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4-2-2009

Methodology for the Olefination Of Aldehydes

and Ketones Via the Meyer-Schuster Reaction
Susana Sorina Lpez
Florida State University

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

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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

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.
ii

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

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
1.1.2
1.1.3
1.1.4
1.1.5
1.1.6
1.1.7

Olefination Strategies for the Synthesis of ,-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

LIST OF FIGURES

Figure 1: Aldol condensation..................................................................................

Figure 2: Acid-catalyzed aldol condensation..........................................................

Figure 3: Base-catalyzed aldol condensation..........................................................

Figure 4: Peterson olefination.................................................................................

Figure 5: Wittig reaction.........................................................................................

Figure 6: Examples of three different ylide categories...........................................

Figure 7: Horner-Wadsworth-Emmons reaction ....................................................

Figure 8: HWE stereoselectivity.............................................................................

Figure 9: Two possible reaction pathways of propargyl alcohols ..........................

Figure 10: Acetylide addition/Meyer-Schuster reaction.........................................

Figure 11: Lewis-acid catalyzed mechanism for activating propargyl alcohols.....

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

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 ,-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

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

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

gram(s)

GC

gas chromatography

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
ix

coupling constant (in NMR)

kilo

KOH

potassium hydroxide

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

multiplet (spectral), meter(s), milli

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

quartet (spectral)

re

rectus (stereochemistry)

Rf

retention factor (in chromatography)

rt

room temperature

singlet (spectral); second(s)

si

sinister (stereochemistry)

SN1

unimolecular nucleophilic substitution

SN2

bimolecular nucleophilic substitution

SN

nucleophilic substitution with allylic rearrangement

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 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.

xiii

CHAPTER I
INTRODUCTION

1.1.1 Olefination Strategies for the Synthesis of , -Unsaturated Esters

O
O

+
H

O
R

H2 O

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 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 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.

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 -trimethylsilylsubstituted organometallic compounds which convert carbonyl compounds to alkenes via a silylcarbinol.

R1
R2

OH
R
R3

R3Si

R1
R1

R1
Si

R2

R2

R4

R1

R3

R2

R3

R1

R4

acid

+
R3

base

R4

R1
R2
R3Si

OH

base

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 -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
O

PPh3

+
H

O
R

Figure 5. Wittig reaction

3

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

O
R

(R )3P

R3
1

(R )3P
X
X= Cl, Br, I,
R2
R2
OTs
alkyl halide
phsophonium salt

base

R
(R1)3P

R5

R4

R2

-(R1)3P O

R5

R3

(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.

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

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).

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
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).

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.

acetylide
addition

O
R2

R1

R3

H R3

MeyerSchuster
rearrangement

R2
OH

R1

R2

R1

R3
H

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.

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.

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

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 , - 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
,-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.

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 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

12

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.

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 % AuClAgSbF6
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 % AuClAgSbF6
10 equiv EtOH

OH
R
OEt

THFCH2Cl2 (1:1)
rt, 3060 min

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, , -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

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) 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

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 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.

20

Table 5. Catalytic screenings of alternative Lewis-acids

21

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

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 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

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 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.
25

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

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 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 1,1diethoxy-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 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.

5 mol% [Au+]
5.0 equiv EtOH

OH

CO2Et

THFCH2Cl2 (1:1)

OEt

EtOH
H2O

H3O+
OH O
R

R
OEt

EtOH
+H2O

OEt
OEt

OH
OEt
OEt

(not observed)
6
5 mol % AuClAgSbF6
5 equiv n-PrOH

OH

OEt

CO2Et

CO2nPr

THFCH2Cl2 (1:1)
ca. 1:1
transesterification:
(does not occur)

5 mol% Au/AgSbF6, 5 equiv n-PrOH

THFCH2Cl2 (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 ,-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

OEt

CH2Cl2/EtOH (4:1)

EtOH
H2O
R

EtOH
OEt
OEt
OEt

EtOH
OEt
OEt

CO2Et

H2O
EtOH R

OH
OEt
OEt

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

Based on the consistent lack of -hydroxy ester by-products (i.e., 6), the scandium(III) triflatecatalyzed MeyerSchuster 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 , -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).
29

OH

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 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.

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 () 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)

32

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-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) 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) 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.

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) 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)
The title compound was prepared in a similar manner as described above (76% yield); 1H NMR
(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)
The title compound was prepared in a similar manner as described above (92% yield); 1H NMR
(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).

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) 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);

13

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)
The title compound was prepared in a similar manner as described above (97% yield); 1H NMR
(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)
The title compound was prepared in a similar manner as described above (97% yield); 1H NMR
(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)
The title compound was prepared in a similar manner as described above (75% yield); 1H NMR
(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).

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) 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)
1

H 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).

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) 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);
1

H 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)
The title compound was prepared in a similar manner as described above (98% yield); 1H NMR
(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)
The title compound was prepared in a similar manner as described above (99% yield); 1H NMR
(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).

37

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38

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.
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128 (2006), pp. 97059710.
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Ref.17f.
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White DH, Fleming WP, Trotter JW,J. Am. Chem. Soc. 1977, 99: 549. (b) Duraisamy M,
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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. 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.

40

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.

41