methodology for the olefination of aldehydes and ketones via the

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Electronic Theses, Treatises and Dissertations The Graduate School

4-2-2009

Methodology for the Olefination Of Aldehydesand Ketones Via the Meyer-Schuster ReactionSusana Sorina LpezFlorida State University

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Recommended CitationLpez, Susana Sorina, "Methodology for the Olefination Of Aldehydes and Ketones Via the Meyer-Schuster Reaction" (2009).Electronic Theses, Treatises and Dissertations. Paper 1060.

FLORIDA STATE UNIVERSITY

COLLEGE OF ARTS AND SCIENCES

METHODOLOGY FOR THE OLEFINATION OF ALDEHYDES AND

KETONES VIA THE MEYER-SCHUSTER REACTION

By

SUSANA SORINA LPEZ

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

ii

The members of the Committee approve the Thesis of Susana Sorina Lpez 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.

iii

Quiero dedicar esta tesis a mis padres, Oscar y Susana Mercedes Lpez por todos los

sacrificios que han hecho a lo largo de los aos para ayudarme a convertirme

en la mujer que soy hoy. Sin su amor y apoyo esto no habra 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

ii

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.

iii

TABLE OF CONTENTS List of Tables ............................................................................................. vi List of Figures ............................................................................................ vii List of Symbols .......................................................................................... ix Abstract .................................................................................... xiv 1. Introduction............................................................................................ 1 1.1.1 Olefination Strategies for the Synthesis of ,-Unsaturated Esters.. 1 1.1.2 Wittig Reaction ................................................................................. 3 1.1.3 Horner-Wadsworth-Emmons............................................................ 5 1.1.4 Meyer-Schuster Rearrangement of Propargyl Alcohols ................... 6 1.1.5 Mechanism .................................................................................... 8 1.1.6 Earlier Work in the Dudley Lab........................................................ 9 1.1.7 Conclusion ..................................................................................... 11 2. Results and Discussion .......................................................................... 12 2.2.1 Lewis-acid Catalyzed Rearrangement of Ethoxyalkynyl Carbinols 12 2.2.2 Gold catalyzed Meyer-Schuster Reaction of Secondary Ethoxyalkynyl Carbinols .................................................. 13 2.2.3 Substrate Scope and Stereoselectivity ....................................... 17 2.2.4 Conclusion ................................................................................. 18 2.2.5 Alternative Catalysts for the Meyer-Schuster Reaction of Secondary and Tertiary Ethoxyalkynyl Carbinols ...................................... 20 2.2.6 Screening of Alternative Catalysts ............................................. 21 2.2.7 Effects of Additives ................................................................... 23 2.2.8 Optimization of Reaction Conditions and Stereoselectivity ...... 24 2.2.9 Two-stage Olefination of Aldehydes and Ketones .................... 25 2.3.1 Mechanistic Hypothesis of the Lewis-acid Catalyzed

iv

2.3.2 Meyer-Schuster Reaction ........................................................... 28 2.3.3 Conclusion ................................................................................. 31 3. Experimental ... ........................................................................ 32 REFERENCES .......................................................................................... 38 BIOGRAPHICAL SKETCH ...................................................................... 41

v

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

vi

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 ,-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

vii

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 ,-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

viii

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

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

ix

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 Hckel 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

x

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

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

xi

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

xii

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

xiii

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 Horner-

Wadsworth-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 MeyerSchuster rearrangement. The Meyer-Schuster reaction is a

little-known but potentially powerful rearrangement that converts propargyl alcohols into , -

unsaturated 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-, -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 MeyerSchuster 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.

1

CHAPTER I

INTRODUCTION 1.1.1 Olefination Strategies for the Synthesis of , -Unsaturated Esters

O

O

H R

O

O

O

R+

+H2O

Figure 1. Aldol reaction

The homologation of aldehydes and ketones to ,-unsaturated esters (Fig. 1), an indispensable

tool for generating carboncarbon bonds, is typically achieved using aldol condensation1, Wittig,

HornerWadsworthEmmons (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 base-

catalyzed dimerization reaction to produce 3-hydroxybutanal.

Reactions of this nature are commonly referred to as aldol additions because that 3-

hydroxybutanal is both an alcohol and an aldehyde. The initial protocol involved the use of a Brnsted

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.

2

Figure 2. Acid-catalyzed aldol dehydration

Figure 3. Base-catalyzed aldol dehydration

Dehydration of the aldol addition product gives rise to an ,-unsaturated carbonyl compound.

Thus, one can achieve the two-step homologation of aldehydes to ,-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 , -unsaturated esters have emerged over the years.

The aldol addition of a -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 -trimethylsilyl-

substituted organometallic compounds which convert carbonyl compounds to alkenes via a -

silylcarbinol.

3

R1Si

M

R1R1

R2R3 R4

O+

R3Si

OHR1

R4R2

R3

R3Si

OHR1

R3R2

R4

base

base

acid

R2

R1 R3

R4

R2

R1 R4

R3

Figure 4. Peterson olefination

The -silyl carbanions can be prepared by various methods but the subsequent addition to the

carbonyl compound gives a diastereomeric mixture of -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

OPPh3 H R

O

O

O

R

++ Ph3P O

Figure 5. Wittig reaction

R1= alkyl, aryl; R2=alkyl, aryl, CO2R, CN, CONR2, CH=NR, SR, SOR, SO2R, SeR, SiR3, OR, BO2R2; R3, R4=alkyl, aryl, H

4

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 ,-

unsaturated esters. The reaction of ester stabilized ylides with ketones is rare.

XR2

R3 (R1)3P

X= Cl, Br, I, OTs R

2

R3(R1)3P X

R2

R3(R1)3P

R2

R3(R1)3P

R4 R5

O

-(R1)3P O

base

alkyl halide phsophonium salt phosphorus ylide (phosphorane) R4, R5= alkyl, aryl, alkynyl, H

R5

R4 R2

R3

olefin

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.

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

5

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

H R

O

O

O

R

++P OEt

OEt

OPOEt

O

HO 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).

6

Figure 8. HWE stereoselectivity

The Wittig and HWE reaction both use stoichiometric phosphines, phosphine oxides, or

phosphonates to provide , -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 , -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 - or -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 , -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 , -

unsaturated 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

7

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).

8

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 , -unsaturated esters.

A major advantage of using the acetylide addition/MeyerSchuster reaction strategy for the olefination

of aldehydes and ketones (Fig. 10) is the efficiency of the initial carboncarbon bond-forming reaction:

alkyne addition.

Figure 10. Acetylide addition/MeyerSchuster reaction

However, the second stage of this strategythe MeyerSchuster reactionis generally limiting.

The reaction protocol uses high temperatures and acidic conditions which limit the reaction scope.

Therefore, advances in the MeyerSchuster 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.

acetylideaddition

MeyerSchusterrearrangementR2

R1OHR

3R1 R2

O

HR3 R3 R1

R2

H

O

9

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 MeyerSchuster reactions of tertiary ethoxyalkynyl carbinols for the

synthesis of ,-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 (1b3b, R3=OEt, Fig. 12) for the synthesis of ,-unsaturated esters.

10

Figure 12. Gold-catalyzed MeyerSchuster reactions of tertiary ethoxyalkynyl carbinols

The combination of the electron-rich ethoxyacetylenic -system and soft gold (III) chloride

catalyst13 provided excellent reactivity in the MeyerSchuster reaction: consumption of the intermediate

tertiary ethoxyalkynyl carbinols occurred within minutes of adding the catalyst. The MeyerSchuster

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

11

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 , - 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 by-

products. 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

,-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 , -unsaturated esters.

12

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 MeyerSchuster reaction.17a, 17b, 17c, 17d, 17e,

17f, 17g, 17h, 17i Whereas our Laboratory has focused on electronically activated propargyl alcohols for the

synthesis of ,-unsaturated esters,15,16 Zhang and co-workers reported a method for obtaining ,-

unsaturated 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

MeyerSchuster 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 ,-unsaturated ketones

13

2.2.2 Gold-catalyzed Meyer-Schuster Reaction of Secondary Ethoxyalkynyl Carbinols

Secondary ethoxyalkynyl carbinols could be converted into the corresponding ethyl trans-,-

unsaturated 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 , -

unsaturated 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.

14

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/Z-

selectivity of the reaction.

Figure 16. Condtions used for catayltic screenng

Table 1. Catalyst screenings

MeOH

MeMe

Me

MeMe

OEtOR

O(10 mol %)

5.0 equiv EtOHCH2Cl2

15

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).

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.

OH

OEt

CO2Et10 mol % AuClAgSbF6

10 equiv EtOH

16

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.

MeOH

MeMe

Me

MeMe

OEtOR

OAuCl or AuCl3(10 mol %)

5.0 equiv CH2Cl2

17

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.

Figure 19. Optimized conditions for the gold (I) silver hexafluoroantimonate Meyer-Schuster rearrangement

Table 4. Series of representative secondary alcohol substrates

R

OH 5 mol % AuClAgSbF610 equiv EtOH

THFCH2Cl2 (1:1)rt, 3060 min

ROEt

OEt

O

1 2

18

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, , -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 -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

19

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) MeyerSchuster rearrangement.21 The strength of this latter approach

stems from the use of acetylide nucleophiles to generate the initial carboncarbon 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 MeyerSchuster 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 MeyerSchuster 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 25often

late transition metal salts with an affinity for -bonds over non-bonded electron pairsbrings attention

to alternative Lewis basic sites (Fig. 20) and suggests the possibility of exploiting a previously

unexplored mechanism for promoting the MeyerSchuster rearrangement: activation of the propargylic

alcohol via the alkyne -bond rather than the hydroxyl group.26

Figure 20. Lewis basic sites of propargyl alcohols

20

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 MeyerSchuster 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.

21

Table 5. Catalytic screenings of alternative Lewis-acids

22

2.2.7 Effects of additives

Further information on these Lewis acid-catalyzed MeyerSchuster 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

23

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 MeyerSchuster 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 14 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 (2g3g, entries 11 and 12).

Entries 710 reveal that stereoselectivity was better for disubstituted alkenes than trisubstituted alkenes.

Figure 21. Optimized conditions for Cu(II) and Sc(III) Meyer-Schuster rearrangement

24

Table 7. Ethanol as an additive vs. ethanol as co-solven

25

2.2.9 Two-stage Olefination of Aldehydes and Ketones

When performed immediately following addition of ethoxyacetylene to a carbonyl compound,

the MeyerSchuster 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 MeyerSchuster reactions of secondary and tertiary

propargyl alcohols are shown in Table 7 (23). 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 MeyerSchuster 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.

26

Given the dearth of methods suitable for the homologation of hindered ketones into , -

unsaturated esters,28 the two-stage acetylide addition/MeyerSchuster 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,

1h3h, 98%), 28 verbenone (entry 2, 1c3c, 97%), benzophenone (entry 3, 1i3i, 99%), and

adamantanone (entry 4, 1a3a, 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

27

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 MeyerSchuster

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 1,1-

diethoxy-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 -

hydroxy ester by-products (i.e., 6) from initial hydration of the alkyne. -Hydroxy esters (6) have not

been observed in any of the MeyerSchuster reactions catalyzed by soft Lewis acids in our study.

Figure 22. Hypothesized gold catalyzed reaction pathway

R

OH

OEt

5 mol% [Au+]5.0 equiv EtOH

THFCH2Cl2 (1:1)R

CO2Et

R

OEtOEt

R OEt

OOH

H3O+EtOH H2O

R OEt

OHOEt

+H2O

(not observed)

EtOH

5 mol % AuClAgSbF65 equiv n-PrOH

THFCH2Cl2 (1:1)

CO2Et CO2nPr+

ca. 1:15 mol% Au/AgSbF6, 5 equiv n-PrOH

THFCH2Cl2 (1:1)

transesterification:(does not occur)

OH

OEt

7

6

28

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 ,-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.

29

Figure 25. Hypothesized scandium (III) triflate-catalyzed reaction

Based on the consistent lack of -hydroxy ester by-products (i.e., 6), the scandium(III) triflate-

catalyzed MeyerSchuster reactions of secondary alcohols 228 likely also proceed via intermediate 1,1-

diethoxy-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 , -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 , -unsaturated ester (3).

R

OH

OEtR

CO2Et

R OEt

OHOEt

EtOH

R

OEtOEt

EtOHH2O

R OEt

OEtOEtEtOH H2O

EtOH

1 mol% Sc(OTf)3

CH2Cl2/EtOH (4:1)2

79

3

30

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.

OH

OEt

1 mol% Sc(OTf)3

CH2Cl2

CO2R

R = Et: 2R = nPr: 2'1

31

2.3.1 Conclusion

Acetylide addition followed by the Lewis acid catalyzed MeyerSchuster reaction of

ethoxyalkynyl carbinols provides a strategy for the olefination of aldehydes and ketones. Many different

Lewis and protic acids catalyze MeyerSchuster reactions of ethoxyacetylenes; Lewis acids that

demonstrate an affinity for -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 MeyerSchuster 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 , -

unsaturated 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.

32

CHAPTER III

EXPERIMENTAL

3.3.1 General Information

1H NMR and 13C NMR spectra were recorded on 300 MHz spectrometer using CDCl3 as the

deuterated solvent. The chemical shifts () 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 (230499 mesh particle

size)

33

3.3.2 Synthesis of Substrates

General procedure for the preparation of ethoxyalkynyl carbinols (12)

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-1-

propyn-3-ol (2b) in 83% yield (0.34 g).

1-Ethoxy-3-methyl-3-tert-butyl-1-propyn-3-ol (2b) 1H NMR (300 MHz, CDCl3) 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); 13C NMR (75 MHz, CDCl3) 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 cm1; 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) 0.860.90 (m, 3H), 1.211.46 (m, 10H), 1.37 (t, J=7.1 Hz, 3H), 1.561.70 (m, 3H),

4.09 (q, J=7.1 Hz, 2H), 4.39 (q, J=6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) 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 cm1; HRMS (CI)

calcd for C12H22O2 (M+H+) 199.1698. Found 199.1692.

34

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) 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) 14.2, 25.2, 35.8, 38.0, 71.0, 74.3, 94.0; IR (neat) 3431, 2956, 2714,

2264, 1629 cm1; HRMS (EI) calcd for C9H16O2 (M+) 156.1150. Found 156.1103.

1-Cyclohexyl-3-ethoxy-prop-2-yn-1-ol (2f)


(300 MHz, CDCl3) 0.831.3 (m, 6H), 1.38 (t, J=7.1 Hz, 3H), 1.571.84 (m, 6H), 4.10 (q, J=7.1 Hz,

2H), 4.18 (t, J=5.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) 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 cm1; HRMS (CI) calcd for C11H18O2 (M+H+)

183.1385. Found 183.1390.

3-Ethoxy-1-phenyl-prop-2-yn-1-ol (2g)


(300 MHz, CDCl3) 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), 7.317.40 (m, 3H), 7.527.56 (m, 2H); 13C NMR (75 MHz, CDCl3) 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 cm1; HRMS (EI) calcd

for C11H12O2 (M+) 176.0834. Found 176.0837.

General procedure for the preparation of ,-unsaturated esters (23)

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).

35

(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); 1H NMR (300 MHz, CDCl3, E isomer) 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) 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); 13C

NMR (75 MHz, CDCl3, E/Z mixture) 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 cm1; 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) 0.86

0.90 (m, 3H), 1.261.31 (m, 8H), 1.28 (t, J=7.1 Hz, 3H), 1.421.47 (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)


(300 MHz, CDCl3) 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)


(300 MHz, CDCl3) 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)


(300 MHz, CDCl3) 1.121.31 (m, 5H), 1.29 (t, J=7.1 Hz, 3H), 1.641.77 (m, 5H), 2.042.17 (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).

36

(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); 1H NMR (300 MHz, CDCl3, E isomer) 1.34 (t, J=7.1 Hz, 3H), 4.27 (q, J=7.1 Hz, 2H), 6.44 (d,

J=16.0 Hz, 1H), 7.377.40 (m, 3H), 7.517.54 (m, 2H), 7.69 (d, J=16.0 Hz, 1H); 1H NMR (300 MHz,

CDCl3, Z isomer) 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), 7.337.38 (m, 3H), 7.567.59 (m, 2H).

General two-step procedure for the preparation of ,-unsaturated esters (13)

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) 1H NMR (300 MHz, CDCl3) 1.27 (t, J=7.1 Hz, 3H), 1.86 (br s, 6H), 1.931.96 (m, 6H), 2.43 (br s,

1H), 4.07 (br s, 1H), 4.13 (q, J=7.1 Hz, 2H), 5.58 (s, 1H).

37

(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) 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), 2.202.45 (m, 1H), 2.532.63 (m, 2H), 4.084.20 (m, 2H), 5.32 (s, 1H), 7.13 (s, 1H); 1H NMR (300 MHz, CDCl3, major isomer) 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), 2.202.45 (m, 1H), 2.532.63 (m, 2H), 4.084.20 (m, 2H), 5.46

(s, 1H), 5.77 (s, 1H); 13C NMR (75 MHz, CDCl3, E/Z mixture) 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 cm1; HRMS (EI) calcd for C14H20O2 (M+) 220.1463. Found 220.1462.

(2-Isopropyl-5-methyl-cyclohexylidiene)-acetic acid ethyl ester (3h)


(300 MHz, CDCl3, E/Z mixture, diagnostic peaks) 2.55 (ddd, J=12.9, 5.5, 1.5 Hz), 3.14 (dd, J=12.9,

4.3 Hz), 3.483.52 (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) 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)


(300 MHz, CDCl3) 1.11 (t, J=7.1 Hz, 3H), 4.05 (q, J=7.1 Hz, 2H), 6.37 (s, 1H), 7.207.23 (m, 2H),

7.307.39 (m, 8H).

38

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11. D.A. Engel and G.B. Dudley, Org. Lett. 8 (2006), pp. 40274029.

39

12. Examples of MeyerSchuster reactions of ethoxyalkynyl carbinols using hard Lewis or protic acids: (a) M. Duraisamy and H.M. Walborsky, J. Am. Chem. Soc. 105 (1983), pp. 32523264. (b) S.C. Welch, C.P. Hagan, D.H. White, W.P. Fleming and J.W. Trotter, J. Am. Chem. Soc. 99 (1977), pp. 549556. (c) D. Crich, S. Natarajan and J.Z. Crich, Tetrahedron 53 (1997), pp. 71397158.

13. The combination of an electron-rich -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. 97059710.

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 MeyerSchuster reaction is not a true rearrangement. For mechanistic investigations of the MeyerSchuster reaction, see:.(a)M. Edens, D. Boerner, C.R. Chase, D. Nass and M.D. Sciavelli, J. Org. Chem. 42 (1977), pp. 34033408. (b)J. Andres, R. Cardenas, E. Silla and O. Tapia, J. Am. Chem. Soc. 110 (1988), pp. 666674. (c)S. Yamabe, Tsuchida and S. Yamazaki, J. Chem. Theory Comput. 2 (2006), pp. 13791387.

15. S.S. Lpez, D.A. Engel and G.B. Dudley, Synlett (2007), pp. 949953.

16. The question as to what reaction pathway(s) leading from the propargyl acetate to the ,-unsaturated 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. 447450.(b)V. Cadierno, J. Dez, S.E. Garca-Garrido, J. Gimeno and N. Nebra, Adv. Synth. Catal. 348 (2006), pp. 21252132. (c) C. Sun, X. Lin and S.M. Weinreb, J. Org. Chem. 71 (2006), pp. 31593166. (d) M. Yu, G. Li, S. Wang and L. Zhang, Adv. Synth. Catal. 349 (2007), pp. 871875. (e) E. Bustelo and P.H. Dixneuf, Adv. Synth. Catal. 349 (2007), pp. 933942. (f)N. Marion, P. Carlqvist, R. Gealageas, P. de Frmont, F. Maseras and S.P. Nolan, Chem.Eur. J. 13 (2007), pp. 64376451. (g)S.I. Lee, J.Y. Baek, S.H. Sim and Y.K. Chung, Synthesis (2007), pp. 21072114. (h)M.J. Sandelier and P. DeShong, Org. Lett. 9 (2007), pp. 32093212. (i)Y. Sugawara, W. Yamada, S. Yoshida, T. Ikeno and T. Yamada, J. Am. Chem. Soc. 129 (2007), pp. 1290212903.

18. Protic acids in the absence of gold are significantly less effective (ref. 2). Examples of the protic-acid-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

40

21. K.H. Meyer and K. Schuster, Chem. Ber. 55 (1922), pp. 819822

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. 29812984. (b)P. Chabardes, Tetrahedron Lett. 29 (1988), pp. 62536256. (c)B.M. Choudary, A. Durga Prasad and V.L.K. Valli, Tetrahedron Lett. 31 (1990), pp. 75217522. (d)K. Narasaka, H. Kusama and Y. Hayashi, Chem. Lett. (1991), pp. 14131416. (e)M. Yoshimatsu, M. Naito, M. Kawahigashi, H. Shimizu and T. Kataoka, J. Org. Chem. 60 (1995), pp. 47984802. (f)C.Y. Lorber and J.A. Osborn, Tetrahedron Lett. 37 (1996), pp. 853856. (g)T. Suzuki, M. Tokunaga and Y. Wakatsuki, Tetrahedron Lett. 43 (2002), pp. 75317533.

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. 18551856.

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. 1418014181.

27. Examples of MeyerSchuster reactions of ethoxyalkynyl carbinols using hard Lewis or protic

acids:(a)M. Duraisamy and H.M. Walborsky, J. Am. Chem. Soc. 105 (1983), pp. 32523264. (b)S.C. Welch, C.P. Hagan, D.H. White, W.P. Fleming and J.W. Trotter, J. Am. Chem. Soc. 99 (1977), pp. 549556. (c)D. Crich, S. Natarajan and J.Z. Crich, Tetrahedron 53 (1997), pp. 71397158.

28. The MeyerSchuster 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.

41

BIOGRAPHICAL SKETCH

Susana Sorina Lpez 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 Lpez, 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.

The Florida State UniversityDigiNole Commons4-2-2009

Methodology for the Olefination Of Aldehydes and Ketones Via the Meyer-Schuster ReactionSusana Sorina LpezRecommended Citation

methodology for the olefination of aldehydes and ketones via the

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