (i.e., acidic catalysts). 7 Methods for the synthesis of propargyl alcohols from aldehydes and ketones in combination with the Meyer-Schuster rearrangement provide two-step routes for the olefination of α, β-unsaturated esters. A major advantage of using the acetylide addition/Meyer–Schuster reaction strategy for the olefination of aldehydes and ketones (Fig. 10) is the efficiency of the initial carbon–carbon bond-forming reaction: alkyne addition. acetylide addition O R2 R1 R3 H R3 Meyer–Schuster rearrangement R2 OH R1 R2 O R1 R3 H Figure 10. Acetylide addition/Meyer–Schuster reaction However, the second stage of this strategy—the Meyer–Schuster reaction—is generally limiting. The reaction protocol uses high temperatures and acidic conditions which limit the reaction scope. Therefore, advances in the Meyer–Schuster reaction translate directly into advances in olefination methods. 1.1.5 Mechanism Coordination of the alkyne using soft, late-transition-metal Lewis acids, 8 including cationic gold catalysts 9,10 , provides a fundamentally different mechanism for activating propargyl alcohols (Fig. 11) Also, sensitive functionalities may be more tolerant of ‘soft’ alkyne activation than ‘hard' activation of the oxygen atom, providing complementary selectivity. 8 Figure 11. Lewis-acid catalyzed mechanism for activation of propargyl alcohols 1.1.6 Earlier Work in the Dudley Lab Alkyne addition to carbonyl groups is relatively insensitive to sterics, whereas the resulting congested tertiary ethoxyalkynyl carbinols are sterically and electronically primed for rearrangement. In 2006, we reported gold-catalyzed Meyer–Schuster reactions of tertiary ethoxyalkynyl carbinols for the synthesis of α,β-unsaturated ethyl esters (Fig. 12).11,12 In conjunction with ethoxyacetylide addition to ketones, this work provided the blueprint for general implementation of the two-stage olefination strategy outlined below (1b→3b, R3=OEt, Fig. 12) for the synthesis of α,β-unsaturated esters. 9 Figure 12. Gold-catalyzed Meyer–Schuster reactions of tertiary ethoxyalkynyl carbinols The combination of the electron-rich ethoxyacetylenic π-system and soft gold (III) chloride catalyst13 provided excellent reactivity in the Meyer–Schuster reaction: consumption of the intermediate tertiary ethoxyalkynyl carbinols occurred within minutes of adding the catalyst. The Meyer–Schuster reactions were conducted open to the air without external heating or cooling. Yields for both the acetylide addition and the formal rearrangement14, 14a, 14b and 14c were essentially quantitative in the majority of cases, but stereocontrol of the olefin geometry was non-existent. The second drawback of the reported conditions is the requirement for 5 mol % of the (expensive) gold catalyst. At 5 mol % catalyst loading, the reactions were complete within minutes, but at 1 mol %, the reaction failed to reach full conversion even after prolonged reaction times.11 10 1.1.7 Conclusion The Aldol, the Wittig and the HWE reactions are well known reactions for the conversion of aldehydes and ketones in to α, β- unsaturated esters. The aldol condensation is most attractive from the atom economy perspective, but it is the least general in terms of scope and efficiency. Although the Wittig and the HWE although more efficient, they produce toxic and/or undesirable phosphorus byproducts. Moreover, the steric sensitivity of these classical methods impeded the olefination of hindered ketones, which led us to seek an alternative synthetic route for the preparation of the sterically congested α,β-unsaturated esters. The use of electron-rich ethoxyacetylenic propargyl alcohols in combination with a gold(III)chloride catalyzed Meyer-Schuster rearrangement, provided an efficient alternative route to obtain the desired α, β-unsaturated esters. 11 CHAPTER II RESULTS AND DISCUSSION 2.2.1 Lewis-acid Catalyzed Rearrangement of Ethoxyalkynyl Carbinols The last few years have seen a surge of interest in the Meyer–Schuster reaction.17a, 17b, 17c, 17d, 17e, 17f, 17g, 17h, 17i Whereas our Laboratory has focused on electronically activated propargyl alcohols for the synthesis of α,β-unsaturated esters,15,16 Zhang and co-workers reported a method for obtaining α,βunsaturated ketones through independent activation of Lewis basic sites of electronically neutral propargyl alcohols (Fig. 13).17d They and others17f have shown that pre-activation of the hydroxyl group as an acetate ester followed by a gold-catalyzed hydrolysis process of the propargyl acetate delivers Meyer–Schuster products. 18,18a, 18b and 19 The Yamada Lab used high-pressure carbon dioxide, base, and a silver catalyst to merge this multi-step process into a single operation (Fig. 14).17i . Figure 13. Activation of Lewis basic sites of electronically neutral propargyl alcohols Figure 14. Single step formation of α,β-unsaturated ketones 12 2.2.2 Gold-catalyzed Meyer-Schuster Reaction of Secondary Ethoxyalkynyl Carbinols Secondary ethoxyalkynyl carbinols could be converted into the corresponding ethyl trans-α,βunsaturated esters with moderate to good stereocontrol using a mixed catalyst system of gold(I) chloride and silver(I) hexafluoroantimonate (Fig. 15)15. Figure 15. Gold (I) and silver (I) hexafluoroantimonate Meyer-Schuster rearrangement Inclusion of camphorsulfonic acid as a co-catalyst resulted in better selectivity for the trans isomer. In particular, our efforts focused on the rearrangement of secondary propargyl alcohols with simple alkyl substituents. These aliphatic substrates are less reactive towards the Meyer-Schuster reaction than tertiary propargyl alcohols, which ionize more easily. However, the dampened reactivity of secondary alcohols (and the steric distinction between the alkyl substituent and a hydrogen atom) provides greater control and the opportunity to enhance stereoselectivity in the formation of α, βunsaturated ester products. This study11 focuses on using electron-rich alkoxyacetylenes to control selectivity so as to access the Meyer-Schuster rearrangement,1 a formal [1, 3]-hydroxy migration followed by tautomerization. We examined three main variables: gold catalyst, additive, and solvent. 13 As shown in Table 1, minor differences were observed among the various gold catalysts. Both gold (I) and gold (III) were effective. Silver (I) hexafluoroantimonate (AgSbF6) showed little activity on its own, but when employed in conjunction with the gold catalysts it exerted a positive effect on the E/Zselectivity of the reaction. <catalyst> (10 mol %) OH Me Me Me OEt 5.0 equiv EtOH CH2Cl2 O Me Me OR Me Figure 16. Condtions used for catayltic screenng Table 1. Catalyst screenings 14 Solvent screenings were conducted (Table 2). Both dichloromethane and water were both suitable solvents, whereas THF was not. Interestingly, however, reactions conducted in a mixed system of THF and CH2Cl2 were most efficient (qualitatively) and selective for the E-alkene isomer (quantitatively). OH 10 mol % AuCl•AgSbF6 OEt CO2Et 10 equiv EtOH <solvent> Figure 17. Conditions for solvent screenings Table 2. Solvent screenings Additives were employed to accelerate the rearrangement and increase the stereoselectivity (Table 2). Among the protic additives, which are envisioned to assist in the formal [1, 3]-hydroxy migration, ethanol was significantly more effective than other agents tested. Inclusion of camphorsulfonic acid (CSA) in the reaction mixture improved the stereoselectivity of most reactions; however, in this protocol the substrates must tolerate more acidic conditions. 15 OH Me Me Me AuCl or AuCl3(10 mol %) <additive> 5.0 equiv OEt CH2Cl2 O Me Me OR Me Figure 18. Conditions used for additive screenings Table 3. Additive screenings Addition of camphorsulfonic acid (CSA) accelerated the reaction, whereas an acid scavenger [2, 6-di-(tert-butyl)-4-methylpyridine, DTBMP] inhibited the reaction. These results, along with earlier experiments, 18 indicate that exchangeable protons play an important supporting role in the gold- catalyzed rearrangement. 16 2.2.3 Scope and limitations- Substrate Stereoselectivity Reactions were typically conducted under an inert atmosphere of argon using anhydrous THF and CH2Cl2, but similar results were obtained in ‘open-flask' reactions using reagent-grade solvents. The small amount of water present in reagent-grade ethanol does not interfere with (and may facilitate) the reaction. Further experimentation indicated that a catalyst loading of 5 mol% was optimal. 5 mol % AuCl•AgSbF6 10 equiv EtOH OH R OEt THF–CH2Cl2 (1:1) rt, 30–60 min 1 O R OEt 2 Figure 19. Optimized conditions for the gold (I) silver hexafluoroantimonate Meyer-Schuster rearrangement Table 4. Series of representative secondary alcohol substrates 17 We tested the rearrangement protocol on a series of representative secondary alcohol substrates (1a-f, Table 4]).19 Neopentyl alcohol (1a) gave rise to nonenolizable enoate 2a with nearly complete stereoselectivity (entry 1a). Alkyl-substituted alcohols 1b-d afforded enoates 2b-d (entries 2a-4a) to the complete exclusion of dehydration products (cf. path a of Fig. 9). Sequential addition of the silver and gold precatalysts in solution to the reaction mixture provided optimal stereoselectivity and reproducibility. In fact, simultaneous addition of the solutions of the gold and silver salts to the reaction mixture provided the enoate products with slightly better selectivity, but we consider the sequential addition protocol to be more easily duplicated and thus preferable. Premixing the gold and silver salts gave poorer results with respect to selectivity, as did addition of the precatalysts as solids. 2.2.4 Conclusion In summary, α, β-unsaturated esters were prepared from ethoxyalkynyl carbinols using cationic gold catalysts. Substitution on the alcohol substrate, including aryl, alkyl, and vinyl groups, is well tolerated, with aliphatic substituents providing the highest stereoselectivity. Neither Rupe-type elimination products (from loss of water) nor β-hydroxy ester products (from addition of water) were observed. The use of the secondary ethoxyalkynyl carbinols proved useful due their dampened reactivity, allowing investigation of the mechanistic hypothesis of the rearrangement reactions. The mild, efficient, and convenient reaction conditions should find use in chemical synthesis. This work illustrates the potential role of activated, electron-rich alkyne substrates in the rapidly emerging field of catalysis using soft, late-transition-metal cations. 20 18 2.2.5 Alternative Catalysts for the Meyer-Schuster Reaction of Secondary and Tertiary Ethoxyalkynyl Carbinols Terminal alkynes offer an alternative addition/rearrangement pathway for the homologation of aldehydes and ketones that can be executed in the two-stage process outlined in Figure 12: (1) alkyne addition to the carbonyl and (2) Meyer–Schuster rearrangement.21 The strength of this latter approach stems from the use of acetylide nucleophiles to generate the initial carbon–carbon bond; acetylide nucleophiles are suitable for addition to even the most hindered of carbonyl systems. Therefore, step (1) of the two-step process is quite general. In contrast, the Meyer–Schuster rearrangement, on the other hand, has received little attention 22, 22a, 22b, 22c, 22d, 22d, 22e, 22f, 22g over the years due to the limited scope, harsh conditions, and the competing Rupe rearrangement pathway.23 Efficient methods for promoting Meyer–Schuster rearrangements thereby expand the olefination of aldehydes and ketones, including hindered ketones that may not be suitable substrates for any of the other olefination strategies listed above. The recent emergence of ‘soft’ Lewis acids24a, 24b and 25—often late transition metal salts with an affinity for π-bonds over non-bonded electron pairs—brings attention to alternative Lewis basic sites (Fig. 20) and suggests the possibility of exploiting a previously unexplored mechanism for promoting the Meyer–Schuster rearrangement: activation of the propargylic alcohol via the alkyne π-bond rather than the hydroxyl group.26 Figure 20. Lewis basic sites of propargyl alcohols 19 Data and observations reported herein include (1) alternative catalysts that are more economical and widely available than gold or silver salts, (2) lower catalyst loadings than our previously reported methods using gold and silver salts, (3) excellent stereoselectivity in the formation of the E-alkene isomer for most disubstituted alkenes, and (4) new mechanistic data suggesting that the higher stereoselectivity associated with the new catalysts may stem from a subtle alteration of the reaction mechanism. 2.2.6 Screening of alternative catalysts Under the hypothesis that late transition metal-catalysis of the Meyer–Schuster reaction of ethoxyalkynyl carbinols is derived from Lewis acid/base interactions, we became interested in identifying similar (or better) catalytic activity in other Lewis acids. Table 5 provides a summary of our catalyst screenings, which focused primarily (though not exclusively) on soft transition metal salts.27a,27b,27c From this general catalyst screening emerged three top choices: copper (II) triflate, indium (III) chloride, and scandium (III) triflate. Of these, indium (III) chloride is the least reactive; the copper and scandium catalysts are comparable in reactivity. All three are air-stable powders and are convenient to handle and use. 20 Table 5. Catalytic screenings of alternative Lewis-acids 21 2.2.7 Effects of additives Further information on these Lewis acid-catalyzed Meyer–Schuster reactions was gleaned by observing the effect of additives on the reaction rate (qualitatively) and stereoselectivity (quantitatively). Table 6 recounts the outcome of a small grid of reactions in which the three top Lewis acid catalyst choices were each coupled with two acidic and two basic additives: 1 mol % CSA, 1.0 equiv acetic acid (AcOH), 1 mol % 2, 6-di-tert-butyl-4-methylpyridine (DTBMP), and 1.0 equiv magnesium oxide (MgO). Table 6. Effect of additives on top three Lewis-acid catalysts 22 Studying the effect of additives aids in the identification of optimal conditions, and it provides insight into the reaction mechanism. Lewis and protic acids catalyze the Meyer–Schuster reaction, so one would expect acidic additives to accelerate the reaction and basic additives to quench or retard the reaction. This hypothesis is supported by the data presented in Table 6. However, the fact that basic additives retard but do not quench the reaction suggests that protic acid, though helpful, is not required for catalytic activity. Therefore, one can choose between a short reaction time (e.g., entries 9 or 14) and reaction conditions that are presumably free of protic acid (e.g., entry 5). 2.2.8 Optimization of reaction conditions and stereoselectivity All of these experiments were conducted on an exploratory scale to gauge reactivity and selectivity. Because the scandium (III) and copper (II) catalysts in the absence of additives were significantly more reactive and slightly more selective than indium (III) chloride, the triflate salts were employed throughout the next stage of the methodology. Entries 1–4 in Table 7 document the comparison between including ethanol as an additive (5 equiv, as in our earlier studies)11, 15 and employing ethanol as a co-solvent, which provided superior results under the current conditions (entries 3 and 4). Aliphatic substituents on the propargyl alcohols were universally tolerated, whether the substituent was linear (2d), branched (2f), or even quaternary (2e). Some erosion of stereoselectivity was observed in the benzylic case (2g→3g, entries 11 and 12). Entries 7–10 reveal that stereoselectivity was better for disubstituted alkenes than trisubstituted alkenes. Figure 21. Optimized conditions for Cu(II) and Sc(III) Meyer-Schuster rearrangement 23 Table 7. Ethanol as an additive vs. ethanol as co-solven 24 2.2.9 Two-stage Olefination of Aldehydes and Ketones When performed immediately following addition of ethoxyacetylene to a carbonyl compound, the Meyer–Schuster reactions described above complete a two-stage olefination of aldehydes and ketones. Illustrative examples are presented in this section. Scandium (III) and copper (II)-catalyzed Meyer–Schuster reactions of secondary and tertiary propargyl alcohols are shown in Table 7 (2→3). In all cases, both catalysts provided similar results, with scandium (III) triflate consistently (albeit perhaps insignificantly) out-performing copper (II) triflate. From an industrial perspective, the scarcity of scandium salts is off-set by the fact that scandium (III) triflate is water-soluble, recoverable after aqueous workup, and reusable without noticeable loss of activity. The experiment outlined in Figure 21 provides insight into the compatibility of the Meyer– Schuster reaction conditions with common functionality. N-Boc-serine methyl ester (4) was converted into tert-butyldimethylsilyl (TBS) ether 5, which was then included in the reaction mixture during the conversion of 2f to 3f (75% yield; cf. Table 7, entry 6). Figure 21. Compatibility of the Meyer–Schuster reaction conditions with common functionality Recovery of 5 from this control experiment in 99% yield indicates that the present Meyer– Schuster reaction conditions will prove to be compatible with typical alkyl esters, amine carbamates, and silyl ethers. 25 Given the dearth of methods suitable for the homologation of hindered ketones into α, βunsaturated esters,28 the two-stage acetylide addition/Meyer–Schuster strategy as applied to hindered ketones is particularly valuable. We earlier investigated the utility of gold (III) chloride (5 mol %) as a catalyst for such processes. 11 Table 8 illustrates that only 1 mol % of the less-expensive scandium (III) triflate provides similarly outstanding results: near-quantitative overall yield for the olefination of menthone (entry 1, 1h→3h, 98%), 28 verbenone (entry 2, 1c→3c, 97%), benzophenone (entry 3, 1i→3i, 99%), and adamantanone (entry 4, 1a→3a, 96%). Verbenone gave rise to 3c as a 58:42 mixture of olefin isomers, whereas the isomeric mixture of esters 3h could not be reliably estimated by 1H NMR. Table 8. Homologation of hindered ketones 26 2.3.0 Mechanistic Hypothesis of the Lewis-acid Catalyzed Meyer-Schuster Reaction Earlier experiments in our Lab using gold and silver salts to catalyze the Meyer–Schuster reaction of ethoxyalkynyl carbinols support a mechanism in which the alcoholic additive included in the reaction mixture (i.e., ethanol) becomes incorporated into 50% of the product via an intermediate 1,1diethoxy-allene (7, Fig. 22).15 This gold-catalyzed reaction pathway is distinct from that of analogous reactions catalyzed by protic or hard Lewis acids27, 27a, 27b, and 27c, which are known27b and 27c to produce βhydroxy ester by-products (i.e., 6) from initial hydration of the alkyne. β-Hydroxy esters (6) have not been observed in any of the Meyer–Schuster reactions catalyzed by soft Lewis acids in our study. 5 mol% [Au+] 5.0 equiv EtOH OH CO2Et R R THF–CH2Cl2 (1:1) OEt EtOH –H2O H3O+ OH O R R OEt –EtOH +H2O • 7 OEt OEt OH OEt OEt R (not observed) 6 5 mol % AuCl•AgSbF6 5 equiv n-PrOH OH OEt CO2Et + CO2nPr THF–CH2Cl2 (1:1) ca. 1:1 transesterification: (does not occur) 5 mol% Au/AgSbF6, 5 equiv n-PrOH THF–CH2Cl2 (1:1) Figure 22. Hypothesized gold catalyzed reaction pathway 27 Isomerization of the Z-enoates to the E-enoates does not occur under the reaction conditions: extending the reaction time does not have a significant effect on the product ratio, and resubjecting the enoate mixtures to the rearrangement conditions does not change the ratio of stereoisomers. Therefore, we assume that the non-thermodynamic product distribution is purely the result of kinetic control. Perhaps the most compelling observation relevant to the mechanistic hypothesis laid out (Fig. 22) is that when n-propanol was used in place of ethanol, the resulting product mixture comprised ethyl and propyl esters in a roughly 1:1 ratio. Figure 23.Reaction of α,β-unsaturated ester in Meyer-Schuster conditions Figure 24. Reaction of ester product in Meyer-Schuster conditions When this experiment was repeated on 2e using scandium (III) triflate as the catalyst (Fig. 23), the ratio of ethyl to propyl esters (3e:3e′) was 25:75 (as estimated by 1H NMR). In other words, there was only about 25% retention of the ethyl ester in the product mixture. According to the mechanism outlined in Figure 22, however, the ethoxy group should be at least 50% retained, even at high levels of n-propanol. Transesterification does not occur under the reaction conditions (Fig. 24), so we conclude that the scandium (III) triflate-catalyzed reactions proceed by a slightly different mechanism than those catalyzed of cationic gold salts. One such potential mechanism is outlined in Figure 25. 28 OH R 1 mol% Sc(OTf)3 2 OEt CH2Cl2/EtOH (4:1) 3 EtOH –H2O R • 7 –EtOH OEt OEt OEt EtOH OEt OEt CO2Et R R H2O –EtOH R OH OEt OEt 9 Figure 25. Hypothesized scandium (III) triflate-catalyzed reaction Based on the consistent lack of β-hydroxy ester by-products (i.e., 6), the scandium(III) triflatecatalyzed Meyer–Schuster reactions of secondary alcohols 228 likely also proceed via intermediate 1,1diethoxy-allene 7 (Fig. 25). Addition of a second equivalent of ethanol to allene 7 would give rise to ortho-ester 9, which can then hydrolyze via 8 to reach the α, β-unsaturated ester (3). Ortho-ester intermediate 9 thus easily accounts for up to 67% incorporation of the alcohol additive, but we observed 75% (nearly statistical) incorporation of n-propanol in the experiment recounted in Figure 23. This high level of incorporation can be explained by dynamic alcohol exchange reactions of ortho-ester 9. A series of experiments were conducted in which the incorporation of the alcohol additive (propanol) was tracked with respect to the amount of alcohol added (Table 8). 29 In each case, the ratio of propyl and ethyl esters (3e:3e′) was less than but close to statistical incorporation of propanol. These data are consistent with a hemi-labile intermediate (e.g., 9) that can undergo partial equilibration before giving way irreversibly to the observed α, β-unsaturated ester (3). 29 OH 1 1 mol% Sc(OTf)3 <n-propanol> OEt CH2Cl2 CO2R R = Et: 2 R = nPr: 2' Figure 26. Conditions for Meyer-Schuster rearrangement with n-propanol Table 8. Statistical incorporation of n-propanol An attractive feature of this mechanistic hypothesis is that it can account for the high stereoselectivity observed for the E-olefin isomer in the scandium (III) triflate-catalyzed Meyer– Schuster reactions of secondary alcohols. 28 Direct hydrolysis of allene 7 would most likely occur under kinetic control, whereas vinyl ortho-ester 9 provides the opportunity for thermodynamic establishment of olefin geometry using the exaggerated steric profile of ortho-ester 9. 30 2.3.1 Conclusion Acetylide addition followed by the Lewis acid catalyzed Meyer–Schuster reaction of ethoxyalkynyl carbinols provides a strategy for the olefination of aldehydes and ketones. Many different Lewis and protic acids catalyze Meyer–Schuster reactions of ethoxyacetylenes; Lewis acids that demonstrate an affinity for π-bonds were most effective in our methodology. After a detailed screening of many catalysts, we recommend scandium (III) triflate for the excellent reactivity and optimal stereoselectivity that it provides in the Meyer–Schuster reactions, even at low catalyst loading. The method would appear to be limited only by the ability to access the requisite propargyl alcohols via ethoxyacetylide addition to carbonyls, and such reactions are known to be quite general. Stereoselectivities in the two-stage olefination of aldehydes range from good to excellent, whereas α, βunsaturated esters derived from ketones are obtained with little to no stereocontrol. This method is likely to find widespread application in organic synthesis, particularly for its unique ability to complete the olefination of hindered ketones in excellent yield. 31 CHAPTER III EXPERIMENTAL 3.3.1 General Information 1 H NMR and 13 C NMR spectra were recorded on 300 MHz spectrometer using CDCl3 as the deuterated solvent. The chemical shifts (δ) are reported in parts per million (ppm) relative to the residual CHCl3 peak (7.26 ppm for 1H NMR, 77.0 ppm for 13C NMR). The coupling constants (J) were reported in hertz (Hz). IR spectra were recorded on an FTIR spectrometer on NaCl discs. Mass spectra were recorded using chemical ionization (CI) or electron ionization (EI) technique. Yields refer to isolated material judged to be ≥95% pure by 1H NMR spectroscopy following silica gel chromatography. All chemicals were used as received unless otherwise stated. Tetrahydrofuran (THF) and methylene chloride (CH2Cl2) were purified by passing through a column of activated alumina. The n-BuLi solutions were titrated with menthol dissolved in tetrahydrofuran using 1,10-phenanthroline as the indicator. The purifications were performed by flash chromatography using silica gel F-254 (230–499 mesh particle size) 32 3.3.2 Synthesis of Substrates General procedure for the preparation of ethoxyalkynyl carbinols (1→2) To a THF solution (7 mL) of ethyl ethynyl ether (0.7 g, ca. 40% by weight in hexanes, ca. 9 mmol) was added n-BuLi (1.5 mL, 3.4 mmol, 2.3 M) dropwise over 5 min at −78 °C under argon atmosphere. The solution was allowed to warm to 0 °C over 1 h and held at 0 °C for an additional 30 min. The solution was then recooled to −78 °C and pinacolone (1b, 0.30 mL, 2.4 mmol) was added in one portion. The solution was allowed to warm to room temperature over 1 h and held at room temperature for an additional 3 h. Saturated aqueous NH4Cl solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (gradient elution with 20:1 to 7:1 hexanes/ethyl acetate) to give 1-ethoxy-3-methyl-3-tert-butyl-1propyn-3-ol (2b) in 83% yield (0.34 g). 1-Ethoxy-3-methyl-3-tert-butyl-1-propyn-3-ol (2b) 1 H NMR (300 MHz, CDCl3) δ 1.03 (s, 9H), 1.37 (t, J=7.1 Hz, 3H), 1.41 (s, 3H), 1.71 (s, 1H), 4.08 (q, J=7.1 Hz, 2H); 13 C NMR (75 MHz, CDCl3) δ 14.3, 25.2, 25.6, 38.4, 41.9, 73.9, 74.2, 92.8; IR (neat) 3479, 2971, 2873, 2261, 1481, 1392, 1369, 1219, 1094, 1007, 908, 878 cm−1; HRMS (CI) calcd for C10H19O2 ([M+H]+) 171.1385. Found 171.1390. Ethoxy-dec-1-yn-3-ol (2d) The title compound was prepared in a similar manner as described above (>99% yield); 1H NMR (300 MHz, CDCl3) δ 0.86–0.90 (m, 3H), 1.21–1.46 (m, 10H), 1.37 (t, J=7.1 Hz, 3H), 1.56–1.70 (m, 3H), 4.09 (q, J=7.1 Hz, 2H), 4.39 (q, J=6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.0, 14.2, 22.6, 25.3, 29.2, 29.2, 31.7, 38.7, 39.7, 62.4, 74.4, 93.6; IR (neat) 3381, 2927, 2263, 1722, 1467 cm−1; HRMS (CI) calcd for C12H22O2 (M+H+) 199.1698. Found 199.1692. 33 1-Ethoxy-4, 4-dimethyl-pent-1-yn-3-ol (2e) The title compound was prepared in a similar manner as described above (97% yield); 1H NMR (300 MHz, CDCl3) δ 0.97 (s, 9H), 1.38 (t, J=7.1 Hz, 3H), 4.03 (d, J=6.0 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 14.2, 25.2, 35.8, 38.0, 71.0, 74.3, 94.0; IR (neat) 3431, 2956, 2714, 2264, 1629 cm−1; HRMS (EI) calcd for C9H16O2 (M+) 156.1150. Found 156.1103. 1-Cyclohexyl-3-ethoxy-prop-2-yn-1-ol (2f) The title compound was prepared in a similar manner as described above (76% yield); 1H NMR (300 MHz, CDCl3) δ 0.83–1.3 (m, 6H), 1.38 (t, J=7.1 Hz, 3H), 1.57–1.84 (m, 6H), 4.10 (q, J=7.1 Hz, 2H), 4.18 (t, J=5.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.3, 25.9, 25.9, 26.4, 28.1, 28.6, 38.3, 44.6, 67.0, 74.5, 94.3; IR (neat) 3411, 2980, 2460, 1719, 1450 cm−1; HRMS (CI) calcd for C11H18O2 (M+H+) 183.1385. Found 183.1390. 3-Ethoxy-1-phenyl-prop-2-yn-1-ol (2g) The title compound was prepared in a similar manner as described above (92% yield); 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=7.1 Hz, 3H), 2.02 (d, J=6.0 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 5.51 (d, J=6.0 Hz, 1H), 7.31–7.40 (m, 3H), 7.52–7.56 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 14.4, 38.8, 64.6, 74.8, 95.4, 126.5, 128.0, 128.5, 129.2; IR (neat) 3401, 2981, 2226, 1718, 1450 cm−1; HRMS (EI) calcd for C11H12O2 (M+) 176.0834. Found 176.0837. General procedure for the preparation of α,β-unsaturated esters (2→3) To a 4:1 v/v CH2Cl2/ethanol solution (10 mL) of 1-ethoxy-dec-1-yn-3-ol (2d, 0.10 g, 0.51 mmol) in an open flask was added Sc(OTf)3 (2.5 mg, 0.005 mmol). Progress of the reaction was monitored by TLC analysis. After 1 h, the reaction mixture was concentrated under reduced pressure and purified using silica gel column chromatography (hexanes/ethyl acetate, 50:1) to give ethyl (E)-dec-2-enoate (3d) in 70% yield (70 mg). 34 (E/Z)-3,4,4-Trimethyl-1-pent-2-enoic acid ethyl ester (3b) The title compound was prepared in a similar manner as described above (89% yield, E/Z ratio, 58:42); 1 H NMR (300 MHz, CDCl3, E isomer) δ 1.10 (s, 9H), 1.28 (t, J=7.1 Hz, 3H), 2.16 (br d, J=1.1 Hz, 3H), 4.14 (q, J=7.1 Hz, 2H), 5.74 (q, J=1.1 Hz, 1H); 1H NMR (300 MHz, CDCl3, Z isomer) δ 1.20 (s, 9H), 1.28 (t, J=7.1 Hz, 3H), 1.84 (br d, J=1.3 Hz, 3H), 4.14 (q, J=7.1 Hz, 2H), 5.63 (q, J=1.3 Hz, 1H); 13 C NMR (75 MHz, CDCl3, E/Z mixture) δ 14.1, 14.3, 15.1, 23.9, 28.5, 29.0, 36.4, 37.9, 59.4, 60.0, 112.9, 116.6, 158.5, 167.2, 167.5, 167.9; IR (neat, E/Z mixture) 2970, 2873, 1719, 1634, 1466, 1372, 1262, 1182, 1123, 1054, 868 cm−1; HRMS (EI) calcd for C10H18O2 (M+) 170.1307. Found 170.1306. (E)-Dec-2-enoic acid ethyl ester (3d) The title compound was prepared as described above (70% yield); 1H NMR (300 MHz, CDCl3) δ 0.86– 0.90 (m, 3H), 1.26–1.31 (m, 8H), 1.28 (t, J=7.1 Hz, 3H), 1.42–1.47 (m, 2H), 2.19 (ddd, J=14.6, 7.1, 1.2 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 5.80 (br d, J=15.6 Hz, 1H), 6.96 (dt, J=15.6, 7.0 Hz, 1H). (E)-4,4-Dimethyl-pent-2-enoic acid ethyl ester (3e) The title compound was prepared in a similar manner as described above (97% yield); 1H NMR (300 MHz, CDCl3) δ 1.08 (s, 9H), 1.29 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 5.73 (d, J=15.9 Hz, 1H), 6.97 (d, J=15.9 Hz, 1H). (E)-4,4-Dimethyl-pent-2-enoic acid ethyl ester (3e) The title compound was prepared in a similar manner as described above (97% yield); 1H NMR (300 MHz, CDCl3) δ 1.08 (s, 9H), 1.29 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 5.73 (d, J=15.9 Hz, 1H), 6.97 (d, J=15.9 Hz, 1H). (E)-3-Cyclohexyl-acrylic acid ethyl ester (3f) The title compound was prepared in a similar manner as described above (75% yield); 1H NMR (300 MHz, CDCl3) δ 1.12–1.31 (m, 5H), 1.29 (t, J=7.1 Hz, 3H), 1.64–1.77 (m, 5H), 2.04–2.17 (m, 1H), 4.18 (q, J=7.1 Hz, 2H), 5.75 (dd, J=15.8, 1.4 Hz, 1H), 6.91 (dd, J=15.8, 6.7 Hz). 35 (E/Z)-3-Phenyl-2-propenoic acid ethyl ester (3g) The title compound was prepared in a similar manner as described above (93% yield, E/Z ratio, 77:23); 1 H NMR (300 MHz, CDCl3, E isomer) δ 1.34 (t, J=7.1 Hz, 3H), 4.27 (q, J=7.1 Hz, 2H), 6.44 (d, J=16.0 Hz, 1H), 7.37–7.40 (m, 3H), 7.51–7.54 (m, 2H), 7.69 (d, J=16.0 Hz, 1H); 1H NMR (300 MHz, CDCl3, Z isomer) δ 1.24 (t, J=7.1 Hz, 3H), 4.17 (q, J=7.1 Hz, 2H), 5.95 (d, J=12.6 Hz, 1H), 6.95 (d, J=12.6 Hz, 1H), 7.33–7.38 (m, 3H), 7.56–7.59 (m, 2H). General two-step procedure for the preparation of α,β-unsaturated esters (1→3) To a THF solution (2.6 mL) of ethyl ethynyl ether (0.13 g, ca. 40% by weight in hexanes, ca. 2 mmol) was added n-BuLi (0.40 mL, 0.75 mmol, 2.0 M) dropwise over 5 min at −78 °C under argon atmosphere. The solution was allowed to warm to 0 °C over 1 h and held at 0 °C for an additional 30 min. The solution was then recooled to −78 °C and 2-adamantanone (1a, 75 mg, 0.50 mmol) was added in one portion. The solution was allowed to warm to room temperature over 1 h and held at room temperature for an additional 3 h. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. To the concentrated mixture in an open flask were added CH2Cl2 (8 mL), absolute ethanol (2 mL), and Sc(OTf)3 (2.5 mg, 0.005 mmol). After 6 h, the reaction mixture was concentrated under reduced pressure and purified using silica gel column chromatography (hexanes/ethyl acetate, 50:1) to give adamantan-2-ylidene-acetic acid ethyl ester (3a) in 96% yield over two steps (106 mg). Adamantan-2-ylidene-acetic acid ethyl ester (3a) 1 H NMR (300 MHz, CDCl3) δ 1.27 (t, J=7.1 Hz, 3H), 1.86 (br s, 6H), 1.93–1.96 (m, 6H), 2.43 (br s, 1H), 4.07 (br s, 1H), 4.13 (q, J=7.1 Hz, 2H), 5.58 (s, 1H). 36 (4,6,6-Trimethyl-bicyclo[3.1.1]hept-3-en-(2E/Z)-ylidene)-acetic acid ester (3c) Title compound was prepared in a similar manner as described above (97% yield); 1H NMR (300 MHz, CDCl3, minor isomer) δ 0.86 (s, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.40 (s, 3H), 1.68 (d, J=7.9 Hz, 1H), 1.90 (d, J=1.5 Hz, 3H), 2.20–2.45 (m, 1H), 2.53–2.63 (m, 2H), 4.08–4.20 (m, 2H), 5.32 (s, 1H), 7.13 (s, 1H); 1 H NMR (300 MHz, CDCl3, major isomer) δ 0.84 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.44 (s, 3H), 1.58 (d, J=8.8 Hz, 1H), 1.86 (d, J=1.4 Hz, 3H), 2.20–2.45 (m, 1H), 2.53–2.63 (m, 2H), 4.08–4.20 (m, 2H), 5.46 (s, 1H), 5.77 (s, 1H); 13C NMR (75 MHz, CDCl3, E/Z mixture) δ 14.3, 14.4, 21.7, 21.8, 23.2, 23.6, 26.4, 26.5, 37.5, 38.1, 45.3, 47.8, 48.2, 49.0, 49.1, 53.1, 59.2, 59.3, 107.6, 110.0, 117.6, 121.6, 156.9, 158.0, 159.6, 161.2, 166.8, 167.4; IR (neat) 2979, 2930, 2870, 1708, 1622, 1466, 1443, 1380, 1370, 1226, 1164, 1040, 874, 705 cm−1; HRMS (EI) calcd for C14H20O2 (M+) 220.1463. Found 220.1462. (2-Isopropyl-5-methyl-cyclohexylidiene)-acetic acid ethyl ester (3h) The title compound was prepared in a similar manner as described above (98% yield); 1H NMR (300 MHz, CDCl3, E/Z mixture, diagnostic peaks) δ 2.55 (ddd, J=12.9, 5.5, 1.5 Hz), 3.14 (dd, J=12.9, 4.3 Hz), 3.48–3.52 (m), 4.13 (q, J=7.1 Hz), 4.14 (q, J=7.1 Hz), 5.63 (br s); 13C NMR (75 MHz, CDCl3, E/Z mixture) δ 14.3, 18.1, 19.5, 20.5, 20.8, 21.8, 23.4, 26.1, 26.8, 27.0, 27.6, 30.4, 31.6, 33.6, 33.9, 35.4, 36.1, 40.0, 43.5, 50.8, 52.6, 55.9, 59.3, 59.4, 113.3, 116.3, 164.8, 167.1. Ethyl 3,3-diphenylpropenoate (3i) The title compound was prepared in a similar manner as described above (99% yield); 1H NMR (300 MHz, CDCl3) δ 1.11 (t, J=7.1 Hz, 3H), 4.05 (q, J=7.1 Hz, 2H), 6.37 (s, 1H), 7.20–7.23 (m, 2H), 7.30–7.39 (m, 8H). 37 LIST OF REFERENCES 1. L. Kürti and B. Czakó, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier, New York, NY (2003) 2. (a) B.E. Maryanoff and A.B. Reitz, Chem. Rev. 89 (1989), pp. 863–927. 3. S.E. Kelly In: B.M. Trost and I. Fleming, Editors, Alkene Synthesis, Comprehensive Organic Synthesis Vol. 1, Pergamon, Oxford (1991), pp. 729–817. 4. B.M. Trost, Science 254 (1991), pp. 1471–1477. 5. Brandsma L, Acetylenes, Allenes and Cumulenes Elsevier; Amsterdam: 2003. 6. Modern Acetylene Chemistry Stang PJ, Diederich F,VCH; Weinheim: 1995. 7. S. Swaminathan and K.V. Narayanan, Chem. Rev. 71 (1971), pp. 429–438. 8. Lewis Acids in Organic Synthesis Yamamoto H,Wiley-VCH; New York: 2000. 9. (a)Dyker G,Angew. Chem. Int. Ed. 2000, 39: 4237. (b) Hashmi AS,Gold Bull. 2003, 36: 3. (c) Ma S, Yu S, Gu Z,Angew. Chem. Int. Ed. 2006, 45: 200. (d) Asao N,Synlett 2006, 1645. 10. Asao N, Sato K,Org. Lett. 2006, 8: 5361. (b )Staben ST, Kennedy-Smith JJ, Huang D, Corkey BK, LaLonde RL, Toste FD,Angew. Chem. Int. Ed. 2006, 45: 5991. (c) Belting V, Krause N,Org. Lett. 2006, 8: 4489. (d)Wang S, Zhang L,Org. Lett. 2006, 8: 4585. (e) Huang B, Yao X, Li C.-J,Adv. Synth. Catal. 2006, 348: 1528. (f) Seregin IV, Gevorgyan V,J. Am. Chem. Soc. 2006, 128: 12050. (g)Carretin S, Blanco MC, Corma A, Hashmi AS,Adv. Synth. Catal. 2006, 348: 1283. (h)Park S, Lee D,J. Am. Chem. Soc. 2006, 128: 10664. (i) Nakamura I, Sato T, Yamamoto Y,Angew. Chem. Int. Ed. 2006, 45: 4473. (j)Kang J.-E, Kim H.-B, Lee J.-W, Shin S,Org. Lett. 2006, 8: 3537. (k) Sun J, Conley MP, Zhang L, Kozmin SA,J. Am. Chem. Soc. 2006, 128: 9705. (l) Liu Y, Liu M, Guo S, Tu H, Zhou Y, Gao H,Org. Lett. 2006, 8: 3445. (m) Robles-Machin R, Adrio J, Carretero JC,J. Org. Chem. 2006, 71: 5023. (n) Harrison TJ, Kozak JA, Corbella-Pane M, Dake GR,J. Org. Chem. 2006, 71: 4525. (o) Fürstner A, Hannen P,Chem. Eur. J. 2006, 12: 3006. (p) Georgy M, Boucard V, Campagne J.-M,J. Am. Chem. Soc. 2005, 127: 14180. (q) Fukuda Y, Utimoto K,Bull. Chem. Soc. Jpn. 1991, 64: 2013. 11. D.A. Engel and G.B. Dudley, Org. Lett. 8 (2006), pp. 4027–4029. 38 12. Examples of Meyer–Schuster reactions of ethoxyalkynyl carbinols using hard Lewis or protic acids: (a) M. Duraisamy and H.M. Walborsky, J. Am. Chem. Soc. 105 (1983), pp. 3252–3264. (b) S.C. Welch, C.P. Hagan, D.H. White, W.P. Fleming and J.W. Trotter, J. Am. Chem. Soc. 99 (1977), pp. 549–556. (c) D. Crich, S. Natarajan and J.Z. Crich, Tetrahedron 53 (1997), pp. 7139–7158. 13. The combination of an electron-rich π-system and soft Lewis acid catalyst has also been used in cycloisomerization reactions: J. Sun, M.P. Conley, L. Zhang and S.A. Kozmin, J. Am. Chem. Soc. 128 (2006), pp. 9705–9710. 14. Because the 1,3-hydroxy shift is not concerted and there is ample opportunity for the hydroxy to exchange with water in the reaction medium, the Meyer–Schuster reaction is not a true rearrangement. For mechanistic investigations of the Meyer–Schuster reaction, see:.(a)M. Edens, D. Boerner, C.R. Chase, D. Nass and M.D. Sciavelli, J. Org. Chem. 42 (1977), pp. 3403–3408. (b)J. Andres, R. Cardenas, E. Silla and O. Tapia, J. Am. Chem. Soc. 110 (1988), pp. 666–674. (c)S. Yamabe, Tsuchida and S. Yamazaki, J. Chem. Theory Comput. 2 (2006), pp. 1379–1387. 15. S.S. López, D.A. Engel and G.B. Dudley, Synlett (2007), pp. 949–953. 16. The question as to what reaction pathway(s) leading from the propargyl acetate to the α,βunsaturated ketone is catalyzed by cationic gold salts remains open. For further discussion, see Ref.17f. 17. Recent examples: Refs. (a) I. Imagawa, Y. Asai, H. Takano, H. Hamagaki and M. Nishizawa, Org. Lett. 8 (2006), pp. 447–450.(b)V. Cadierno, J. Díez, S.E. García-Garrido, J. Gimeno and N. Nebra, Adv. Synth. Catal. 348 (2006), pp. 2125–2132. (c) C. Sun, X. Lin and S.M. Weinreb, J. Org. Chem. 71 (2006), pp. 3159–3166. (d) M. Yu, G. Li, S. Wang and L. Zhang, Adv. Synth. Catal. 349 (2007), pp. 871–875. (e) E. Bustelo and P.H. Dixneuf, Adv. Synth. Catal. 349 (2007), pp. 933–942. (f)N. Marion, P. Carlqvist, R. Gealageas, P. de Frémont, F. Maseras and S.P. Nolan, Chem.—Eur. J. 13 (2007), pp. 6437–6451. (g)S.I. Lee, J.Y. Baek, S.H. Sim and Y.K. Chung, Synthesis (2007), pp. 2107–2114. (h)M.J. Sandelier and P. DeShong, Org. Lett. 9 (2007), pp. 3209–3212. (i)Y. Sugawara, W. Yamada, S. Yoshida, T. Ikeno and T. Yamada, J. Am. Chem. Soc. 129 (2007), pp. 12902–12903. 18. Protic acids in the absence of gold are significantly less effective (ref. 2). Examples of the proticacid-catalyzed Meyer-Schuster rearrangement of ethoxyalkynyl carbinols: (a) Welch SC, Hagan CP, White DH, Fleming WP, Trotter JW,J. Am. Chem. Soc. 1977, 99: 549. (b) Duraisamy M, Walborsky HM,J. Am. Chem. Soc. 1983, 105: 3252. (c) Crich D, Natarajan S, Crich JZ,Tetrahedron 1997, 53: 7139. 19. Satisfactory characterization data (1H NMR, 13C NMR, IR, HRMS) were obtained for all compounds. Yields refer to at least 50 mg of material isolated in >95% purity. 20. For a previous report on the combined use of oxygen-activated alkynes and cationic gold catalysts, see: Zhang L, Kozmin SA,J. Am. Chem. Soc. 2004, 126: 11806 39 21. K.H. Meyer and K. Schuster, Chem. Ber. 55 (1922), pp. 819–822 22. Examples:.(a)M.B. Erman, I.S. Aul'chenko, L.A. Kheifits, V.G. Dulova, J.N. Novikov and M.E. Vol'pin, Tetrahedron Lett. (1976), pp. 2981–2984. (b)P. Chabardes, Tetrahedron Lett. 29 (1988), pp. 6253–6256. (c)B.M. Choudary, A. Durga Prasad and V.L.K. Valli, Tetrahedron Lett. 31 (1990), pp. 7521–7522. (d)K. Narasaka, H. Kusama and Y. Hayashi, Chem. Lett. (1991), pp. 1413–1416. (e)M. Yoshimatsu, M. Naito, M. Kawahigashi, H. Shimizu and T. Kataoka, J. Org. Chem. 60 (1995), pp. 4798–4802. (f)C.Y. Lorber and J.A. Osborn, Tetrahedron Lett. 37 (1996), pp. 853–856. (g)T. Suzuki, M. Tokunaga and Y. Wakatsuki, Tetrahedron Lett. 43 (2002), pp. 7531–7533. 23. The Rupe rearrangement ( H. Rupe and E. Kambli, Helv. Chim. Acta 9 (1926), p. 672 ). 24. (a)T.-L. Ho, Hard and Soft Acids and Bases Principle in Organic Chemistry, Academic, New York, NY (1977).(b)P.K. Chattaraj, H. Lee and R.G. Parr, J. Am. Chem. Soc. 113 (1991), pp. 1855–1856. 25. In: H. Yamamoto, Editor, Lewis Acids in Organic Synthesis, Wiley-VCH, New York, NY (2000). 26. For seminal examples illustrating this concept, see: M. Georgy, V. Boucard and J.-M. Campagne, J. Am. Chem. Soc. 127 (2005), pp. 14180–14181. 27. Examples of Meyer–Schuster reactions of ethoxyalkynyl carbinols using hard Lewis or protic acids:(a)M. Duraisamy and H.M. Walborsky, J. Am. Chem. Soc. 105 (1983), pp. 3252–3264. (b)S.C. Welch, C.P. Hagan, D.H. White, W.P. Fleming and J.W. Trotter, J. Am. Chem. Soc. 99 (1977), pp. 549–556. (c)D. Crich, S. Natarajan and J.Z. Crich, Tetrahedron 53 (1997), pp. 7139–7158. 28. The Meyer–Schuster reactions of tertiary alcohols may take a different course. Further investigations are planned and will be communicated in due course. 29. Reactions conducted with less than a full equivalent of propanol were slow and inefficient, and are omitted from Table 8. 40 BIOGRAPHICAL SKETCH Susana Sorina López was born on September 23rd 1980 in Miami Beach, Florida. She grew up in North Miami, Florida moving to Hollywood, Florida during her freshman year of high school where her parents, Oscar and Susana Mercedes López, still reside. Susana was classically trained in voice and the flute as well as in various forms of dance, including ballet, tap jazz and modern from an early age. During her high school years, she figure skated competitively winning several competitions at the sectional, regional and national level. Upon graduating high school in 1999, she received a theatre and dance scholarship to attend Lees-McRae College in Banner Elk, North Carolina but decided to return to South Florida after her freshman year to pursue pre-medical studies. Susana received her Associates of Science in Biology from Broward Community College in the spring of 2003. She began her undergraduate studies in the fall of 2003 at Barry University and discovered a passion for organic chemistry while taking the course for her pre-medical major requirements. She changed her major in the fall of 2004 to chemistry and did active research under the direction of Dr. George Fisher and Dr. Paul I. Higgs. She also worked under the guidance of Dr. Anthony J. Pearson of Case Western Reserve University in Cleveland, Ohio during the summer of 2005. In the fall of 2005 Susana graduated with a Bachelors of Science degree from Barry University and continued to do research at Barry until moving to Tallahassee, Florida in the summer of 2006 to pursue her graduate studies at Florida State University. 41