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MICHIGAN STATE UNIVERSITY
EAST LANSING, MICH 48824-1048

This is to certify that the
dissertation entitled

IMPROVING THE STILLE REACTION
FROM RATE ENHANCEMENT TO GERMANIUM

presented by
Jerome M. Lavis

has been accepted towards fulfillment
of the requirements for the

Doctoral degree in Chemistry

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IMPROVING THE STILLE REACTION
FROM RATE ENHANCEMENT TO GERMANIUM

By

Jerome M. Lavis

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
Department of Chemistry

2004

ABSTRACT

IMPROVING THE STILLE REACTION
FROM RATE ENHANCEMENT TO GERMAN IUM

By
Jerome M. Lavis
The Stille cross-coupling reaction though widely used in organic synthetic
chemistry suffers from certain drawbacks. Many groups have sought to alleviate those
problems. We endeavored to improve on the Stille reaction by avoiding handling of the
toxic organostannane intermediate and by increasing the rate of the reaction. We also
sought to replace the tin by a less toxic metal: germanium. Those studies are discussed in

full in the following thesis.

To Jennifer and Gabrielle for their love and support.

iii

ACKNOWLEDGEMENTS

I would like to thank Professor Robert E. Maleczka, Jr. for his guidance and
advices during my studies at Michigan State University. I would also like to thank
Professors Michael Rathke, Milton Smith and Gary Blanchard for serving on my
guidance committee.

I would like to thank William Gallagher and Damon Clark for their cooperation in
the microwave study and Nicole Torres for her cooperation on the kinetic study.

I would like to thank Kermit Johnson for his help in the NMR experiments.

I would like to thank my wife for her support and understanding during my
studies. I would like to thank my daughter Gabrielle for her endless smiles when I would
come home.

I would like to thank all the members of the Maleczka group for their friendship
and help, especially Jill Muchnij, Lamont Terrell, Susan Whitehead, Joe Ward, Erik

Ruggles, and Ina Terstiege.

iv

TABLE OF CONTENT

LIST OF TABLES ..................................................................................................................................... VIII
LIST OF SCHEMES ..................................................................................................................................... IX
LIST OF ABBREVIATIONS .................................................................................................................... XIII
LIST OF ABBREVIATIONS .................................................................................................................... XIII
CHAPTER 1. INTRODUCTION ................................................................................................................... 1
CHAPTER 2. KINETIC ANALYSIS. ............................................................................................................ 5
2. I. INTRODUCTION ..................................................................................................................................... 5
2.1.1. Methods of Rate Improvement .................................................................................................... 5
2.1.2. Nature of the Trialkyltin .............................................................................................................. 7

2. l .3. Objectives .................................................................................................................................... 8

2.2. RESULTS ............................................................................................................................................... 8
2.2. 1. Synthesis of the Stannanes ........................................................................................................... 8
2.2.2. Measuring the Kinetics .............................................................................................................. 10
2.2.3. Choice of the Internal Standard ................................................................................................. l 1
2.2.4. Kinetics ...................................................................................................................................... 11
2.2.5. Conclusions ............................................................................................................................... 16
2.2.6. Further Work ............................................................................................................................. 17
CHAPTER 3. MICROWAVE ONE POT STILLE CROSS-COUPLING .................................................... l8
3.]. INTRODUCTION............................. ...................................................................................................... 18
3.1 . 1. Microwave Irradiation ............................................................................................................... 18
3.1.2. Previous Work on Microwave Accelerated Stille Reactions ..................................................... 19
3.1.3. Objectives .................................................................................................................................. 20

3.2. RESULTS ............................................................................................................................................. 20
3.2.]. Generation of Tributyltin Hydride ............................................................................................. 20
3.2.2. The Search for the Right Protocol ............................................................................................. 22

3.2.3. Scope of the Reaction ................................................................................................................ 28

3.2.4. Free-Radical Hydrostannations ................................................................................................. 31
3.2.5. Stereocontrol of the Reaction .................................................................................................... 33
3.2.6. Conclusion ................................................................................................................................. 36
CHAPTER 4. CROSS-COUPLING OF TRIALKYLVINYLGERMANES ................................................ 37
4.1. INTRODUCTION ................................................................................................................................... 37
4.1.1. From Tin to Germanium ............................................................................................................ 37
4.1.2. The Use of Germanium ............................................................................................................. 37
4.1.3. Previous Cross-Coupling of Germanes ...................................................................................... 38

4. I .4. Objectives .................................................................................................................................. 40
4.2. INITIAL RESULTS: A WINDOW OF HOPE ............................................................................................. 40
4.2.1. Preparation of the Germanes ..................................................................................................... 40
4.2.2. Initial Couplings ........................................................................................................................ 42
4.2.3. Proposal of a Mechanism ........................................................................................................... 43
4.3. SEARCH FOR OPTIMAL CONDITIONS .................................................................................................... 45
4.4. SCOPE OF THE REACTION ................................................................................................................... 47
4.5. MECHANISTIC INVESTIGATION ........................................................................................................... 50
4.6. CONSLUSION ...................................................................................................................................... 59

CHAPTER 5. ATTEMPS AT ALLYLIC STILLE COUPLING IN THE SYNTHESIS OF

SUPERSTOLIDE A. ..................................................................................................................................... 61
5.1. INTRODUCTION ................................................................................................................................... 61
5.1.1. Application to Total Synthesis ................................................................................................... 61
5.1.2. Superstolide A ........................................................................................................................... 61
5.1.3. Retrosynthetic Analysis of Superstolide A ................................................................................ 62
5.1.4. Allylic Stille Couplings ............................................................................................................. 63

5. I .5. Directing Effects of Substituants ............................................................................................... 65
5.1.6. Objectives .................................................................................................................................. 67

vi

5.2. RESULTS ............................................................................................................................................. 67

5.2.1. Synthesis of the Model .............................................................................................................. 67
5.2.2. Initial Cross-couplings of the Model Compound ....................................................................... 71
5.2.3. Search for a Working Protocol .................................................................................................. 72
5.2.4. Conclusions ............................................................................................................................... 74
EXPERIMENTALS ...................................................................................................................................... 75

vii

LIST OF TABLES

TABLE 2.1. RELATIVE KINETIC EFFECTS FOR THE STANNANES. .................................................................... 13

TABLE 2.2. RELATIVE KINETIC EFFECT FOR THE ELECTROPHILE. .................................................................. I4

viii

LIST OF SCHEMES

SCHEME 1.1. THE STILLE COUPLING. .............................................................................................................. 1
SCHEME 1.2. STILLE MECHANISM. .................................................................................................................. 2
SCHEME 1.3. ESPINET’S MECHANISM. ............................................................................................................. 3
SCHEME 2.1. THREE STEP MECHANISM. .......................................................................................................... 5
SCHEME 2.2. RATE ACCELERATION OF A STILLE COUPLING. ........................................................................... 6
SCHEME 2.3. RATE INCREASE FROM COPPER. .................................................................................................. 6
SCHEME 2.4. EFFECT OF THE TRIALKYLTIN. .................................................................................................... 7
SCHEME 2.5. PALLADIUM CATALYZED SYNTHESIS OF THE STANNANES. ......................................................... 8
SCHEME 2.6. RADICAL INITIATED SYNTHESIS OF THE STANNANES. ................................................................. 9
SCHEME 2.7. REFERENCE REACTION. ............................................................................................................ 10
SCHEME 2.8. INTERNAL STANDARD TEST. ..................................................................................................... I 1
SCHEME 2.9. KINETICS RESULTS. .................................................................................................................. 12
SCHEME 2.10. KINETICS FOR THE COUPLING OF PHENYL BROMIDE. .............................................................. 13
SCHEME 2.1 1. EFFECT OF THE STEREOCHEMISTRY. ....................................................................................... 15
SCHEME 2.12. KINETICS WITH Pd(PPh3)4. ...................................................................................................... I6
SCHEME 3.1 MICROWAVE ACCELERATED AMIDE FORMATION. ..................................................................... 19
SCHEME 3.2. LEUKART REDUCTIVE AMINATION. .......................................................................................... 19
SCHEME 3.3. LARHED SYSTEMS ..................................................................................................................... 20
SCHEME 3.4. HAYASHI’S METHOD OF GENERATING TRIBUTYLTIN HYDRIDE ................................................. 21
SCHEME 3.5. GENERATION OF TIN HYDRIDE CONTROL. ................................................................................ 22
SCHEME 3.6. EFFECT OF MICROWAVES ON HYDROSTANNATION. .................................................................. 22
SCHEME 3.7. STILLE CROSS-COUPLING ALONE. ............................................................................................. 23
SCHEME 3.8. INTIAL ONE POT COUPLING. ..................................................................................................... 24
SCHEME 3.9. FORMATION OF Bu3SnH VIA Bu3SnF. ....................................................................................... 26
SCHEME 3.10. OPTIMIZATION REACTION. ...................................................................................................... 26
SCHEME 3.1 1. FIRST GENERATION SYSTEM. .................................................................................................. 27
SCHEME 3.12. OPTIMIZED CONDITIONS ......................................................................................................... 28

ix

SCHEME 3.13. ONE-POT HYDROSTANNATION/STILLE RESULTS. ................................................................... 30

SCHEME 3.14. BUSSACCA’S MECHANISM. ..................................................................................................... 31
SCHEME 3.15. ONE POT FREE RADICAL HYDROSTANNATION/ STILLE RESULTS. ........................................... 32
SCHEME 3.16. HYDROSTANNATION EQUILIBRIUM. ........................................................................................ 33
SCHEME 3.17. MECHANISM OF THE RADICAL INITIATED HYDROSTANNATION. ............................................. 34
SCHEME 3.18. CROSS-OVER EXPERIMENT. .................................................................................................... 34
SCHEME 3.19. ISOMERIZATION. ..................................................................................................................... 35
SCHEME 3.20. CONTROLS. ............................................................................................................................. 36
SCHEME 4.1. INITIAL SYNTHESIS OF VINYL GERMANES. ............................................................................... 37
SCHEME 4.2. KOSUGI’S INITIAL RESULT. ....................................................................................................... 38
SCHEME 4.3. KOSUGI’S GERMATRANES. ........................................................................................................ 38
SCHEME 4.4. IKENAGA’S COUPLING. ............................................................................................................. 38
SCHEME 4.5. COMPETITION BETWEEN TIN AND GERMANIUM. ....................................................................... 39
SCHEME 4.6. FALLER’S GERMATRANES. ........................................................................................................ 39
SCHEME 4.7. OSHIMA’S TRIFURYLGERMANES. .............................................................................................. 39
SCHEME 4.8. HYDROGERMYLATION WITH Bu3GeH ....................................................................................... 41
SCHEME 4.9. GERMANIUM — IODIDE EXCHANGE ............................................................................................ 41
SCHEME 4.10. COMPARISON OF COUPLING CONSTANTS. ............................................................................... 42
SCHEME 4.11. HYDROGERMYLATION WITH Ph3GeH ...................................................................................... 42
SCHEME 4.12. INITIAL CROSS-COUPLING REACTION ..................................................................................... 43
SCHEME 4.13. ADDITION/ELIMINATION MECHANISM .................................................................................... 44
SCHEME 4.14. FALLER’S PROPOSED MECHANISM .......................................................................................... 44
SCHEME 4.15. SCREENING OF STILLE CONDITIONS. ....................................................................................... 45
SCHEME 4.16. SCREENING OF HECK CONDITIONS. ......................................................................................... 46
SCHEME 4.17. EVOLUTION OF THE YIELD WITH TEMPERATURE ..................................................................... 47
SCHEME 4.18. CATALYST LOADING. .............................................................................................................. 47
SCHEME 4.19. COMPARISON OF STILLE AND HECK CONDITIONS. .................................................................. 48
SCHEME 4.20. CROSS-COUPING RESULTS. ..................................................................................................... 49

SCHEME 4.21. CROSS-COUPLING OF UNHINDERED VINYL GERMANES. ......................................................... 51

SCHEME 4.22. Pd-H PROCESS AND EXPECTED PRODUCTS. ............................................................................ 52
SCHEME 4.23. COUPLING OF DISUBSTITUED PROPARGYLIC SPECIES. ............................................................ 53
SCHEME 4.24. BUSSACCA TYPE MECHANISM. ............................................................................................... 53
SCHEME 4.25. HALLBERG TYPE MECHANISM. ............................................................................................... 53
SCHEME 4.26. SYNTHESIS OF THE Z-GERMANE .............................................................................................. 54
SCHEME 4.27. CROSS-COUPLING OF THE Z-GERMANE. .................................................................................. 54
SCHEME 4.28. ISOMERIZATION OF GERMANE CONTROLS. ............................................................................. 55
SCHEME 4.29. ACTIVATION OF THE GERMANE ............................................................................................... 56
SCHEME 4.30. EFFECT OF PROXIMAL HYDROXYL GROUP .............................................................................. 57
SCHEME 4.31. PROXIMAL EFFECT OF HYDROXYL GROUP .............................................................................. 57
SCHEME 4.32. COMPARISON EFFECT OF DISTAL HYDROXYL GROUP ............................................................. 58
SCHEME 4.33. REGIOSELECTIVITY. ................................................................................................................ 59
SCHEME 4.34. CROSS-COUPLING OF A DISUBSTITUTED GERMANE. ............................................................... 59
SCHEME 5.]. SUPERSTOLIDE A. ..................................................................................................................... 61
SCHEME 5.2. ROUSH’S SYNTHESIS OF THE ClS-DECALIN ................................................................................ 62
SCHEME 5.3. RETROSYNTHETIC ANALYSIS OF SUPERSTOLIDE A. .................................................................. 62
SCHEME 5.5. ALLYLIC STILLE CROSS-COUPLING. ......................................................................................... 63
SCHEME 5.6. MECHANISM OF ALLYLIC STILLE REACTION. ........................................................................... 63
SCHEME 5.7. CROSS-COUPLING OF ALLYLIC CARBONATES. .......................................................................... 64
SCHEME 5.8. REGIOCONTROL OF THE REACTION. .......................................................................................... 64
SCHEME 5.9. STEREOCONTROL OF THE REACTION. ........................................................................................ 65
SCHEME 5.10. DIRECTING EFFECTS. .............................................................................................................. 66
SCHEME 5.] 1. ALKYNES AS A n-CHELATOR. ................................................................................................. 66
SCHEME 5.12. CHELATION OF ALKYNES. ....................................................................................................... 67
SCHEME 5.13. PROPOSED DIRECTING EFFECT. ............................................................................................... 67
SCHEME 5.14. FIRST MODEL TARGET ............................................................................................................ 68
SCHEME 5.15. ATTEMPTS AT THE SYNTHESIS OF 72. ...................................................................................... 68

Xi

SCHEME 5.16. SYNTHESIS ATTEMPTS STARTING FROM CYCLOHEXANONE. .................................................. 69

SCHEME 5.17. STABLE CYCLIC KETO-ENAL. ................................................................................................. 69
SCHEME 5.18. EPOXIDE OPENING ATTEMPTS. ............................................................................................... 70
SCHEME 5.19. SECOND GENERATION ............................................................................................................. 70
SCHEME 5.20. ATTEMPTED CROSS-COUPLING. .............................................................................................. 71
SCHEME 5.21. THIRD GENERATION ................................................................................................................ 71
SCHEME 5.22. ONE POT SYNTHESIS OF THE MODEL. ..................................................................................... 72
SCHEME 5.23. ACETYLATION ......................................................................................................................... 72
SCHEME 5.24. ATTEMPTED CROSS-COUPLING CONDITIONS. ......................................................................... 73

xii

AIBN

aq

DHP

DIBAL

DMAP

DMF

DMS

eq

HMPA

HRMS

LRMS

mL

mmol

m.p.

MW

NBS

NMP

Ph

PMHS

I‘.t.

LIST OF ABBREVIATIONS
2,2’-azobisisobutyronitrile
aqueous
cyclohexyl
dihydropyrane
diisobutylaluminum hydride
4-(dimethylamino)pyridine
N,N-dimethylformamide
Dimethyl sulfide
equivalent
hexamethyl phosphoramide
high resolution mass spectrometry
low resolution mass spectroscopy
Molar
milliliter
millimole
melting point
Microwave
N-bromosuccinimide
N-methyl-2-pyrrolidinone
phenyl
polymethylhydrosiloxane

room temperature

xiii

sat.

TBAF

THF

THP

TMS

saturated
tetrabutylammonium fluoride
tetrahydrofuran
tetrahydropyrane
trimethylsilyl

Watt

Xiv

Chapter 1. Introduction

The search for useful synthetic methods of carbon — carbon bond formation is
ongoing. Among C—C bond forming reactions, transition metal catalyzed cross-coupling
reactions have proven particularly powerful and are now commonly used. Representative
of these reactions are the Heck,1 Sonogashira} Suzuki3 couplings, and among others, the
Stille reaction.

The Stille reaction typically involves the cross-coupling of a vinyl or arylstannane
with a alkyl or aryl halide under palladium catalysis (Scheme 1.1).4 Since Stille’s work
throughout the 1980’s this reaction has been recognized as a very useful synthetic
method. It has been used in the preparation of numerous natural products,5 medicinal
agents‘5 etc. . ..

Scheme 1.1. The Stille Coupling.
R/VSnBU3 + Rl/Vx _LPdcatal St R/\/‘\,Rl + BU3SnX

R and R' = alkyl, aryl
X = halogen, OTf, ONf, OAc

Over the years, numerous groups have adapted or improved the reaction.7 For
example, Genet et al. have demonstrated the reaction in aqueous media,8 and Curran and
Larhead have used it in fluorous phase.9 While Espinet has continued efforts to better
understand the mechanism of the reaction.10

The mechanism of the Stille reaction has traditionally been described as a three
step catalytic process (Scheme 3.1). This mechanism is commonly used to explain the

reaction and predict the products.ll

Scheme 1.2. Stille Mechanism.

R
— Pd (0) R
rfl F3
R’ Br
Reductive Oxidative
Elimination Insertion
r—JR R
Pd‘”) —
R'f Br—Pdm)

 
   
 

Transmetallation

R
Bu3SnBr '—
Bu3Sn

In the above mechanism, the transmetallation has been shown to be the rate
determining step. This is consistent with the observation that the reaction is zero order in
electrophile and first order in stannane. Another key parameter of the reaction is that
excess ligand retards the reaction, which means ligands probably play a key role during
the transmetallation. This lead to the initial proposal that the transmetallation step went
through a dissociative pathway. During their ongoing study of the Stille reaction, Espinet
et al.10 have refined that mechanism in order to explain the sometimes divergent results
observed for the reaction. These divergences depended on the nature of the electrophile
and the solvent. Hence they now propose a more complete picture of the mechanism of

the reaction as shown in Scheme 1.3.

Scheme 1.3. Espinet’s Mechanism.

 

 

R‘-x
RI
PdL _ ' _
R'-R2 / n x Pld L
L
RI
1 .A
$1 $2—Pld-L . 1}]
RZ-Pd-L Bu3Sn—X L—Pld-L
i X
R2$nBu3
+
RI
2 1
R1 R1 R SnBus L—Pd-L
' j I
L—Pd-L + Rth-L A
R2 L
I t t
2,! Iii/L L,‘ 1'11 \=‘
(I: : “~L Pd-"C-"SnBU3
Bu3Sn—X L/l l
x
Cyclic Open

In this mechanism there exists two possible pathways that are in keeping with the
different observed kinetics. Pathway A goes through a cyclic transition state leading to an
associative L for R substitution. This pathway is favored for organic halide electrophiles
and for solvents with moderate coordinative ability towards Pd. Pathway B goes through
an open transition state and thus favors a dissociative L for R substitution. This will be
favored by very good leaving groups like organic triflates and by solvents that are good

ligands for palladium.

Even though the Stille reaction is commonly used, it suffers from a series of
problems. The most important one being the toxicity of the organotins. This in itself
usually prohibits the use of the reaction on industrial scale.12 Given their toxicity, one
would want to minimize exposure to the organotins intermediates. Moreover, another
major handicap is the difficulty in separating the cross-coupled product from the
organotin byproducts. To minimize these two problems: toxicity and isolation, the
reaction has been made catalytic in tin by Maleczka et al.[3 In this approach all organotin
intermediates are generated in situ thus limiting handling to the less toxic tin halides.

Finally, the Stille reaction classically takes hours at elevated temperatures to
proceed. Many of the newly reported improvements to the Stille coupling have attempted
to accelerate the reaction. Additives like CuI or LiCl have been used in order to increase
the rate of the reaction and lower the reaction temperature.

In the course of this research we too sought to better appreciate the kinetic side of
the reaction. We also looked to increase the rate of the reaction so as to to allow synthesis
of the cross-coupled products in minutes instead of hours since time is always an
important factor on both the industrial and bench top scales. Finally, we tried to remove

the tin altogether by replacing it with the less toxic germanium.

Chapter 2. Kinetic Analysis.

2.1. Introduction

As mentioned in Chapter 1, several studies have aimed at understanding the
kinetics of the Stille reaction. An early focus of these studies was to ascertain which step
of the reaction was rate determining.

Scheme 2.1. Three Step Mechanism.

R
_ Pd (0) _ R
#4 /"
R' Br
Reductive Oxidative
Elimination Insertion
R R
R'—//— Br-Pd‘”)

 
 

Transmetallation

   

R
Bu3SnBr /=J
8113811

The Stille coupling involves an oxidative insertion, a transmetallation and a
reductive elimination (Scheme 2.1). Kinetic studies have shown that the rate of the
reaction is zero order in electrophile while it is first order in the stannane. This shows that
the rate determining step is the transmetallation step.”"5"6 With the slow step of the
process identified, the problem became to understand more clearly the influences on the
transmetallation step and thereby the reaction.

2.1.1. Methods of Rate Improvement

Like most organometallic reactions, the rate (and yields) of the Stille reaction is

highly dependent on the nature of the catalyst. Extensive studies were performed by

Farina et al. in order to identify the best possible ligands and palladium sources. It was

found that Pd(dba)2 and AsPh3 or tri-(2-furyl) phosphine (TFP) was a good catalyst
system,17 allowing the reaction to be carried out at room temperature and to considerably
accelerate the reaction as shown in Scheme 2.2. This great rate improvement arises from
the different effects of the excess ligands. Strongly binding ligands like
triphenylphosphine greatly retard the reaction when in excess, while weakly bonding
ligands like TFP or AsPh3 retard the reaction to a lesser extent.

Scheme 2.2. Rate Acceleration of a Stille Coupling.
I o
O + VSnBu3 szdba3/L1gand : ©/\
THF, 50 °C

entry Ligand rel. Rate % Yield

 

 

 

1 PPh3 1.0 15.2
2 TFP 105 >95
3 AsPh3 1 100 >95

 

Another improvement to the speed of the reaction came with the combination of
copper and palladium in the catalyst system. The addition of CuI to the reaction mixture
has been shown to increase the rate of the reaction to various degree depending on the
nature of the ligand used (Scheme 2.3).18

Scheme 2.3. Rate Increase from Copper.

I Pd db /L' d
O + VSnBU3 2 a3 Igan E ©/\
Cul, dioxane, 50 °C

 

 

 

312121. “2.5.121?“
1 1:4:0 2.66 85
2 114:] 13.5 91
3 124:2 303 >95
4 1:420 7210 >95
5 1:422 9640 >95

 

A large rate increase was observed with strongly binding ligands like PPh3
(entries 1-3). However only a marginal rate improvement was observed with softer
ligands like AsPh3 (entries 4,5). The reason for the copper effect is proposed to be two
fold. One is the ability of the copper to scavenge free ligands. As previously mentioned,
free ligands can be detrimental to the reaction because they retard the transmetallation
process. Copper, by scavenging these ligands, allows the transmetallation intermediate to
exist in greater concentrations. Copper can scavenge more readily strongly coordinating
ligands and less soft ligands, thus explaining the observed results. Another possible effect
is a transmetallation of copper for tin which would lead to a vinylcopper specie that
reacts faster than the organotin with the organopalladium intermediate. This role of
copper is proposed to be especially likely in strongly polar solvents.

2.1.2. Nature of the Trialkyltin

Since the kinetics of the Stille reaction are first order in stannane, and since the
reaction involves a transmetallation it seems logical to assume that the nature of the
trialkyltin substituent will be of importance. Throughout the various studies that have
been made one can extract some information on the comparison of some trialkyltins, or
tetralkyltins, but no in depth systematic study as been made.

Scheme 2.4. Effect of the Trialkyltin.

szdba3 (2 mol%)/AsPh3 (8 mol%)

OTf L'Cl 3
NMP, 80°C 0

O

 

 

Entry Stannane Rate (103 mn")

 

1 PhSnBU3 40.5

2 PhSnMe3 53.1

 

To the best of our knowledge, the only direct rate comparison made during
previous studies was by Farina and is shown in Scheme 2.4.'9 Here, the trimethylphenyl
stannane was 31% more reactive than its tributylphenyl counter parts. Other qualitative

41”“ or F arinal9 have been reported though no rate data were put

results published by Stille
forth.
2.1.3. Objectives

Since all studies made so far report the transmetallation as the rate limiting step,
the paucity of studies looking at relative reactions rates per the alkyl group on the
trialkylvinyl tin itself was surprising. It was thus our objective to provide data on the
relative rate of cross-coupling for various trialkylvinyl tins.
2.2. Results
2.2.1. Synthesis of the Stannanes

The stannanes to be studied were synthesized using a protocol initially developed

by Terstiege in our laboratory and later expanded by Pellerito (Scheme 2.5).2°"3

Scheme 2.5. Palladium Catalyzed Synthesis of the Stannanes.

R3SnCI (1.2 eq), PMHS(1.5eq)

 

 

 

KF(2.5 eq) R
:——R t /=/ + JL
TBAF, THF, H20 R3Sn R3Sn R
PdC12(PPh3)2
Entry Alkyne Product % Yield E/lnt
: 0
1 A0“ (I) Me3Sn/\><OH (3) 63 IOO/o E
0
2 l Bu3Sn/\><OH (4) 80 100 /o E
1 o
3 Cy3Sn/\><OH (5) 20 100 A: E
4 I Ph3Sn/\><OH (6) 10 100% E

3 M0“ (7) 45 um
4

 

This involves hydrostannation of an alkyne with the triorganotin hydride specie
being generated in situ. Polymethylhydrosiloxane (PMHS) in the presence of KF and
TBAF was used as the hydride source (via the hypercoordination of silicon). Trialkyltin
chloride was used as the tin source. The reactions were performed under palladium
catalysis to generate the E and internal trialkylvinyl stannanes. The hydrostannation
results show that in the case of unhindered alkynes (entry 5) regiochemistry was an issue
with both the E and internal products being obtained. The rate of the reaction is also
dependant on the size of the alkyl substituents about the trialkyltin chlorides, with the
trimethyltin chloride reacting faster than the trialkyltins substituted with larger groups.
Radical conditions were employed to access the Z-vinylstannanes (Scheme 2.6).2l

Scheme 2.6. Radical Initiated Synthesis of the Stannanes.

R3SnCl (1.2 eq), PMHS(1.5 eq)

 

 

 

_ KF(2.5 eq) _ R R3Sn R
_" R TBAF, THF, H20 ' R3Sn/ + H—
70 °C, AIBN 5.x z-x
Entry Alkyne Product % Yield £72
I é 4011 (2) Eggnwofl <7) 67 1/1
0
2 2 Cy3SnflwOH (3) 73 100/oz
3a 2 (8) 62 1/4

Cy3Sn \ 4OH

 

a reaction was stirred for 2 days to ensure equilibrium.

It was interesting to note that the radical initiated hydrostannation using
tricyclohexyltin hydride gave a much higher ratio of the Z product (Z-8) than would have
been normally expected (entry 3).22 Moreover when the reaction was stopped before
completion this was the only isomer obtained (entry 2). Since the tributyl counter part
gives a mixture of Z and E isomer even when the reaction is stopped early, this

observation may be of synthetic utility.

2.2.2. Measuring the Kinetics

With the trialkylvinyl stannanes in hand, preparations were made to measure the
relative rates in Stille reaction. lH-NMR was chosen to follow the reactions in part
because our initial attempts using a React-IR did not generate enough resolution for
quantification.

The kinetics were measured by considering the rate of the reaction at the origin.
The rate law is of the form d[X]/dt = k-II([Xi]j) with j being the order for the compound
Xi. At the very beginning of the reaction one can consider the concentration of the
reagents as constant and so the rate law becomes d[X]/dt = K which after integration
gives [X] = Kot where K is the Slope of the tangent at the origin. With such a
measurement it is only possible to compare relative rates. As such we established a
reaction of reference to which the different rates would be normalized.

Scheme 2.7. Reference Reaction.

/\>< szdba3 (2.5 mol%) / AsPh3 (10 mol%) /\><
\ = \
R38" OH Internal Standard, Ar-X, 50 °C Ar OH

 

The reaction illustrated in Scheme 2.7 was performed with various stannanes and
electrophiles on a 0.2 mmol scale of the stannane. szdbag (2.5 mol%) and AsPh3 (10
mol%) were stirred together for 20 minutes in order to pre-form the catalyst. Then the
stannane was dissolved in 0.7 mL of THF to which was added 0.05 mL of deuterated
benzene in order to allow the lock of the signal. Just before the experiment was started
the electrophile (0.4 mmol) was added and the sample was inserted into the pre-heated
NMR Spectrometer. The reaction was run at 50 °C in order for the reaction to be

observable within the time frame of the experiment.

10

2.2.3. Choice of the Internal Standard

Since the reactions were going to be followed by NMR, an internal standard was
required for an accurate determination of the yield. The internal standard needed to be in
a clear area of the NMR spectra and a spectator during the reaction. We considered three
different potential standards that could match those requirements: cyclooctadiene,
anisole, and acetophenone. We compared the kinetics for those three internal standards
(Scheme 2.8) in order to determine the suitable one(s).

Scheme 2.8. Internal Standard Test.

/\>< szdba3 (2.5 mol%) / AsPh3 (10 mol%) AX
\ : \
Cy3Sn OH Internal Standard, Ph-Br, 50 °C Ph OH

 

 

 

5 9
Entry Internal Standard Rate (mmol/min)
I cyclooctadiene 0.001
2 anisole 0.008
3 acetophenone 0.008

 

Since both anisole and acetophenone gave almost identical results (entries 2 and
3) we could use either as internal standards. On the other hand cyclooctadiene gave very
differing results and in particular very low yields and so was abandoned as a standard.
This difference is most likely due to the chelation of the palladium by cyclooctadiene
which in turns destroys the catalytic effectiveness of the metal.
2.2.4. Kinetics

Four types of trialkylvinyl stannanes were studied, where the alkyl groups were
either methyl, butyl, cyclohexyl or phenyl substituents. Those tins were tested with four
different electrophiles: bromobenzene, iodobenzene, bromoacetophenone and
bromoanisole. We thus have two electronically neutral aryl halides, an activated one, and

a deactivated one.

11

The results for those experiments are shown in Scheme 2.9. The rates displayed
have been normalized to a reaction of reference. This reference was done for the cross-
coupling of (E)-2-methyl-4-tributylstannanyl-but-3-en-2-ol (4) with bromobenzene (entry
6) and the rate was arbitrarily chosen as 1. All rate are thus expressed in reference to the

reaction of entry 6.

Scheme 2.9. Kinetics Results.

M szdba3(2.5mol%)/AsPh3(10mol%): Ar/\><OH

 

 

 

R33" 0“ lntemal Standard, Ar-X, 50 °c
3-5 9-11
Entry Stannane Ar-X Product Relative Rate
1 Me3Sn/\><OH (3) Ph-l 9 3.6
2 3 Ph-Br 9 2.8
3 3 p-(MeO)—C6H4-Br 10 0.6
4 3 p-(CH3CO)-C6H4-Br 11 1 1.6
5 Bu3Sn/\><OH (4) Ph-I 9 1.8
6 4 Ph-Br 9 Q)
7 4 p-(MeO)-C(,H4-Br 10 0.5
8 4 p-(CH3CO)-C6H4-Br 1 1 8.2
9 Gym/\XOH (5) Ph-I 9 0.2
10 5 Ph-Br 9 0.5
I I 5 p-(MeO)-C6H4-Br 10 0.4

M
(II

p-(CH3CO)-C6H4-Br I 1 l

 

The size of the trialkylvinyl stannane was critical in the rate of the reaction.
Triphenylvinyl stannane (6) had kinetics too slow for the time frame and temperature of
the experiment and are thus not represented in Scheme 2.9. Moreover, for a given
substrate the trimethylvinyl stannane (3) reacted faster than the tributylvinyl stannane (4)
which in turns reacts faster than the tricyclohexylvinyl stannane (5) (Scheme 2.9, entries
1,5,9 / 2,6,10 / 3,7,11 / 4,8,12). This can be best Shown by plotting the kinetics for one

substrate as shown in Scheme 2.10.

12

Scheme 2.10. Kinetics for the Coupling of Phenyl Bromide.

100‘

90 /
.. /

70 / M.»
60 "'

 

Yield / .w" —— Me3Sn
(0/0) 50 / [f .............. T "" Bu3Sn

 

 

 

40 .f- """ (3)/33“
3O / 'l'

20 .' '
I
/,.
10 '

0

 

0 {4 2'8 4’2 56 7'0 8‘4 9'8 112 ' 140 ' 168 ' 196 Y 224 T
Time (mn)

We also wanted to determine the consistency of the effect of the trialkylvinyl

stannane across various electrophiles. Specifically we asked if the kinetic effect was

consistent for the full range of substrates used.

Table 2.1. Relative Kinetic Effects for the Stannanes.

 

entry Aryl Halide kph/kg" Ran/kc, kMchy

Br
I 2.8 2.0 5.6

I .
2 Cf 2.0 9.0 18.0
Br
3 O 1.2 1.3 1.5
M60

Br
4 YO 1.4 8.2 11.6
0

 

 

13

To do this comparison we measured the ratio of the different rates for reactions of
the various vinyltins against the different electrophiles (example: rates for trimethylvinyl
tin (3) / rate for the tributylvinyl tin (4), ko/kgu). The relative kinetics for the different
substrates are shown in Table 2.1. The relative rates are within the same order of
magnitude but there is no real consistency on the rate enhancement when we change
substrates. For example the rate increase going from a trimethylstannane to a
tributylstannane is 2.8 for bromobenzene but only 1.2 for bromoanisole. Nevertheless, the
rate increase from trimethylstannanes to tributylstannanes remains in the 1.2-2.8 range
for most of the substrates which shows some consistency in the acceleration. The rate
increase of tributylstannane over tricyclohexylstannane does not seem to follow any
regular pattern ranging from 1.3 to 9.0, with the higher values for the more activated
substrates.

We also compared the influence of the different aryl halides reacting with a single
trialkylvinyl stannane. The relative rate effects are shown in Table 2.2.

Table 2.2. Relative Kinetic Effect for the Electrophile.

O” O” ‘O ”O
MeO COCH3
13 14 15

 

 

12
entry stannane Ins/R14 I‘M/kn k13/k12 kis/krz k15’k13 I‘M/k1:
l Me3Sn/\><OH (3) 3.2 1.3 4.7 19.2 4.1 6.0
2 Bu3Sn/\><OH (4) 4.5 1.8 2 16.4 8.1 3.6
3 (”fin/\XOH (5) 5.0 0.4 1.3 2.5 2.1 0.5

 

Once again the effects are within the same order of magnitude with the general

trend of electron poor electrophiles reacting faster as shown by the observed trend of

14

bromo-acetophenone (15) > phenyl halide (13, 12) > bromo anisole (12). However the
rates between phenyl bromide (13) and phenyl iodide (14) seems to be very similar with
phenyl iodide being the generally faster reacting electrophile, except with tricyclolvinyl
stannane.

We also wanted to have a sense of the kinetics of the reaction based on the
stereochemistry of the stannane, E vs. Z vs. internal. The results are shown in Scheme
2.11.

The rates follow the trend of E > Z > internal. Additionaly, the tributylvinyl
stannanes still reacts faster than the tricyclohexylvinyl stannanes of corresponding
stereochemistry by a 10:1 rate enhancement.

Scheme 2.11. Effect of the Stereochemistry.

0 0
R s W014 szdba3 (2.5 moi/o)/AsPh3 (10 “10th PhWOH
3 11 Internal Standard, Ph-Br, 50 °C

 

 

 

Entry Stannane Product Rel. Rate
W W .
I Bu3Sn \ 0” ph \ 0H 23
(E7) (15-16)
2 SnBu3 Ph 1 4
W011 Won '
(Z-7) (Z-16)
/“\/\/\ /“\/\/\ 0
Bu3Sn OH Ph OH
(17) (18)
4 Cy3Sn \ OH Ph \ OH 029
(E-8) (E-16)
5 SnCy3 Ph 013
MO“ W011 '
(Z-8) (Z-16)

 

Finally, we tested how the results would change if we modify the reaction
conditions by replacing the catalyst by Pd(PPh3)4 (Scheme 2.12). The results show that

the order of reactivity remains but that the overall rate is slowed considerably. This was

15

to be expected according to the results obtained by Farina in which he showed that the
szdba3/AsPh3 was much faster than the Pd(PPh3)4 system.l7

Scheme 2.12. Kinetics with Pd(PPh3)4.

Pd(PPh3)4 (2.5 mol%)
R3Sn/\><OH 7 Pia/\XOH

Internal Standard, Ph-Br, 50 °C 9

 

 

Entry Stannane Relative Rate.

Mast/9%” (3) 0.021
Bu3S MO” (4) 0.01

11

Cy3S /\><OH (5) 0.0048

n

 

 

* rates relative to entry 6 of Scheme 2.9

In this case we show a rate increase from methyl to butyl and from butyl to
cyclohexyl to be of 2.1 (see table 2.1, entry 1). Those values fall in the same range as
those observed with the previous catalyst system, even though the overall rate has been

decreased by a factor of 50.

2.2.5. Conclusions

We have shown that the order of reactivity of the stannane is trimethyl > tributyl
> tricyclohexyl > triphenyl. We have also observed that electron deficient arylhalides
react faster than electron rich arylhalides for all the stannanes tested. The rate increase
from trimethyl to tributyl seem to be small for most substrates (average of 2 fold) while
the increase from butyl to cyclohexyl is more substantial (average of 6 fold). We hope
that the results provided will help people in their choice of the “non-transferable” alkyl
substituent on the tin and be able to find a compromise between rate, toxicity, and

transfer reactions.

16

2.2.6. Further Work
Further work needs to be done in order to investigate the inconsistencies in the
effects of the substituants and electrophiles. More electrophiles could be used as well as

more alkyl substituants on the tin.

17

Chapter 3. Microwave One Pot Stille Cross-Coupling
3.1. Introduction

As discussed in Chapter 2, the difference in rate when using various trialkyltins is
significant but the rates remain within the same order of magnitude. In order to increase
the speed of the reaction further, one could envision the use of microwave irradiation to
accelerate the Stille cross-coupling.

3.1.1. Microwave Irradiation

Microwave irradiation is thought to have at least two effects on organic
reactions.” The first being a pure thermal effect, as reactions are able to reach very high
temperatures within very short lengths of time. Furthermore, microwave flash heating
allows for a better homogeneity of the temperature distribution within the reaction when
compared to classical heating.24 A second thermal effect is what is commonly called
“superheating effect.” It corresponds to an elevation of the boiling point in liquid systems
where there is no stirring. For example, when subjected to microwave irradiation the
boiling point of water raises from 100 °C to 105 °C or from 82 °C to 120 °C in the case
of acetonitrile.”

The second effect results from the direct excitation of the bonds at the molecular
level provoked by the irradiation. The consequences are three fold. Collision efficiency is
increased by mutual orientation of the dipolar molecules. The activation energy can be
lowered and local hot spots created. The consequence of these effects is that microwave

1.26 Moreover,

irradiation allows some reactions to proceed faster as shown in Scheme 3.
some reactions that do not proceed (or do so moderately under very harsh conditions) are

viable under microwave flash heating (Scheme 3.2).27

18

Scheme 3.] Microwave Accelerated Amide Formation.

O
©/\NH2+ Ocozfl 150°C G/KH/D
30min
MW 80%

Heat 8%

Scheme 3.2. Leukart Reductive Amination.

 

O NHCHO
202°C

+ HCONH2 + HCOZH O O

MW >98%

Heat 2%

Microwave reactions can be performed in a very reproducible manner and with
great control of the reaction conditions by focusing the wave to allow homogeneity of the
field within the reactor. In such focused microwave reactors, the temperature can be
measured by an IR detector and pressure can also be monitored. This allows a better
understanding of the reaction processes while avoiding rupture of the cell. Of course
these features come at a price and focused microwave reactors retail for $20,000 or more.
As such, standard kitchen microwave ovens are often looked to as a cost effective
alternative to the purpose built microwave reactors. However, reproducibility issues and
other problems linked to the use of such ovens are well known and include:
Non-homogeneity of the field and creation of “sweet” spots within the oven.

No means to measure the temperature or pressure of the reaction mixture.
3.1.2. Previous Work on Microwave Accelerated Stille Reactions

Recently Larhed, Hallberg, and others28 have shown that the cross-coupling time
for fluorous and organic phase Stille couplings can be reduced to only minutes by using
microwave flash heating. Microwaves have also been used to effect Stille cross-coupling

on alumina impregnated with potassium fluoride in minutes?9 This represents a

19

considerable acceleration of a reaction that, for most substrates, normally proceeds at
reaction temperatures of 45-100 °C with reaction times ranging from hours to days
(Scheme 3.3).

Scheme 3.3. Larhed Systems.

C F CH CH —s + — =
( 613 2 213 “ (2R DMF,6OW,2min \ /

(70 - 90%)

 

3.1.3. Objectives

In an effort to decrease the reaction time of the Stille cross-coupling we proposed
to also use microwave irradiation to increase the rate of the reaction. However, in doing
so, we also wanted to minimize the time required to prepare, handle, and isolate the toxic
organostannane intermediates. Thus we wanted to minimize exposure to hazardous
substrates by generating the organostannanes intermediates in situ and to accelerate the
process of going from commercial starting materials to cross-coupled products. Thus the
objective of the study is to devise a one-pot microwave assisted hydrostannation/Stille

- 2
cross-coupling. 13‘ O

3.2. Results
3.2.1. Generation of Tributyltin Hydride

Focusing first on the in situ generation of organotins, we considered the
possibility of using microwave flash and superheating to improve Hayashi’s method of
tributyltin hydride generation (Scheme 3.4). This method involves the reduction of
(Bu3Sn)zO with polymethylhydrosiloxane (PMHS). Unfortunately, only half of the

available tin is converted in tributyltin hydride unless high temperatures are used.30

20

Scheme 3.4. Hayashi’s Method of Generating Tributyltin hydride.

PMHS PMHS
BU3SDO-SIR3 + 81.13an
Heat, THF Heat, THF

 

 

(Bu3Sn)zO 2 Bu3SnH

Since microwave irradiation can produce intense heat, we considered the use of
that irradiation to facilitate the release of the second equivalent of tin from bis-
(tributyltin)oxide. In attempting this, the choice of solvent was the first question to be
addressed. As the microwave is set at a specified frequency (2.45 GHz), the heating
capacity of the irradiation is very dependent on the ability of the solvent molecule to
absorb the energy of electromagnetic wave. Since the frequency used in kitchen
microwave is designed to excite water molecules, water would be the best reaction
solvent by virtue of its heating capacity. Solvents with absorption frequencies similar to
that of water would also be suitable. DMF is such a solvent. On the other hand another
common organic solvent, THF is not well heated by a microwave of frequency 2.45 GHz.
Even after prolonged irradiation, THF remains cool to the touch. Thus to employ THF in
microwave accelerated reactions, a co-solvent like DMF or water would be required.

To start our study, control experiments needed to be performed using a
conventional oil bath as the heat source. The data from these controls could then be
compared against the analogous reactions carried out in a microwave oven. The results of
this study are shown in Scheme 3.5.

When microwave irradiation was used instead of an oil bath to heat the reaction
(Scheme 3.5), the yields did not go beyond 26%. This strongly suggests that the second
equivalent of Bu3SnH was not released. In light of these results we turned our focus to
the use of our tin halide method of generating trialkyltin hydride previously described in

Chapter 2.

21

Scheme 3.5. Generation of Tin Hydride Control.

R R'
\ Br PMHS,(Bu3Sn)20(1eq.) \ \ OH

/OH + 0%

/ PdC12(PPh3)2 (1 mol 2.)

Yield (°/o) Yield (%)

 

 

 

Ent Alk ne Solvent Product
ry y MWa Heat”
1 9 (19) THF/1120 20 26 52
// OH
2 X (1) DMF 21 21 65
¢ OH

 

’ 140 W, 25 min
b 80 °C, 6 hours

3.2.2. The Search for the Right Protocol

Proof of Principle

We first compared a palladium mediated hydrostannation under conventional
thermal conditions to the same reaction under microwave irradiation. The results are
shown in Scheme 3.6.

Scheme 3.6. Effect of Microwaves on Hydrostannation.

Me3SnF, PMHS, TBAF

szdba3 (l mol%)/AsPh3 (4 mol%)
%OH = M635 /\><OH

 

II
1 THF 3

 

Entry Time Energy % Yield

 

1 2 hours A = 80 °C 80

2 3 minutes MW 140 W 76

 

The comparison was made for the hydrostannation of 2-methyl-2-but-3-ynol (1),
using trimethyltin fluoride/PMHS as the trimethyltin hydride source. Both methods of
heating afforded (E)-2-methyl-4-tn°methylstannanyl-but-3-en-2-ol (3) in excellent yield,

but the microwave irradiation took only 3 minutes while the thermal process needed 2

22

hours. Thus a definite acceleration of such a hydrostannation with in situ generation of
Bu3SnH under microwave irradiation was possible.

We then proceeded to gain a better understanding of the Stille processes under
microwave irradiation. A quick investigation was done by varying different parameters
such as solvents and catalysts as shown in Scheme 3.7.

Scheme 3.7. Stille Cross-coupling Alone.

szdba3 (1 mol%)

L' d 4 1°/
M SAXOH + \ 3’ 'ga" ( m0 °) 2 \ \ OH
63 n 3 Solvent, 70 W,6min 2'

 

 

 

Entry Ligand Solvent °/o Yield
1 AsPh3 DMFzTHF 33
(1:1)
2 AsPh3 DMF 40
3 TFP DMF 43
4 TF P THF 0

 

The reaction was performed on (E)-2-methyl-4-trimethylstannanyl-but-3—en-2-ol
(3) and (E)-B-bromostyrene with szdba3/A8Ph3 as catalyst and DMFzTHF (1:1) as the
solvent. The solution was irradiated at 70 W for 3 minutes twice (entry 1). The time
interval was chosen because it was observed that the reaction vessel needs at least 2
minutes at this power to reach a state in which the solvent is at reflux within the tube and
because this allowed the opportunity to check the reaction by TLC. The yield obtained
under such conditions was 33%. When the solvent was changed to pure DMF the yield
rose to 40% (entry 2), and when the ligand was changed to TFP, the yield increased to
43% (entry 3). Finally, when THF alone was used as the solvent, no cross-coupling

product was observed and the reaction was still cool to the touch since the THF was not

23

heated by microwave irradiation (entry 4). Nonetheless, the feasibility of the cross-
coupling was demonstrated albeit in moderate yield.

We next needed to test both the hydrostannation and Stille steps together. This
was important as we were unsure if the microwave facilitated cross-coupling would be
adversely affected by the hydrostannation’s reagents and conditions under microwave
irradiation. Using the methods previously described for the generation of the vinyltin via
in situ generated tributyltin hydride and the Stille cross-coupling independently, we tested
the feasibility of performing the entire reaction sequence in one pot under microwave
flash heating conditions (Scheme 3.8).

Scheme 3.8. Intial One Pot Coupling.

1) Me3SnF, PMHS, TBAF, DMF R R'

 

 

 

/R<R' szdba3(l mol%)/TFP (4 mol%) _ W0”
é OH 2) DMF,bromostyrene 7
Entry Alkyne Conditions Product Yield (°/o)
0” Mw
1 X1211 (22) 70 W,4min 23 44
1 MW
2 2%“ H 70W,4min 2‘ 26
OH
22 A
3 2Ph( ) 80 °C, 16 hrs 23 33

 

szdba3 (1 mol%) and TFP (4 mol%) were dissolved in THF in a Pyrex tube.
After 20 minutes the solution was orange and trimethyltin fluoride (1.2 eq) was added
followed by the alkyne (1 eq), PMHS (1 eq), and TBAF (catalytic). The reaction was then
subjected to microwave irradiation at 70 W for 4 minutes (Scheme 3.8, entry 1, and 2).
The control experiment was ran at 80 °C overnight (Scheme 3.7, entry 3) and yielded

similar results as the microwave experiments.

24

The results were encouraging as the reaction time was greatly decreased without
significant loss in yield. Unfortunately the yields were again moderate (26 and 44%).
Increasing the microwave power during the reaction created a gel and amine was released
from DMF. It is likely that we further polymerized PMHS by a fluoride mediated sol-gel
process as the gel only formed when TBAF was present. However the coupling reaction
was still proceeding, which was proof that the principle was sound and that the one-pot
hydrostannation/Stille cross-coupling could be performed under microwave flash heating

conditions.

Finding the Right Reaction Conditions

With the proof of principle in hand we needed to optimize the reaction conditions
in order to make the process synthetically useful. The following parameters were among
those to be optimized:

The power of the microwave irradiation
The time of the reaction

The catalyst

The solvent

The first parameter to be explored was the solvent. Our previous results showed
that DMF was a better solvent than THF for the Stille cross-coupling (Scheme 3.7, entries
3 and 4), however, we ran the risk of PMHS polymerization if the power of the
irradiation or if the time of reaction had to be increased. Another common solvent in
Stille cross-coupling is NMP, but its high boiling point and good solvatation properties
make it difficult to remove at the end of the reaction. Finally THF has the problem of

being near transparent to microwave irradiation and thus unable to promote the reaction.

25

In light of the problems caused by those three solvents we opted for a mix of THF and
water (9:1). The water would provide for a heat sink, removing the problem associated
with THF alone, while also allowing us to get away from the problems associated with
DMF and NMP.

Given our decision to the use of water as cosolvent, we reconsidered our method
for tin hydride generation. Although we had previously used tributyltin fluoride/PMHS as
our tributyltin hydride source, reacting tributyltin chloride with aqueous KF in the
presence of PMHS also affords Bu3$nH via Bu3SnF (Scheme 3.9). Since the water used
to dissolve the KF could also serve as our heat sink, we used tributyltin
chloride/PMHS/KF as the tin hydride source for subsequent hydrostannations.

Scheme 3.9. Formation of Bu;SnH via Bu3SnF.

THF, H20 PMHS, KF

Bu3SnCI + KF [Bu33np] 4. Bu3SnH

 

 

After those two essential parameters had been selected, we tested the other
parameters against the one-pot hydrostannation/Stille cross-coupling of 2-methyl-2-but-
3-ynol (1) with bromobenzene shown in Scheme 3.10. In doing so, we had to define the
proper catalytic system. We initially used szdba3 and ASPh3 as our catalyst since it
previously generated good yields of products during the Stille cross-coupling of (E)-2-
methyl~4-trimethylstannanyl-but-3~en-2-ol (3) with (E)-B-bromostyrene (Scheme 3.8,
entry 2).

Scheme 3.10. Optimization Reaction.

_Ho 1) Bu3SnCl, PMHS, KF, Pd, MW \ 0H
— < 2) Ph-Br, Pd, MW

I THF/1120 24

 

We tested this system over a range of microwave power settings while irradiating

for 3 to 5 minutes intervals. The reaction shown in Scheme 3.10 was followed by TLC. In

26

our initial experiments, at the end of the irradiation period the reaction vessel would be
air cooled for approximately 15 minutes before it could be safely opened. This created a
problem since the cross-coupling could continue under thermal conditions during the cool
down. In order to stop the reaction and have a more accurate picture of its progress at the
point irradiation stopped, we rapidly cooled the vessel by dipping it into cool water for 2
minutes. The drop in temperature was thus much faster and the chances that the reaction
would continue much reduced. Under those conditions it became apparent that the
reaction could not be run to completion regardless of power (from 70 W to 700 W) or
reaction time (3 min intervals to 10 min intervals). Under all conditions tested, the yields
would top out at 60%. Also a black solid was formed over time (presumably palladium
black), indicating catalyst decomposition.3 '

Since the catalyst was being destroyed during the reaction we added fractions of
fresh catalyst after the hydrostannation and between the periods of irradiation (Scheme
3.11). Even with the extra catalyst, some unreacted (E)-2-methyl-4-tributylstannanyl-but-
3-en-2-ol (4) remained.

Scheme 3.11. First Generation System.

1) Bu3SnC1, PMHS, KFaq, THF, TBAF
szdba3 (l mol%)/AsPh3 (4 mol%)

HO '
: 140 W, 5 mm 4 won
\ 2) Ph-Br, szdba3 (1 mol%)/AsPh3 (4 mol%)

1 140 W, 5 min 24
3) szdba3 (l mol%)/AsPh3 (4 mol%)
140 W, 5 min, etc..

 

 

Increasing the power of the irradiation improved neither the yield nor the
conversion. Indeed, increased power only appeared to destroy the catalyst faster while
increasing the risk of explosion (vide infia). It thus seemed that irradiation at 140 W

offered the best compromise between stability and speed.

27

However, even at 140 W, the reactions were not going to completion. Since a
probable cause for the incomplete reactions was the destruction of the catalyst, a more
thermally stable catalyst was sought. We opted for Pd(PPh3)4 which is typically not as
good for Stille cross-couplings but is more robust. When only one aliquot of Pd(PPh3)4 (1
mol %) was used in the one-pot reaction, we still did not observe completion of the
reaction, but after numerous trials and combinations, it appeared that adding a second
aliquot of Pd‘o) after the hydrostannation and a third aliquot after 5 minutes of coupling
time allowed the reaction to go to completion.

We now had an optimized set of conditions (Scheme 3.12). Using Pd(PPh3)4
catalyst in three portions of 1 mol % each (one for the hydrostannation and two for the
cross-coupling), the hydrostannation was done in 3 minutes, and the cross-coupling was
completed in two intervals of 5 minutes each, all at 140 W.

Scheme 3.12. Optimized Conditions

1) Bu3SnCl, PMHS, RF”, THF, TBAF
Pd(PPh3)4 (1 mol%)

HO '
140 W. 3 mIn : Won
2) Ph-Br, Pd(PPh3)4 (1 mol%)

140 W, 5 min 24
3) Pd(PPh3)4 (1 mol%)
140 W, 5 min

 

4

—

3.2.3. Scope of the Reaction

Our standard conditions were thus: The alkyne (1 mmol), Bu3SnCl (1.2 mmol),
PMHS (1.5 mmol), KF (2.5 mmol), and Pd(PPh3)4 (1 mol %) were mixed in a solution of
THF (10 mL) and water (1 mL). Since the reaction was run in a non-focused microwave
oven, the pressure tube was placed standing in a holder, in the middle of the microwave
oven and rotation of the oven plate was stopped. By placing the reaction in a fixed place

we aimed to limit the influence the uneven “sweet” spots created within the oven. The

28

reaction mixture was irradiated for 3 minutes at 140 W then the solution was cooled by
placing the vessel in a water bath at room temperature. The aryl-halide (2 mmol) and
Pd(PPh3)4 (1 mol %) were then added and the reaction irradiated for 5 minute at 140 W.
After water cooling the vessel a third aliquot of Pd(PPh3)4 (1 mol %) was added and the
reaction irradiated for a further 5 minutes at 140 W. The reaction vessel was water cooled
and the reaction contents were separated between a saturated solution of ammonium
hydroxide and ether. The mixture was extracted with ether, and the organic phase was
washed with saturated KF. The combined organic phase was dried over MgSO4, filtered,
and evaporated in vacuo. Column chromatography gave the final products in 50-95%
yield.

One should take note that the risk of explosion of the vessel was not negligible.
Since we had no means of measuring either the temperature or the pressure within the
vessel, the pressure could build up and the seal fail provoking an explosion. The initial
seals used had a life expectancy of 2-3 reactions so we switched to Teflon coated O-rings
which proved to have a life expectancy of around 10-15 reactions. The other source of
explosion was the existence of weak spots in the Pyrex that could be created by scrubbing
the tube during cleaning. So, we stopped using brushes in the cleaning of the vessels.
Once all these measures were taken, there were almost no explosions and a survey of
substrates could be made. Different alkynes and electrophiles were cross-coupled and the

results are shown in Scheme 3.13.

29

Scheme 3.13. One-Pot Hydrostannation/Stille Results.

1)Bu3SnC1(I.2 eq). KFaq(2.5 eq), PMHS (1.5 eq)
Pd(PPh3)4 (1 mol%), 140 W, 3 min, THF

 

 

R—E : R./\/ R
2) R'X, Pd(PPh3)4 (2 mol%), THF
140 W, 10 min
Entry Alkyne Electrophile Product % Yield

 

(24) 94

1 +2 (1) PhBr

HO

Ph/\><0H
/
2 1 Ph/\Br Film (31) 90

Br / (Bu
3 1-3.. : (25) a Q]: (32) 86
OH OH

(33) 91

 

ITMX
/
5 O/ (19) PhBr /@ (34) 57
0“ Ph \ OH
Et
/ Br Et
6 HzN / (26) O \ NH (35) 90
Et Et 2
E Et
\

t
7 26 MB!" 36 81
Ph PhWNH2( )
8 51E": (27) l O “B" \ \ (37) 70
(41) EtO O

9 "'PI/ (28) mBr OH (38) 55
OH Ph PhWn-Pr

/
10 “0% (2) PhBr PhMOH (16) 57

E/Z/intemal = 9: l .7227

Br \ Ph
11 Ph—: (29) O OA/ (39) 86
MeO MeO

E/Z=41:27
12 MeOzC-E (30) PhBr PhA/C02Me (4o) 80

 

Most of the alkynes employed in Scheme 3.13 (entries 1-8) were trisubstituted at
the propargylic position. Such highly substituted alkynes are strongly biased towards

formation of the E—distal stannane upon palladium mediated addition of tributyltin

30

hydride and thus subsequent cross-couplings were not complicated by a non-
regioselective hydrostannation. In contrast, palladium catalyzed hydrostannations of
unhindered alkynes typically afford mixtures of both distal and proximal vinylstannanes.
As such, it is not surprising that less substituted alkynes (entries 9-10) gave cross-coupled
products in somewhat lower yields or as isomeric mixtures.

Interestingly, alkynes that highly favor formation of the proximal vinyltins upon
Pd—catalyzed hydrostannation (phenyl acetylene and methyl propionate; entries 11-12)
gave cross-coupled products corresponding to those expected from the distal vinyltins.
We assume these last two substrates react via a mechanism similar to that proposed by
32,10g

Busacca for the cross-coupling of methyl a-tributylstannylacrylate (Scheme 3.14).

Scheme 3.14. Bussacca’s Mechanism.

   
 

Heck
Reaction
=<C02Me,\
I 5118113 R COzMe
Pd $118113
R/ \I ”‘1
R—I J Transmetallation
Pd(0)
Reductive R COZMC
Elimination Pd
CO Me -
RN 2 B-hydridc
R/\/C02MC Pd. H elimination

3.2.4. Free-Radical Hydrostannations
Though we had initially used only palladium mediated hydrostannations of the
alkyne, in principle this step could also be carried out under free radical conditions.21

Thus we wanted to determine if those conditions were also amenable to the one-pot

protocol. To also expand the usability of this process we wanted to show that the protocol

31

did not need Bu3SnH generated from PMHS and BU3SI'IC1, but that B113an could be
used directly (Scheme 3.13, entries 3-5). This would allow the reaction to be carried out
when the presence of PMHS and/or KF is unsuitable. The reaction conditions remained
the same as previously described, with the exception of AIBN replacing the palladium
catalyst in the hydrostannation step (Scheme 3.15). Two methods were used in the
hydrostannation: (A) tributyltin chloride, KF or (B) tributyltin hydride.

Scheme 3.15. One Pot Free Radical Hydrostannation/ Stille Results.

1) Bu3SnH source A or B

AIBN, H O, 140 W, 3 min, THF
R—: 2 = RINR

2) R'X, Pd(PPh3)4 (2 mol%)
THF, 140 W, 10 min

 

 

 

Entry Alkyne Electrophile Method Product % Yield E/Z/Int ratio
1 VLE (1) PhBr A HMO}, (24) 86 20:1:1
HO

2 Ph—E (29) 1.4.0013. A 1460—va (39) 85 1009.1:
PI'I

/
/ . .

/
4 HO/\// (41) PhBr B P11\/\/\OH (42) 46 27:4:1
5 1 PhBr B PhAXOH (24) 79 23:10

 

Bu3SnH source: method A: Bu3SnCI, KP, PMHS, TBAF (cat). method B: Bu3SnH.

Even though the hydrostannation appeared to proceeded smoothly, internal
alkynes gave a multitude of products that were not easily separable. So we again turned
our attention towards terminal alkynes. The yields of products obtained above (Scheme
3.15) were moderate to good, but the two step processes started with palladium mediated
hydrostannations tended to afford better yields of cross-coupled products as compared to
the radical initiated reaction sequences.

It was expected that the free radical hydrostannation of the alkynes would give

E/Z ratios of around 3:1 as per previous studies.22 In fact, entries 3-7 Show an increased

32

selectivity for the E-isomer. Moreover, the ratio of isomers measured after the cross-
coupling were different than those measured after the hydrostannation step. For example
in entry 1, the ratio goes from 20:8:1 of E-4/Z-4/int-4 after the hydrostannation to 20:1:1
of E-24/Z-24/intemal (17) after the cross-coupling or from 2.5:1:0 (E/Z/intemal) for the
stannane intermediate to 7:1:0.25 of E-42/Z-42/intemal-42 for the products in the case of
entry 4. We did not expect such a result since Stille cross-couplings typically proceeds
with retention of geometric configuration at the olefin. There were different possibilities

for such an observation, so those results warranted firrther studies.

3.2.5. Stereocontrol 0f the Reaction

To investigate the stereochemical results more closely we studied the two steps of
the reaction process in more details. We first looked at the hydrostannation step alone
during which an initial equilibrium was observed. The ratio of products were dependent
on AIBN. When it was used, the equilibrium was reached in 8 minutes (Scheme 3.16)
giving a 10:2:1 (E/Z/Int) ratio of products. Without AIBN, the equilibrium was reached
after 13 minutes and gave a ratio of 7:6:1 (E/Z/Int).

Scheme 3.16. Hydrostannation Equilibrium.

Bu3SnH (1 eq)
THF, H20 Bu3Sn OH

‘ BU3Sn / OH _ OH
4 B s
140W m "3 n 4 l

E-4 Z-4 Internal-4

 

 

Time (min) With AIBN Without AIBN

 

(cumulated) Ell/Internal Ell/Internal
3 7234:] 1.4:8.2:1
8 10:5 : 1 2 ; 4 : l
13 102521 67:57:]
18 10:5 : l

 

33

It was thus clear that AIBN acts as both an initiator of the reaction and as a
promoter of the E product. This was not completely surprising as AIBN is a radical
initiator and thus able to promote the radical reaction responsible for the isomerization
process of the Z towards the E stannane as shown in Scheme 3.17.

Scheme 3.17. Mechanism of the Radical Initiated Hydrostannation.

Bu3SnH + Initiator. —> Bu3Sn °
, H
ER + Bu3Sn ————> _ °
81.13811 R
H H
_" + Bu3SnH __——. _
Bu3Sn R Bu3Sn R
. 80381] H
Bu3Sn R Bu3Sn R
Bu3Sn H
__ + Bu3Sn
H R

Thermodynamic Product

We next needed to look at the cross-coupling and in particular at whether
products were subject to isomerization in the course of the reaction. Initial experiments
showed that no isomerization of the final products occurred. Similarly there was no cross
over product observed when 2-methyl-4-phenyl-but-3-en-2-ol (24) was subjected to the
reaction conditions in the presence of p-bromotoluene (Scheme 3.18).

Scheme 3.18. Cross-Over Experiment.

©/\><OH Pd(PPh3)4 (2 mol%) _ li:’/\><OH
24 p-bromotoluene 24

140 W, 5 min
THF/HZO

 

34

In light of these results, isomerization of either the vinylstannane or another
reaction intermediate must be occuring. The cross-coupling reaction was thus performed
on both isomers of the stannane, with and without AIBN as shown in Scheme 3.19.

Scheme 3.19. Isomerization.

Pd(PPh3)4 (2 mol%), PhBr

HO \ 2 HO \
70 mph

SnBu3 H20, THF, 10 min
2-4 ‘40 W E-24/Z-24 = 1:172 (68%)

 

Pd(PPh3)4 (2 mol%), PhBr

HOXVSI‘BUJ ; HOXVPh

H20, THF, 10 min
E4 140 W E-24/Z-24 = 99:1 (65%)

 

Pd(PPh3)4 (2 mol%), AIBN
HO \ PhBr

= HO \ Ph
XEDBIg XV,

H20, THF, 10 min

4 . 140 W E-24/Z-24/int-24 = 33:1 : 1 .3
13:1 l:l (E/Z/Int.)

 

The results Show that the isomerization occurs even when no AIBN is present but
to a smaller extent. Isomerization from the Z stannane also occurs when BHT, a radical
scavenger is used although this too occurred to a lesser extent with the isomeric ratio of
the product being then E/Z: 1:3. This indicates that there might be more than one
mechanism involving radical and non radical processes responsible for the isomerization.

It could also be possible that one of the reaction byproducts acts as an
adventitious radical initiator to promote the isomerization. However no isomerization was
observed when the Z stannane (Z-4) was subjected to the conditions in the presence of
BU3SnBr or Bu3SnSnBu3. Similarly, when only some of the elements involved in the
reactions were added with the stannane no isomerization occurred. It is only when the
cross-coupling reaction is allowed to occur that such an isomerization is observed
(Scheme 3.20). This seems to indicate that the isomerization occurs during the course of

the reaction and not of the starting material per se.

35

Scheme 3.20. Controls.

 

Pd(PPh3)4 (2 mol%)
Bu3SnBr (1 eq) _ . _
Bu3Sn Ph 3 no Isomerizanon
— OH or HO — , b d
H20, THF, 140 W, 5 mm 0 serve
Z-4 Z-24

3.2.6. Conclusion

We have successfully devised an efficient one pot hydrostannation/Stille cross-
coupling protocol that, under microwave flash heating, allows one to obtain cross-
coupled product starting from the l-alkyne in a bottle to bottleitime of around 2.5 hours.
When thermal conditions were used, the bottle to bottle time would be extended to 8 to

18 hours or more, thus clearly showing the power of the microwave flash heating.

36

Chapter 4. Cross-Coupling of Trialkylvinylgermanes
4.1. Introduction
4.1.1. From Tin to Germanium

As described in previous Chapters, we can drastically accelerate the Stille cross-
coupling and handle all tin compounds in situ. However, the toxicity of the tin remains a
concern. In practice, the use of any amounts of organotin in any way is unattractive on
large scale. An ecologically sound alternative to tin would alleviate some of the handling
and disposal issues. So, in order to perform Stille type reactions one should look at less
toxic metals with an electronic structure similar to tin. Though less developed for cross-
couplings than boron (Suzuki)3 and silicon,” germanium is a candidate for such
reactions.
4.1.2. The Use of Germanium

Germanium has been used largely in semi-conductor chemistry but not much in
organic processes. However some such studies were performed in the laboratory of
Corriu during the early 1970’s. These detailed the synthesis of vinylgerrnanes using
various metal catalysts (Scheme 4.1).34

Scheme 4.1. Initial Synthesis of Vinyl Germanes.

PPh RhCl
Ph—Z + R3GeH ( 3h : Ph/VGeRg,
0f (PPh3)2PICl2

 

(50- 85%)
The Corriu group did not make further use of the vinylgermanes. In fact, it was

not until the 1990’s that work began to appear that employed these substrates in organic

chemistry.

37

4.1.3. Previous Cross-Coupling of Germanes

At the start of this project there had been almost no cross-coupling of
vinylgermanes reported in the literature. Some radical cyclizations involving
vinylgermanes had been reported by Curran.35 Similarly Pauson Khand reactions36 and
palladium catalyzed cyclizations with vinylgermanes were known.37 Only two papers
existed regarding carbon—carbon bond formation using vinylgermanes in standard cross-
couplings. Kosugi had attempted to use trialkylvinyl germanes with little success.38 Only
p-bromotoluene could successfully be coupled with tributylvinyl germane in 60% yield
(Scheme 4.2). To overcome this reluctance to react, Kosugi developed a more reactive
caged coordinated germanium species in the form of a germatrane in order to perform the
cross-couplings (Scheme 4.3).

Scheme 4.2. Kosugi’s Initial Result.

Br szdba3 / phosphine \

60%

 

Scheme 4.3. Kosugi’s Germatranes.

..~‘ szdba3°CHCl3 (I mol%)
{N ) Ligand (4 mol%)
Ole} 120 °C, 24 hrs, THF
R

(8 - 95%)

 

The other reported successful cross-coupling was made by Ikenaga et a1.39 and
involved the cross-coupling of styryltrimethyl germanes with aryl palladium
tetrafluoroborates generated from arenediazonium tetrafluoroborate and Pd(dba)2
(Scheme 4.4)

Scheme 4.4. Ikenaga’s Coupling.
\ GeMe3 Pd(dba)2 Ph _
m + AerBF4 \—\Ar + Ph/lLAr

38

Duchéne also showed that when both a trialkylstannane and a tn'alkylgermane
were present, standard Stille conditions would afford reaction only at the stannane
leaving the germane unreacted.40 (Scheme 4.5)

Scheme 4.5. Competition between Tin and Germanium.

Pd(PPh3)4
R'-X + NSnBUZ) 4 NR.
R306 toluene, 100 °C, 12 h R368

(56 - 85%)

 

The work of Kosugi has recently been expanded upon by Faller who, unable to
reproduce Kosugi’s work, modified the initial germatrane. In order to increase the
germanium’s electrophilicity he changed the coordination on germanium replacing the
carbon/nitrogen ligand (C3N) by an oxygen/nitrogen analogue (O3N).4l Faller was thus
able to perform a wide variety of couplings (Scheme 4.6).

Scheme 4.6. F aller’s Germatranes.

 

Pd(dba)2 (10 mol%)
R Ligand (20 mol%)
'— 9 KT . )9 or O
R2 (Q6 THF, reflux, 15 hrs R2
0. Q ,N
L..- (SO-75%) (IO-20%)

(E/Z= 1:2 to 1:5.5)

In parallel, Oshima found success using trifiirylgermanes instead of trialkyls.42
Both groups obtained positive results, although their yields were still wide ranging
(Scheme 4.7).

Scheme 4.7. Oshima’s Trifurylgerrnanes.

 

TBAF
Pd,(2-furyl)P

/ \ GeQOMe+ PM 3 = Ph—Q—OMe
o 3 NMP, 100°C

(0-90%)

39

4.1.4. Objectives

Even in the light of F aller and Oshima’s recent results, the use of trialkylgermanes
would still be attractive since they are more easily handled (no glove box) and more
easily obtained (the hydride is commercially available). Thus it was our intent to establish
a more general system, relative to Kosugi’s, for the cross-coupling of vinylgermanes.

4.2. Initial Results: A Window of Hope
4.2.1. Preparation of the Germanes

Before we could search for cross-coupling conditions, the corresponding
trialkylvinyl germanes needed to be prepared. As already mentioned, this chemistry was
pioneered by Corriu in the 70’s and saw some modifications in terms of catalysts and
solvents used. Per the description by Ichinose et a1. 43 we decided to use palladium for
the catalyst instead of rhodium or platinum due to the availability and lower cost of this
catalyst.

The hydrogermylation was thus performed at room temperature under a nitrogen
atmosphere with a stoichiometric ratio of alkyne to trialkyl germanium hydride and with
20 mol% of Pd(PPh3)4. The yields were moderate to high and the method was highly
reproducible (Scheme 4.8).

The stereochemistry was determined by coupling constant analysis and by
comparisons with existing substrates. For 2-methyl-2—but-3-ynol (1) (Scheme 4.8, entry
1) the stereochemistry was proven by replacing the germanium by an iodide44 and then by
comparison to the known vinyliodide (58) (Scheme 4.9). This assignment was based on
the knowledge that exchange with X2 occurs with retention of configuration while

exchange with NBX inverts the geometry of the olefin. Hence, production of the E-

40

vinyliodide indicated that the germane was of the E geometry. This was later confirmed
by analysis of the coupling constants (Scheme 4.10) of the E and Z isomers. (The
synthesis of the Z isomer in Scheme 4.25).

Scheme 4.8. Hydrogermylation with Bu3GeH

 

 

 

Pd(PPh4)3 (3 mol%) B G R
H : R - Bu3Ge/\/R + "3 CT
Bu3GeH, THF

Eex Int-x

Entry Alkyne Product % Yield Elint
0

1 X0” (1) Bu3Ge/\><OH (49) 90 100/oE
2 A011 (2) Bu3Ge \ 40H (50) 64 4.021
3 W30“ (43) Bu3Ge/\’fi;OH (51) 75 3.921

)O
O

(19) /\Q (52) 30 100% E
H Bu3Ge \ OH

0
(25) Bu3Ge/\>< (53) 73 100 /o E
(44) Bu3Ge/\’(A)3\ (54) 78 3.7 : 1

3X

7 /OH (45) Bu3Ge/V\0H (55) 77 12:1
8 Worm (46) Bu3Ge/W‘OTHP (56) 61 1.3 : 1
9 /OTHP (47) BMW/Worm (57) 62 3: 1
OH (48) OH
10 (58) 46 1000/ E
///\Ph Bu3Ge/\)\Ph °

 

Scheme 4.9. Germanium — Iodide Exchange.

I2
Bu3Ge/\><OH 1/\><OH
CHZCIZ 59

49 RT, 1 hrs
60%

 

41

 

im‘

Scheme 4.10. Comparison of Coupling Constants.

J= 18.7 Hz J=l3.6 Hz

H H H
Bu 0.2-Von — OH
3 H 811366

For unknown reasons the hydrogermylation proceeded in better yields when one
equivalent of the alkyne was used instead of two. Moreover the reaction was best worked
up as soon as all starting material has been consumed. For example, in the
hydrogermylation of 2-methyl-3-butyn-2-ol (49) with tn'buytlgermanium hydride
(Scheme 4.8, entry 1), when two equivalents of alkyne were used instead of one the yield
went from 90% to 78%. Likewise, when the reaction was allowed to run for 16 hours
instead of 8 hours, the yield dropped to 62%.

For the hydrogermylation with triphenyl germanium hydride, the protocol used
was the same as for the trialkyl germanes and the results are shown in Scheme 4.11. The
yields and regiochemistry were similar to that obtained for the hydrogermylation with
tributylgermanium hydride.

Scheme 4.11. Hydrogermylation with Ph3GeH

 

 

 

Pd(PPh4)3 (3 mol%) ph Ge R
— 3
H — R = Ph3Ge/VR 4» \Ir
Ph3GeH, THF
E-x Int-x
Entry Alkyne Product % Yield E/int
0
1 //)<OH (l) Ph3Ge/\><OH (60) 81 lOO/o E

”OH (2) PhsGeMOH (61) 53 4.02 l

4

\\

 

4.2.2. Initial Couplings
With the different germanes in hand cross-coupling reactions were attempted. We

initially used reaction conditions similar to those used by Kosugi, which were “Stille-

42

like” cross-coupling conditions. We attempted the coupling using both the triphenyl and

the tributyl vinylgermanes (scheme 4.12)

Scheme 4.12. Initial Cross-Coupling Reaction

 

 

 

szdba3 (20 mol%)
AsPh3 (80 mol%) Ph
R,Ge/\><0H > W
PhBr, NMP 0”
70 °C, 48 hr 2‘24
entry R °/o Yield
1 Bu (49) 28
2 Ph (60) o

 

The triphenyl was unreactive, perhaps owing to the steric hindrance of the
substrate. The coupling of 2-methyl-4-tributylgermanyl-but-3-en-2-ol (1) with
bromobenzene proceeded in very moderate yields. Despite the low yields (entry 1, 28%),
the stereochemistry was intriguing. We obtained exclusively the Z coupled product
instead of the expected E—isomer. This prompted us to consider a different mechanism
than that of a typical Stille.

4.2.3. Proposal of a Mechanism

As seen previously, a typical Stille reaction (Scheme 1.2) goes with retention of
geometry at the vinyl group. Instead we observe what seems to be an inversion. This led
us to propose an addition/elimination mechanism. Such a mechanism would give the

correct stereochemistry as shown in Scheme 4.13.

43

 

 

(I)

it

Scheme 4.13. Addition/Elimination Mechanism

Bu3GeBr PhBr
pd(0)
Reductive Oxidative
Elimination Insertion
BueGePd(”)Br Ph-Pd‘mBr
__ R
_. Bu3Ge
Ph/—\R - -
Addition
Elimination BU3Gc Pd‘l'mr
“it"?

The putative mechanism starts with an oxidative addition, followed by chelation
of the olefin to the palladium. Following syn addition of the aryl-palladium, rotation of
the C—C bond places the palladium and the germanium in an eclipsed orientation. Syn Pd-
Ge elimination would give the observed Z-olefin geometry. Finally, reductive elimination
of the palladium would regenerate the catalyst. Typically Heck reactions can proceed
with either a Pd-H or Pd—M elimination. The latter case has been mostly observed for
silicon,l which possesses an electronic environment similar to that of germanium.
Therefore we believe it reasonable to put forth such mechanism. It is noteworthy that, in
the course of our investigations, Faller proposed a similar type of mechanism for his
germatranes (Scheme 4.14)“ even though, in his case he obtained a mixture of products
resulting from a Pd-Ge and from a Pd-H elimination and never observed the level of Z
selectivity seen in our experiments.

Scheme 4.14. F aller’s Proposed Mechanism.

Ar Ar

 

 

Lzlpd GCO3N -NO3GCPd12

 

fiGeO3N

 

NO3Ge Ar Ar

 

inpd H -HPdIL2 NosGe

44

4.3. Search for optimal conditions

With a Heck mechanism proposed it was only natural to test typical Heck reaction
conditions in an attempt to improve the yields. To do so, a wide variety of conditions
were tested against a standard protocol. For comparison purposes, Stille type protocols
were examined along with the Heck conditions.

Scheme 4.15. Screening of Stille Conditions.

"Pd” (10 mol%), Ligand (40 mol%)

Bu oe/\><0H Additive (20 mol%) ; PthH
3 _

Phl, Solvent

 

 

 

49 60 °C, 16 hrs 2'24
Entry "Pd" Ligand Additive “/o yield
1 szdba3 AsPh3 . 5
2 szdba3 AsPh3 Cu] 0
3 szdba3 TFP 0
4 szdba3 TF P Cu] O
5 szdba3 P(o-Tol)3 - 0
6 szdba3 dppe - 7
7 Pd(OAc)2 AsPh3 - 10
8 Pd(OAc)2 AsPh3 CuI 0
9 Pd(OAc)2 TF P - 0
IO Pd(OAc)2 dppe O
1 l PdC12(o-Tol)2 - - 0

 

For the Stille conditions, we tested different palladium sources and ligands as well
as different substrates (Scheme 4.15). The best ligand / catalyst combination proved to be
AsPh3 in combination with palladium acetate. In addition szdba3 / AsPh3 also provided
some cross-coupled product. We added CuI in some reactions (entries 2, 4, 8) since it is
a known Stille reaction accelerator.” In this case, reactions that worked without Cul
would stop working upon its addition. This suggests that the steps typically accelerated
by the addition of CuI (transmetallation) may not be operative here, and reinforces the

presumption that the reaction does not goes through a Stille type mechanism.

45

 

11)

C0

3')

CIC

me

Our

Scheme 4.16. Screening of Heck Conditions.

on
Bu3Ge/\><0H 1)th

"Pd" (10 mol%), Ligand (20 mol%)
Base (2.5 eq), Additive (leq)

 

 

 

49 mm:
Entry "Pd" Ligand Additive Base Solvent % yield

1 Pd(OAc)2 PPh3 TBAHSO4 K2C03 HzO/MeCN 34
2 Pd(OAc)2 PPh3 TBABr K2C03 HZO/MeCN 39
3 Pd(OAc)2 PPh3 TBABr NaHCO3 DMF 6
4 Pd(OAc)2 . TBAHSO4 NaHCO3 DMF 0
5 Pd(OAc)2 - - NaHCO; MeCN 4
6 Pd(OAc)2 - - NEI3 MeCN 4
7 Pd(OAc)2 PPh3 TBABr Tl(OEt) HZO/MeCN 0
8 Pd(OAc)2 PPh3 TBABr KOH HZO/MeCN 0
9 Pd(OAc)2 PPh3 TBABr A g2C03 HZO/MeCN 30
10 Pd(OAc)2 PPh3 TBABr K2P04 HZO/MeCN O
1 l Pd(OAc)2 PPh3 TB ABr CsF HZO/MeCN 0
12 Pd(OAc)2 P(l-Bu)3 - Cy ZNMe Dioxane 0

 

We then tested differentl Pd sources, ligands, bases, solvents, and catalyst loads
for Heck type conditions as shown in Scheme 4.16. It turned out that Jeffery’s
conditions45 proved to be the best of the Heck type systems (entry 1, 2). Using a biphasic
system with tributyl ammonium bromide as the phase transfer agent, potassium carbonate
as the base, and triphenylphosphine/palladium acetate as the catalyst system allowed the
cross-coupling of (E)-2-methyl-4-tributy1germanyl-but-3-en-2-ol with iodobenzene in
moderate yields.

The temperature of the reaction proved to be critical as can be seen in Scheme
4.17. In most cases the reaction had to be performed above 50 °C with 70 °C emerging as

our standard conditions.

46

Vi

 

Cl“.

4.4

Cor

“01

Scheme 4.17. Evolution of the Yield with Temperature.

TBABr (leq), K2C03 (2. eq)
/\>< Pd(OAc)2 (20 mol%)/ PPh3 (40 mol%) PthH
Bu3Ge \ OH = —

49
16 hours

 

Entry T (°C) °/o Yield

 

l 25 o
2 50 0
3 60 39
4 7o 47
5 9o 28

 

We determined a 20 mol% catalyst loading to be a good compromise between
yield of the reaction, time to completion, stereoselectivity, and amount of catalyst

employed as shown in Scheme 4.18.

Scheme 4.18. Catalyst Loading.

TBABr (ICQ), K2CO3 (2. 6(1)

Pd(OAc)2 /PPh3(l:2) phi
BU3Ge/\><0H = — OH+ Ph/\><0H

Phl (Zeq), MeCN/1120 (9:1) 244 5.24

 

 

 

49 70 °C, 16 hours
Entry Catalyst (mol%) % Yield ll]?
1 5 0 -
2 10 38 100% Z
3 20 47 100% Z
4 50 37 5:1
5 100 30 10:1

 

4.4. Scope of the Reaction
The three best conditions resulting from our Heck and Stille screening were
compared using a range of different substrates in order to determine which of the three

would generally yield the best results (Scheme 4.19).

47

Scheme 4.19. Comparison of Stille and Heck Conditions.

Conditions

 

 

Stille A or B j
/\>< _ Ar OH
\ , _
BU3GC 49 OH or HCCk, ArX
Entry ArX Product °/. Yield % Yield % Yield

(Stille A) (Stille B) (Heck)

l Phl PthH (24) 30 25 47
2 PhBr PthH (24) 28 28 26

3 Bromoanisole W011 (10) 0 - 27
MeO

\ OH
4 p-Bromoacetophcnone (11) - 31 61

 

O

 

Stille A : szdba3 (20 mol%), AsPh; (80 mol%), Germane (leq), AIX (2 eq), NMP, 70 °C, 48 hours
Stille B: : Pd(OAc)2 (20 mol%), AsPh; (80 mol%), Germane (leq). AIX (2 eq), NMP, 70 °C, 48 hours

Heck: TBABr, K2C03, Pd(OAc)2 (20 mol%), PPh; (40 mol%), ArX (2 eq), MeCN/1120, 70 °C, 16 hours

The data showed that even though the Stille cross-coupling protocol can be
competitive for some substrates, the Heck conditions generally proved superior in yield
and in reaction times. Given these results, only Heck type conditions were used as the
scope of the reaction was investigated more fully. The cross-coupling of arylhalides with
E-vinyl germanes that were fully substituted at the allylic carbon with one of the
substituents being a hydroxy (Scheme 4.20) tended to proceed with good to moderate
yields. Again, the Z—product was favored. Activation of the arenes clearly helped increase
the reaction yield. However such electrophiles tended to give more of the E product

suggesting an admixture of mechanistic pathways.

48

Scheme 4.20. Cross-Couping Results.

TBABr (leq), I<2co3 (2.5 eq)

 

 

 

Pd(OAc)2 (20 mol%) / PPh3 (40 mol%) A
BU3GC \ > r\=—_/ + Ar/\/R
ArX (Zeq), MeCN/Ile (9: l)
70 °C, 16 hours
Entry Germane Aryl Halide Product % Yield Z/E
0

l Ema/Q4)” (49) PhBr Ph/\><0H (24) 26 100/02

2 49 Phl 24 47 100%2

3 49 p-Iodotoluene Won (62) 47 100%2
49 p-Bromoanisole W01! (10) 27 100%2

4

MeO
\ OH
49 (ll) 61 4:1
5 0
Br
49 GO \ 0H (63) 68 47:1
6 M902C MeOzC
Br
7 49 O \ 0H (64) 56 4.6:!
02N 02N
Br
49 (I - 0 -
8
Br
49 E I / - 0 -
9
o
/=\

10 49 I cone ' 0 -
49 Wilcozlwe - 0 -
A9“ (52) \(Ej/B \ 0H (65) 61 100%2

Bu3Ge\

 

49

Neither ortho substituted arenes (entries 8, and 9) nor triphenylgermanes were
reactive. This suggests that sterics greatly influence the reaction. Vinyl halides were also
non-reactive even with unhindered germanes or when activated (entries 10 and 11).

In conclusion, the scope of the reaction appears limited to unhindered aryl halides.
Even though the yield of the reaction proved to be moderate, the geometric outcome
pointed to a rather interesting reaction process that warranted further investigation.

4.5. Mechanistic Investigation

The mechanism proposed in Scheme 4.13 raised several questions to be answered.

Can Pd-H elimination occur when it is possible?

Is the reaction stereoselective or stereospecific?

Is more than one mechanism involved?

Is the formation of E product resulting from an isomerization process?

To address the first question we needed to react germanes that were not fully
substituted at the allylic position. Within the context of our putative Heck mechanism, the
Pd-intermediate formed upon addition across the olefin of such a substrate would be
flanked by two carbons possessing B-hydrogens. In theory this would allow us to probe
further the apparent preference for Pd-Ge over Pd-H elimination demonstrated by our

previous results. The results are shown in Scheme 4.21.

50

Scheme 4.21. Cross-Coupling of Unhindered Vinyl Germanes.

TBABr (16(1), K2CO3 (2. 6(1)

 

 

 

m R Pd(OAc)2 (20 mol%) / PPh3 (40 mol%) : A, R + /\/ R + /[L
Bu3Ge \ \=/ Ar \ Ar R
ArX(2eq),MeCN/1120(9:1) z E . t
70 °C, 16 hours "‘ ”‘ m "
Entry Germane Aryl Halide Product “/6 Yield Z/E/Int
Br
1 BU3GCMOH (55) 310‘“) - 0 -
o
—
2 Bu3Ge/VZ‘OH (51) 1 COzMe - O -
E/Int : 3.9/1
0
3 51 66 3 (67) 49 4 : l :20

O

4 Bu3Ge/\’€Z‘OH (50) PM ph/lLflO“

E/Intz4/1 4

H
OH
5a Bu3Ge/\’(/);OH (5'50) 66 M (68) 42 2.2:1:13.1
o
, \ on
68 Bu3Ge 0H (mt-50) 66 4 (69) 35 l:3.4:0
4
o

7 Bu3Ge/\/\OTHP (IS-57) 66 - 0 -

OTHP
8b Bu3GeM74‘OTHP (E-S6) 66 M (70) 36 1 : 1.4 : 11.6
0
\ OTHP
9b BU3GCJLMOTHP (int-56) 66 W (69) 41 1:49:46
4
O

“ calculted from the results of two experiments performed on two different ratios of E/Z isomers of the starting germane
experiment 1 used a 4.321 E/Int; experiment 2 used a 10:1 E/lnt ratio.

b calculted from the results of two experiments performed on two different ratios of E/Z isomers of the starting germane
experiment 1 used a 1.321 E/Int; experiment 2 used a 11:1 E/Int ratio.

(16) 35 52:1: 19

 

In practice, the reaction of 50 and 51 as a mixture of E and internal germane

afforded mixtures of E, Z, and internal products, with the cine product dominating and

51

being formed in yields exceeding the amounts of starting internal germanes. When
stopped early the reaction showed that the ratios of E/internal products seemed
unchanged, suggesting both germanes are reacting at similar rates. In order to obtain the
product formed separately by each of the E and internal germanes, the cross-coupling was
performed with two mixtures of different ratios of E/internal vinyl germanes. The yields
and ratios for the Z and the internal germanes were extracted by calculation. Since the
reaction rate appeared similar for both the E and internal vinylgermanes, it was deemed
reasonable to assume that the E and internal vinylgermanes would give the same relative
yield and ratio of products regardless of their starting ratios. In practice, the internal
germane gave a 1:34 ratio of Z/E product and no internal product while the E germane
gave a ratio of 2.2:1:13.1 (Z/E/int). This showed that both the internal and the E germanes
gave predominantly cine cross-coupling. These results suggest that both E and internal
germanes react primarily through a process resulting in a regiochemical inversion. This
would indicate that while non Heck pathways are operating, Pd-Ge elimination remains
predominant since no products containing germanium or two aryl groups were observed.
The products expected by a Pd—H process are shown in Scheme 4.22.

Scheme 4.22. Pd-H Process and Expected Products.

Bu3GeBr PhBr Bu3GeBr PhBr
// W R 2/ M0) \
Bu3GePd(”)Br Ph- Pd(")Br Bu3GePd(")Br Ph- Pd(")Br
. -
B G
Phb Bu3GeH PdmlBr "3 c H PdmlBr B“3G°/=/
Pd Ge phiH Pd- H Ph'H

Bu Ge
Elimination Elimination 3

52

When (E)-3-phenyl-l-tributylgermanyl-prop-l-en-3-ol (58) was cross-coupled
with iodobenzene (Scheme 4.23) cine substitution was greatly reduced when compared to
the monosubstituted case probably due to the increased sterics. Thus sterics seems to be
the determining factor in the degree of cine substitution observed.

Scheme 4.23. Coupling of Disubstitued Propargylic Species.

 

OH
Ph Pd(OAc)2 / PPh3 (1:2, 20 mol%) HO
L : PhJPh + Ph Ph
GeBu3 TBABr (leq). K2C03 (Zeq) ~
Phl , 0H
58 MeCN / H20 Z-69 o Int-69
70 °C 16 hrs 3°/°
’ ~(Z/int = 3: 1)
Scheme 4.24. Bussacca Type Mechanism.
Addition
R
To 13 d R
: 6 U3
/Pd\ Al' GCBU3
N Br Pd.
Br
Ar-BrJ Transmetallation
Pd(0) R

Reductive /Ar/Sl

Elimination Pd
/B-hydride
elimination

Pd‘H

Scheme 4.25. Hallberg Type Mechanism.

Addition
R
—\_,_G B d R
: e “3
/Pd\ Ar GCBU3
N Br Pd.
Br
Ar—Br\// B:hydride
elimination
Pd(O)
\ R _GCBU3
BrPd-GeBu3

Ar

Br Pd‘H
R A PdFGeBu3/ 3’

R‘“
Ar/K Ar

53

The cine product formation could be explained by either a Bussacca32 type
mechanism as shown in Scheme 4.24 or by the mechanism proposed by Hallberg46 for
vinyl silicates as shown in Scheme 4.25. Bussacca’s mechanism seems more probable
since the other would involve a Pd-H elimination, which we have not otherwise observed.

The second aspect of our study involved the stereoselectivity vs. stereospecificity
issue. In order to address this question we needed to synthesize pure Z-vinylgermane. The
synthesis of this isomer proved to be difficult and a wide variety of conditions were
attempted before a successful method could be devised. The synthesis of the Z germane
is shown in Scheme 4.26 and was finally performed using a hydroboration of the alkynyl-
germane.47

Scheme 4.26. Synthesis of the Z-Germane.
z—“S’e 43.232.21.122. = we? 32:38:” Mex

l THF 70 2.4
6996 3396

 

 

Among the unsuccessful methods attempted were direct hydrogermylation of the

alkyne under ultrasonic irradiation as suggested by Duchénes,48 hydrostannation,

hydroalumination, and catalytic hydrogenation of the alkynyl germane.34

Scheme 4.27. Cross-coupling of the Z-Germane.

Pd(OAc)2 (20 mol%)
BU3Ge _ OH + Phl PPh3 (40 mol%) PthH ijH
~ —— + —
Ph

'

TBABr, K2CO3
2.4 MeCN / H20 Z-24 E-24
70 C’ 6 ”5 49%(2/13 = 4:5)
The cross-coupling of the Z—germane (Z-4) (Scheme 4.27) gave the products with
a 49% yields in 6 hours with a ratio of Z/E = 4:5. This indicated that the reaction is

probably not stereospecific but rather stereoselective. The Z-vinylgermane also reacts

54

much faster than the E-vinylgermane. It is noteworthy that the E product was favored.
Formation of the E-product does not appear to be the consequence of starting material or
product isomerization (Scheme 4.28). Geometrically pure E-product was inert when
resubjected to the reaction conditions. Similarly, subjecting Z-vinylgermane to the
reaction conditions in the absence of the electophile only lead, after 10 hours, to the
destruction of the germane as well as small amounts of phenyl coupled products (both E
and Z), presumably from reaction with PPh3.49

This increased reactivity of the Z germane can be compared to the observation
made by Faller that O-chelated germatranes are more reactive than C-chelated ones.“
The electron donation of the oxygen being postulated to increase the reactivity of the

germanium.

Scheme 4.28. Isomerization of Germane Controls.

TBABr (leq), K2C03 (2. eq)
Pd(OAc)2 (20 mol%)

PPh3 (40 mol%)
Bu3oe/\><0H 4 Bu3Ge/\><0H

MeCN/H20 (9; 1)

 

 

5'49 70 °C, 16 hours ‘9
TBABr (leq), K2C03 (2. eq)
Pd(OAc)2 (20 mol%)
PPh 4O mol°/
BU3GC\=><OH 3 ( o) : Destruction of SM
MeCN/H20 (9:1)
2'49 70 °C, 10 hours

TBABr (leq), K2CO3 (2. eq)
Pd(OAc)2 (20 mol%)

PPh3 (40 mol%)
Ph/\><0H = Ph/\><0H

Phi, MeCN/1120 (9: 1)
E-24 70 °C, 16 hours 52“

 

TBABr (leq), K2C03 (2. eq)
Pd(OAc)2 (20 mol%)

PPh 40 mol"/
PhJOH 3 ( o) 4 PthOH

Phi, MeCNsz (9:1)
2'24 70 °C, 10 hours 2'24

 

In our case the close proximity of the hydroxyl group can have a similar

activating influence by allowing chelation as shown in Scheme 4.29. The Z geometry

55

allows such chelation while the E geometry would separate the hydroxyl from the
germane rendering such effect impossible.

Scheme 4.29. Activation of the Germane.

H
o

Bu3oe;)<

All the data accumulated so far point to the existence of at least three
mechanisms. The Heck type mechanism proposed seems to be the most facile and
proceeds with an inversion of configuration of the olefin geometry. A second mechanistic
pathway gives a retention of configuration but appears to be much slower and lower
yielding. Such a path might very well be that of the Stille type as all the elements for such
a mechanism are present within the reaction mixture. This second mechanism seems to be
more operative when the reaction becomes activated either by the presence of activating
groups on the aryl halides, or when the more reactive Z—germane is used as shown by the
results of Schemes 4.20 and 4.27. Lastly a third mechanism gives rise to the cine
substitutions and seem equally facile as the standard Heck process.

Finally, one last point of interest was explored: the effect of a hydroxyl group on
the cross-coupling. Oxygen functionalities are well known as activating agents and
directing groups in a wide range of reactions. Since all the germanes used so far had a
hydroxyl group its effect needed to be determined. For that purpose we compared the
results of cross-coupling for similar substrates, differing only by the presence and

position of a hydroxyl group.

56

Scheme 4.30. Effect of Proximal Hydroxyl Group.

Br Pd(OAc)2 (20 mol%)
0
V + p PPh3 (40 "ml/(09, No Reaction
EnsGe TBABr, cho,
53 0

 

 

MeCN / H20
70 °C, 16 hrs
Br Pd(OAc)2 (20 mol%)
H0 PPh3 (40 mol%) HO
M + = M
Bu3Ge TBABr, K2C03 Ar
49 O MeCN / H20 24
70 °C, 16 hrs

(61%,E/Z=1/4)

We compared the germanes derived from t-butylacetylene 53 with the germane
from 3-methyl-butynol 49 (Scheme 4.30). Whereas the latter gave a 61% yield, the
former gave no product whatsoever. Thus can see that the proximal hydroxyl group plays
a major role in the cross-coupling reaction. This may be explained by a chelation of the
hydroxyl to the palladium as shown in Scheme 4.31. This phenomenon is known in
palladium mediated hydrostannations where the position of a hydroxyl group allows for
regioselection of the addition, hence showing the palladium-oxygen directing effect and
chelation process.22 The chelation allows the palladium to remain in proximity of the
olefin longer and thus offsetting the steric hindrance.

Scheme 4.31. Proximal Effect of Hydroxyl Group.

X
Pit-OH
Ar’ \

BU3GC

To study the effect of a distal hydroxyl group we compared the results obtained
for the cross-coupling of the vinyl germane derived from pentyne 54 and the one derived

from 5-hydroxy pentyne 51 (Scheme 4.32).

57

Scheme 4.32. Comparison Effect of Distal Hydroxyl Group.

 

Br Pd(OAc)2 (20 mol%) A
PPh3 (40 mol%) M + f + LA
M = Ar
BUsGe I Y0 TBABr, K2C03 \A/ A”
54 o MeCN / H20 0
(£/1m=3.7/ 1) 70 °C, 16 hrs (47/o)

(E/Z/lnt= l/l.l/5)
Br Pd(OAc)2 (20 mol%)

PPh3 (40 mol%) \ Ar M
\ = W + + OH
BU3GCWOH *' YO TBABr, K2CO3 Ar OH W0” Ar

51 o MeCN/H20
(E/lnt = 3.9/ l) 70 °C, 16 hrs (49%)
(E/Z/Int=I/4/20)

 

Although the yields of product were sensibly the same, the stereochemistry of the
product was slightly different with the hydrocarbon substrate giving a ratio of E/Z/Int:
1:1.1:5 while the hydroxyl substrate gave a ration of 1:420. Thus the hydroxyl group
generated more cine substitution than the hydrocarbon substrate.

Since the hydroxyl group was shown to have an effect on the stereoselectivity we
needed to see what would happen when the hydroxyl group was protected, by a THP
group for example. In this case, we observed that when the hydroxyl was free as in the
case of E-50 the Z/E/Int product ratio was 2.2:1:13.1 (E+Z/Int: 1:4.1) (Scheme 4.11,
entry 5), while the protection of the hydroxyl afforded a product ratio of l:1.4:11.6 (E+Z
/Int: 1:4.8) (Scheme 4.11, entry 8). Ergo THP protection did not drastically change the
selectivity which shows that an ether oxygen can also serve as a directing group in this
case.

This cine selectivity generated by the hydroxyl groups could potentially come
from long range chelation of the hydroxyl to the palladium as shown in Scheme 4.33.

However we cannot rule out long range inductive effects.

58

Scheme 4.33. Regioselectivity.

Br

I
Pd

I
I
I

BU3GC l “‘
W”

It seems that the hydroxyl group allows the reaction to occur when sterics would
otherwise not allow it. This effect seems to only be effective at short ranges since a distal
hydroxyl did not increase the yield. The hydroxyl group also acts as a directing group as
the difference in stereoselection shows. So, in order to better understand the relationship
between those two factors we attempted to cross—couple a disubstituted germane with an
hydroxyl group present. Unfortunately, when the cross-coupling was attempted, the
expected cross-coupled products could not be obtained. Although the products could not
be positively identified, strong evidence suggests that we obtained homocoupling
products as shown in Scheme 4.34. This homocoupling was complemented by partial or
total oxidation, and its mechanism is unclear.

Scheme 4.34. Cross-Coupling of a Disubstituted Germane.

Pd(OAc)2 (20 mol%)

 

0” PPh3 (40 mol%) 0 0
n-Pr GeMe =
L 3 TBABr, K2C03 W + /\/IW\(\/
71 Phi “5% 0 66% on
MeCN / H20
70 °C, 16 hrs

4.6. Conslusion

We have been able to develop a method to cross-couple trialkyl vinyl germanes
with aryl halides. Even if the initial results were promising and the hope of achieving a
competitive process could be sustained, we need now note that the other methods
developed using germanium, like germatranes or trifuryl germanes are superior both in

the scope of the reaction as well as the yields. However what is most interesting about

59

this coupling is the inversion of geometric configurations (E germane to a Z product) with
hindered substrates. This makes Z cross-coupled products accessible from the more easily
obtainable E starting materials.

We have shown that the mechanism most likely involves a Heck type process but
that at least one more pathway is operative, making the reaction extremely substrate
sensitive. Attempts could be made at improving the yields, in particular by the use of
ionic liquids and / or by the use of di-carbene type palladium ligands. Such ligands are
known to improve Heck type reactions greatly and ionic liquids could provide an effect
mode of activation or even in situ formation of such ligands.

Further study could also focus on elucidating the other mechanisms of the
reaction or to more clearly determine all the effects of the hydroxyl groups. In particular

the relation to the types of the oxygen, the distance etc.

60

Chapter 5. Attemps at Allylic Stille Coupling in the Synthesis of Superstolide A.
5.1. Introduction
5.1.1. Application to Total Synthesis

Having developed a fast and easy way to affect one-pot hydrostannation/Stille
cross-coupling of alkynes (Chapter 3) we want to apply such method to target synthesis.
A potential target for such an application was found in superstolide A.
5.1.2. Superstolide A

Superstolide A was isolated by D’Auria and its structure determined by 2D NMR
in 1994.50 It is a potent cytotoxic macrolide, showing activity against a number of cancer
lines including non-small cell lung cancer and murine leukemia. Its structure presents
several interesting features including a cis-decalin ring, a polypropionate unit and three
conjugated double bonds, bearing an E,Z,E configuration (Scheme 5.1).

Scheme 5.1. Superstolide A.

 

 

H'Me:
\:

: O E
: ol ro ionate
EMNJL : [p w P ]
:MC: :
Cb” : :
: MCO’ ' ' . :

 
 

hexenoic acid

The polypropionate unit has been synthesized by three different groups“ using

Roush’s crotylboration protocol,52

or a titanium mediated aldol condensations3 However
the cis-decalin system of superstolide A has only been reported by Roush et al. in 1996

(Scheme 5.2).54 His approach involves an intrarnolecular Diels-Alder that simultaneously

61

creates four stereocenters. Despite these efforts, no total synthesis of the molecule exists
at the time of this writing.

Scheme 5.2. Roush’s Synthesis of the cis-Decalin.

 

QPMB
, / QPMB
Moo" I OTBS CF3CH20H :
o w -.,’ OTBS
\ CHO 30 C320“ M60 5 /
76/0 (3 isomers) OHC Me
Me 60% Ofx X

10:1 :1 selectivity

5.1.3. Retrosynthetic Analysis of Superstolide A

Our retrosynthetic analysis divides superstolide A into three fragments as shown

in Scheme 5.3.

Scheme 5.3. Retrosynthetic Analysis of Superstolide A.

Me

81135“ / / M

0

JUL [allylic displacement ] k 13 23 b” g Me

HZN O HZN Q HO’ , if
@( Me (I) Me Me 0
, ./ / M , .

M O .’ H MeO OAc

C l mu :> MC I

 

 

 

 

M .
'5? IO“ . N\n,Me m6
Mewgg Me O I OH
. . M 5\ \ 1 O
[ Hydrostannation/Stille] fmacrolactonization] e

 

 

We planed on coupling the cis-decalin and the iodo hexenoic acid through the
formation of the C5 - C6 bond via our microwave hydrostannation/Stille cross-coupling
protocol. We already know that sterically encumbered alkynes regioselectively afford the
intermediate (E)-vinyltin and that (Z)-3-iodo-2-butenoic acid couples efficiently as
previously illustrated in Scheme 3.13, entry 8. However, while formation of the C5 - C6
bond was to showcase our methodology, getting to that step, rested on our ability to form

the C17 - C13 bond. We sought to create that bond by an allylic Stille cross-coupling.

62

5.1.4. Allylic Stille Couplings

During the course of his work on the palladium catalyzed cross-coupling of vinyl
stannanes with aryl and vinyl halides, Stille also investigated the cross-coupling of allyl
halides. Some examples are shown in Scheme 5.5 ,5 5 '56 while the postulated mechanism is
shown in Scheme 5.6.

Scheme 5.5. Allylic Stille Cross-Coupling.

R2 R2

 

 

 

Pd(dba)2
HM + PhSnMe3 . \
R OAC DMF, LiCl WV“)
23 °c
Entry Substrate Product %Yield
‘ PhMOAc PhMPh 57
Ph \
2 Ph/vph 32
OAc

3 >=\_ H 65
OAc Ph

4 \ H 69
>21. p,

Scheme 5.6. Mechanism of Allylic Stille Reaction.

. LiCI Ligand
X/ I" -Pd‘”)-0Ac Exchange
AcO

LiOAc

 

Oxidative
Insertion

,c1

Pd‘ol .’ 11
.—---Pd< >

k/‘ph RSnMe3

. , ,Ph
Reductive 3”Pd(”) Transmetallation
Elimination \ \
s Me3SnCl

63

This reaction goes through the intermediate of a n-allyl complex formed after an
oxidative insertion of palladium, followed by ligand exchange, transmetallation, and
finally reductive elimination. Similarly, allylic carbonates have also been cross-coupled
as shown by Echavarren.57 (Scheme 5.7).

Scheme 5.7. Cross-Coupling of Allylic Carbonates.

 

 

 

R2 R2
Pd(dba)2
+ 3- _

R'MOCOZR R snBu3 DMF “Cl 'RiMRs

23 °C
Entry Substrate Stannane Product %Yi¢ld
I PITA/\OCOZEI PhSl’lBU3 thph 96
2 ”SnBu3 Ph/W 53

3 (1 My 92
0 $118113 0

4 >=\_ PhSnBu3 >=\7 57
OCOzEt Ph

It is clear by looking at those two sets of examples that the regiochemical

 

outcome of the addition at the the rt-allyl system can be mixed, but that substitution at the
less hindered site is typically favored (Scheme 5.8).55

Scheme 5.8. Regiocontrol of the Reaction.

R Pd
R R l {—d LR!
, . R
{:"Pd 7 <:"Pd—SnBu3 — R R] R
L—‘ LPd —-—* le

R‘SnBU3

 

R/\/\Rl Major

It has also been shown experimentally that this reaction can be subject to
stereocontrol through the choice of solvent.58 Inversion of configuration at the leaving
group position is typical, however, when benzene is used as a solvent, retention of

configuration can be observed (Scheme 5.9).

64

Scheme 5.9. Stereocontrol of the Reaction.

 

 

 

COzMe C02MC COzMe
Q szdba3 t ('1 + 0
”Cl RT, solvent EC] \gdCl
cis trans

entry solvent ratio: cis/iraus

l benzene 100/0

2 dichloromethane 94/6

3 THF 95/5

4 acetone 75/25

5 DMF 29/71

6 acetonitrile 5/95

7 DMSO 3/97

 

Thus more polar solvents will favor a substitution with inversion of configuration
while less polar ones will favor an insertion with retention. Considering the fact that the
transmetallation as well as the reductive elimination goes with retention of the
configuration, we see that the choice of solvent can determine the stereochemical
outcome, by dictating the outcome of the oxidative addition.

5.1.5. Directing Effects of Substituents

The main question associated with palladium n-allyl system is its regiochemicl
outcome. Previous methods of region control were found by either placement of bulky
groups or in the polarizing effect of an oxygenated functionality.59 More recently, Kraffi
et al. have successfully been able to apply directing effects to palladium n-allyl systems
within a cyclohexene ring as shown in Scheme 5.10 by using a tertiary amine directing

group. 60

65

Scheme 5.10. Directing Effects.

 

 

 

NMCz NMCZ NMCZ
OAc - Nuc
é, LlNUC/Cat. é + 78% (3.5.1)
THF
75 °C, 5 hrs Nuc
NMe2 NMez NMez
_..0Ac LiNuc/Cat.
+ 30% (7: 1)
THF .
75 C, 5 hrs Nuc Nuc
NMez NMez
.~~0AC LiNuc/Cat. N“
70%
THF
75 °C, 5 hrs
/\
Nuc = CH(C02Et)2 Cat = ”P
Ph3P'Pd'Cl

It was found in these systems that presence of the amino group could provide an
accelerating effect as well as a directing effect. One should note, that when the acetate
and the amino group were trans to each other, no directing effect could be observed
(Scheme 5.10, reaction 2) due to the inability of the amine to coordinate to the palladium
in such a case. Moreover it was also found that alkyne can act as a n-chelator in
hydrosilylation reactions (Scheme 5.11).6|

Scheme 5.11. Alkynes as a n-Chelator.

0 03113:, 03133

 

Ph/11\'/\ B(C6F5)3 (2 mol%) /K|/\ HIM

\ . = Ph \ '1" ;

\ \ - \
90% 7 : 1

The stereoselctivity observed in the course of the reductions was attributed to the
chelation of the alkyne to the silicon, with an ordinary chelation controlled Felkin-Anh

model predicting the selectivity (Scheme 5.12).

66

Scheme 5.12. Chelation of Alkynes.

 

5.1.6. Objectives

We thus wanted to study the potential for an alkyne to act as directing group
providing both regiocontrol and stereocontrol in an allylic Stille cross-coupling. (Scheme
5.13).

Scheme 5.13. Proposed Directing Effect.

 

QCONH2 QCONH2
00 WW 0,

M60“ --. ",Pd'Cl Moo“ ”/\R
\‘s \\

We question if the alkyne would coordinate the palladium, locking it into place in
a fashion similar to the one proposed to explain the hydroxyl effect in the germanium
cross-coupling as shown in Scheme 4.30. Information from such study would then allow
us to make a more educated decision as to whether we should target superstolide A for
synthesis and to demonstrate our hydrostannation/Stille method.
5.2. Results
5.2.1. Synthesis of the Model

In order to test our hypothesis we chose a model system for initial studies. Our
first goal was to synthesize the different materials that would be used during the cross-
coupling attempts. The first model compound targeted was acetic acid 6-ethynyl-6-

methyl-cyclohex-Z-enyl ester (Scheme 5.14).

67

Scheme 5.14. First Model Target

OAc

0g

72

Attempts were made to synthesis 72 from both cyclohexanone and from

cyclohexenone as shown in Scheme 5.15.

Scheme 5.15. Attempts at the Synthesis of 72.

 

 

 

 

O 0 OAc O
Formylalion CH0 Corey-Fuchs 0% I) Methylation UCHO Fonnylation
\ 2) Corey-Fuchs
73 74 72 76 75
O 0 0 // O 0
i: l) LDA @/ l)Formylation 1) Methylation 6C?” 1) NaOEt b
2) Mel 2) Corey-Fuchs 2) Corey-Fuchs 2) HCOzEt
7s 71% 79 77 so 57% 78
O OH //
(j.— CHCMgBr
Lewis Acid
81 82

Unfortunately none of the above routes could be brought to completion. When
starting with 5-methyl-2-cyclohexenone 73, formylation using ethyl chloroformate with
various bases and at various temperatures could not be achieved and only starting
material was recovered. This reaction had been described in the literature using sodium
dust62 but it could not be reproduced in our hands. Attempts at formylating 2-
cyclohexenone 75 were also unsuccessful. This was unexpected because the methylation
of cyclohexenone was known, but again the reaction could not be reproduced}33

When starting from cyclohexanone 78, the methylation could be achieved with

ease, but all attempts to subsequently formylate, be it in one-pot or after isolation of 2-

68

methyl cyclohexane 79, only led to the formation of the unwanted regioisomer 3-methy1-
2-oxo-cyclohexanecarbaldehyde (83). When the thermodynamic silyl enol ether (85) was
preformed, no reaction occured (Scheme 5.16).

Scheme 5.16. Synthesis Attempts Starting From Cyclohexanone.

 

 

O 0
er ”if
2) ClCO3Et
79 83
OTMS CICO3Et .
\ No Reaction
85

If the forrnylation was performed first to generate 80, then no methylation can
be achieved due to the formation of the very stable keto-enal specie 85 (Scheme 5.17).

Scheme 5 .17. Stable Cyclic Keto-Enal.

We thus turned our attention towards the possible used of an epoxide opening
under Lewis acid catalysis in order to install the alkyne. 1-Methyl-7-oxa-
bicyclo[4.1.0]heptane (81) had been successfully opened regioselctively under various
Lewis acid conditions.64

Unfortunately, when attempted with ethynylmagnesium bromide and with various
Lewis acid (BF3 and MgBrz) the reaction failed to give the desired product in any
significant amounts (Scheme 5.18) and even yielded 2-bromotoluene (85) when

magnesium dibromide was used.

69

Scheme 5.18. Epoxide Opening Attempts.

0 Br
MgBr2 63/
E—MgBr
81 85

90%
With the failure of the synthesis of model compound 72, we targeted a previously
described compound as an alternative for our intended studies (Scheme 5.19).65
Scheme 5.19. Second Generation.

1) LDA HMPA \bka Cu / ACOH
C0,, 2) CIZCCCIZ 75%

86 79% 19%

 

 

DIBAL
87%

LIAIH4
87%

\
\&0 A620 pyr m0 “fl A620, pyr \&

72 % 72%

 

 

 

2,5Dimethyl-cyclohexanone (86) was dehydrogenated involving an
addition/elimination process using NBS as the brominating agent and heat for promoting
the elimination to yield 87. This was followed by generating the enolate by LDA/HMPA
and nucleophilic addition to tetracholoroethylene. Lithium halogen exchange would
generate the enone 88 upon elimination of chlorine. Reduction of the chloro alkyne was
performed using copper in glacial acetic acid. Direct reduction of enone 88 could be
achieved using DIBAL. Whereas DIBAL proved too mild for the reduction of 89. Luche
conditions also failed in this case. LiAll-I4 reduction failed at 0 °C but was successful at
room temperature. These observations suggest participation of the alkyne possibly by
chelation of the aluminum. This chelating effect is possibly disrupted by the presence of

the chlorine group in 88. Indeed in his study of the effect of the chelation of an alkyne

70

during hydrosilyllation, Yamamoto observed that when substituents were placed on the
akyne, bulky groups would hinder the chelation and reduce the selectivity.61
5.2.2. Initial Cross-couplings of the Model Compound

We attempted to cross-couple acetates 91 using standard allylic Stille cross-
coupling conditions: szdba3 as the catalyst, DMF as the solvent, and 3 equivalents of
lithium chloride. Unfortunately the desired product was not observed (Scheme 5.20) and
instead the only product extracted was that from coupling with the alkyne position in a
Sonogashira fashion (94).66

Scheme 5.20. Attempted Cross-Coupling.

OAc///
MC] (3 eq) OAC
+ Bu3Sn / OH Av _
\/>< szdba3 (2 mol%) "“=fi\ R

91 4 DMF 94

 

Since our substrates were actually more hindered than the ultimate target, we
devised a third model that would not present such a situation. We simplified the model
drastically, opting for acetic acid 6-methyl-cyclohex-2-enyl ester (96). This molecule,
would have no hope of achieving regiocontrol or stereocontrol but would serve to
determine the feasibility of the cross-coupling itself. Its synthesis is shown in Scheme
5.21.

Scheme 5.21. Third Generation.

 

0 OH
‘15—. l ) LDA Ej/ DIBALH U
2) Mel, THF or Luche
75 95

20% 25%

This process was not very efficient with a considerable amount of ketone being

lost during distillation. We anticipated that performing the three steps in one pot would

71

allow us to improve the overall yield. Thus methyl-cyclohexenone (73) was not isolated
but reduced directly as shown in Scheme 5.22.

Scheme 5.22. One Pot Synthesis of the Model.

 

0 1) LDA 0“
b 2) Mel, THF
3) LiAiH4
75 25% 95

n-Butyllithium was added dropwise to a solution of diisopropylamine in THF at 0
°C. The solution was stirred at 0 °C for 15 minutes. A solution of 2-cyclohexenone (75)
in THF is added dropwise and the solution was stirred for another 30 minutes. Methyl
iodide (2 eq.) was then added rapidly and a white precipitate immediately formed. The
ice bath was removed and the reaction stirred at room temperature until all the starting
material was consumed. The solution was then filtered and lithium aluminum hydride
was carefully added in small portions. The reaction was allowed to stir at room
temperature for 10 hours and afforded the desired 6-methyl-cyclohex-2-enol (95) in 25%
overall yield. The acetylation was then performed by reacting the enol with acetic
anhydride in pyridine to afford 6-methyl-cyclohex-2-enyl ester (96) (Scheme 5.23).

Scheme 5.23. Acetylation.

OH OAc
A020

pyridine
95 96

5.2.3. Search for a Working Protocol
We then tried to affect the cross-coupling of the acetate using variations of the

standard Stille protocol, as shown in Scheme 5.24.'7

72

Scheme 5.24. Attempted Cross-Coupling Conditions.

 

OAc szdba3(l-5 mol%) \
U Ligand (4-20 mol%)
Solvent, LiCl (3 eq) 7
96 97
$511311}

 

Entry Ligandll Solventb
AsPh3 benzene

 

1
2 TFP benzene
3 TFPP benzene
4 AsPh3 THF
5 TFP THF
6 TFPP THF
7 AsPh3 NMP
8 TFP NMP
9 TFPP NMP
10 AsPh3 DMF
1 1c ASPh} DMF
12 TFP DMF
13 TF PP DMF

 

a szdba3 and the ligand were premixed for 30 minutes.
b the reaction was run at room temperature and at 50 °C.
c in microwave, 140 W for 5 minutes.

szdba3 (l to 5 mol %) and the ligand (4 equivalents relative to palladium) were
premixed for 30 minutes in the solvent. 6-Methyl-cyclohex-2-enyl ester (96) (0.3 mmol)
was added followed by vinyltributyltin (0.3 mmol) and LiCl (1 mmol). The reaction was
first attempted at room temperature then at 50 °C, but never yielded any product. In one
case, the reaction was also attempted in a microwave at 140 W for 5 minutes (entry 11),
but, there again no product was obtained.

Copper is known to be able to accelerate Stille type cross-couplings!8 and was
thus explored. However, with CuI the reaction had to be heated to 100 °C to show any
change. Unfortunately, even after 24 hours, the only product obtained was butyl benzene.
This product can be obtained by two known side reactions: transfer of a phenyl from the

arsine and transfer of a butyl from the stannane.67

73

Since our model compound was coupled by M. Kraft et a1. using malonates as the
nucleophile we must conclude that the problem lies in the nucleophile and not in the

oxidative insertion part of the mechanism that is common to both reactions.

5.2.4. Conclusions

In light of the results obtained we have no choice but to conclude that the
proposed allylic substitution would not be possible since the stannane is not a strong
enough nucleophile in our current systems. Further work is being done on the synthesis
of the decalin system using a one pot hydrostannation/intramolecular Diels Alder

activated under microwave irradiations.

74

EXPERIMENTALS

All air or moisture sensitive reactions were carried out in oven- or flame-dried
glassware under a nitrogen atmosphere unless otherwise noted. All commercial reagents
were used without purification. All solvents were reagent grade. Diethyl ether and THF
were freshly distilled from sodium/benzophenone under nitrogen. Benzene, toluene,
DMSO, diisopropylethylamine and cyclohexane were freshly distilled from calcium
hydride under nitrogen. Except as otherwise noted, all reactions were magnetically
stirred and monitored by thin-layer chromatography with 0.25-mm precoated silica gel
plates or capillary GC with a fused silica column. Flash chromatography was performed
with silica gel 60 A (particle size 230-400 mesh ASTM). Yields refer to
chromatographically and spectroscopically pure compounds unless otherwise stated.
Melting points were determined on a Thomas-Hoover Apparatus, uncorrected. Infrared
spectra were recorded on a Nicolet IR/42 spectrometer. Proton and carbon NMR spectra
were recorded on a Varian Gemini-300 or VXR 500 spectrometer. Chemical shifts for
1H NMR and 13C NMR are reported in parts per million (ppm) relative to CDC]; (8 =
7.24 ppm for 'H NMR or 5 = 77.0 ppm for 13C NMR). High resolution mass spectra
(HRMS) data were obtained at either the Michigan State University Mass Spectrometry
Service Center or at the Mass Spectrometry Laboratory of the University of South
Carolina, Department of Chemistry & Biochemistry. GC/MS were performed with a

fused silica column (30 m by 0.25 mm id).

75

 

[M63Sn/?><OH ]

 

Representative procedure for the hydrostannation of alkynes under palladium
catalysis. Preparation of (E)-2-methyl-4-trimetbylstannanyl-but-3-en-2-ol (3)
(Scheme 2.5, entry 1). PMHS (0.09 mL, 1.5 mmol) was added to a solution of 2—methyl-
but-3-yn-2-ol (1) (0.1 mL, 1.0 mmol), Me3SnCl (0.27 mL, 1.2 mmol), aqueous KF (174
mg, 3.0 mol; 3 mL H20), (PPh3)2PdC12 (7 mg, 0.01 mmol), and TBAF (1 drop of a 1 M
solution in THF) in THF (5 mL). The biphasic reaction mixture was stirred at room
temperature for one hour at which time 1 M NaOH (1 mL) was added and the reaction
was allowed to stir an additional 2 hours. The two phases were then separated, and the
aqueous phase was extracted with diethyl ether (3 X). The combined organics were
washed with brine and dried over MgSO4. Afier filtration, the solvent was evaporated,
and the residue was purified by column chromatography on silica gel [petroleum
ether/EtOAc 95:5, 1% TBA] to afford (178 mg, 63%) of (E)-2-methyl-4-
trimethylstannanyl-but—3-en-2-ol (3) as a clear oil. IR (CC14): 3362 cm]; 1H NMR (300
MHz, CDC13) ,6 6.10 (m, 2 H), 1.64 (br s, l H), 1.27 (s, 6 H), 0.10 (s, 9 H); 13C NMR (75
MHz, CDCl;) 5 154.9, 123.4, 72.2, 30.0, -9.3; HRMS (CI) m/z 235.1037 [(M+-CH3);

calcd. for CgHleSn 235.1046]

 

[ Bu3Sn/\4><OHJ

Preparation of (E)-2-metbyl-4-tributylstannanyl-but-3-en-2-ol (4) (Scheme 2.5, entry

 

2). Applying the above procedure to 2-methyl-but-3-yn-2-ol (1) (0.1 mL, 1.0 mmol),
Bu3SnCl (0.33 mL, 1.2 mol) aqueous KF (174 mg, 3.0 mol; 3 mL H20), (PPh3)2PdC12

(7 mg, 0.01 mmol), and TBAF (1 drop of a 1 M solution in THF) in THF (5 mL) and

76

letting the reaction stir for 2 hours and purification by column chromatography on silica
gel [petroleum ether/EtOAc 95:5, 1% TBA] afforded (E)-2-methyl-4-trimethylstannanyl-
but-3-en-2-ol (4) (300 mg, 80%) as a clear oil. Spectroscopic data were consistent with

those previously reported.68

 

[chm/yon l

 

Preparation of (E)-2-methyl-4-tricyclohexylstannanyl-but-3-en-2-ol (5) (Scheme 2.5,
entry 3). Applying the above procedure to 2—methyl-but-3-yn-2-ol (l) (0.1 mL, 1.0
mmol) using Cy3SnCl (484 mg, 1.2 mmol) aqueous KF (174 mg, 3.0 mol; 3 mL H2O),
(PPh3)2PdCl2 (7 mg, 0.01 mmol), and TBAF (1 drop of a 1 M solution in THF) in THF (5
mL) and letting the reaction stir at 50 °C for 6 hours and purification by column
chromatography on silica gel [petroleum ether/EtOAc 95:5, 1% TBA] afforded (E)-2-
methyl-4-tricyclohexylstannanyl-but-3—en-2-ol (5) (109 mg, 20%) as a white solid mp. =
182-1835 °C. IR (CC14): 3290, 2972, 2914, 2845, 1445 cm"; 1H NMR (300 MHz,
CDCl3) 5 6.11 (d, J= 19.5 Hz, 1 H), 5.93 (d, J= 19.5 Hz, 1 H), 1.80 (m, 4 H), 1.60 (m,
12 H), 1.48 (m, 12 H), 1.28 (s, 6 H), 1.25 (m, 6 H); 13C NMR (75 MHz, CDC13) 8 156.0,

120.5, 72.2, 31.8, 29.2, 28.8, 26.8, 26.2; LRMS : 371.2 (100), 454.2 (M+).

[ Ph3Sn/\:><OH]

 

 

Preparation of (E)-2-methyl-4-tripbenylstannanyl-but-3-en-2-ol (6) (Scheme 2.5,
entry 4). Applying the above procedure to 2-methyl-but-3-yn-2-ol (1) (0.1 mL, 1.0
mmol) using Ph3SnCl (462 mg, 1.2 mmol) aqueous KF (174 mg, 3.0 mol; 3 mL H20),
(PPh3)2PdCl2 (7 mg, 0.01 mmol), hydroquinone (approximately 10 mg) and TBAF (1

drop of a 1M solution in THF) in THF (5 mL) and letting the reaction stir at 50 °C for 16

77

hours and purification by column chromatography on silica gel [petroleum ether/EtOAc
95:5, 1% TBA] afforded (E)-2-methyl-4-tiiphenylstannanyl-but-3-en-2-ol (6) (43 mg,
10%) as a white solid. mp. = 90.8-91 °C; IR (CCl4): 3366, 3065, 3047, 3015, 2974,
1481, 1429, 1076 cm'l; 1H NMR (300 MHz, CDC13) 5 7.54 (m, 5 H), 7.36 (m, 10 H),
6.40 (d, J = 4.4 Hz, 2 H), 1.53 (s, 1 H), 1.34 (s, 6 H); 13C NMR (75 MHz, CDC13) 8
158.9, 137.8, 136.7, 128.2, 128.0, 118,7, 72.4, 29.1; HRMS (BI) m/z 435.0757 [(M-H+).

calcd. for C23H23OSn 435.0775].

BU3Sn \ OH Bu3Sn 0H

E-7 17

 

 

Preparation of (E)-6-tributylstannanyl-hex-S-en-1-ol (E7) and 5-tributylstannanyl-
hex-S-en-l-ol (17) (Scheme 2.5, entry 5). Applying the above procedure to 5—hexyn-1-ol
(2) (0.11 mL, 1.0 mmol) using Bu3SnCl (0.33 mL, 1.2 mmol) and letting the reaction stir
at room temperature for 2 hours and purification by column chromatography on silica gel
[silica; 95:5 petroleum ether/EtOAc, 1% TBA] afforded a 1/1 mixture of (E)-2-methyl-4-
triphenylstannanyl-but-3-en-2-ol (E7) and 5-tributylstannanyl-hex-5-en-l-ol (17) (175
mg, 45%) as a clear oil. Spectroscopic data were consistent with those previously

reported.69

 

SnBu3
W0”

E-7 Z-7

W/
BU3Sn \ OH

Representative procedure for the hydrostannation of alkynes under radical
catalysis. Preparation of (E)-6-tributylstannanyl-hex-S-en-1-ol (E-7) and (2)-6-
tributylstannanyl-bex-S-en-l-ol (Z-7) (Scheme 2.6, entry 1). PMHS (0.09 mL, 1.5

mmol) was added to a solution of 5-hexyn-1-ol (2) (0.11 mL, 1.0 mmol), Bu3SnCl (0.33

78

mL, 1.2 mmol), aqueous KF (174 mg, 3.0 mol; 3 mL H20), and AIBN (50 mg) in THF
(5 mL). The solution was stirred at 80 °C for 2 hours and stopped while some of the
alkyne was still present. The solution was then cooled to room temperature and NaOH
(1N) was added and the resulting mixture stirred for 1 hour. The solution was then
extracted with ether and the combined organic phase washed with saturated KF and
water. The organics were dried over MgSO4, filtered, and concentrated in vacuo.
Purification by column chromatography on silica gel [EtOAc/hexanes 5/95, 1% TEA]
gave a 1:1 mixture of (E)-6-tributylstannanyl-hex-5-en-1-ol (E-7) and (Z)-6-
tributylstannanyl-hex-S-en-l-ol (Z-7) (260 mg, 67%) determined by 1H NMR.

Spectroscopic data were consistent with those previously reported.69

 

SnCy3
W0“

Z-8

 

Preparation of (Z)-6-tricyclohexylstannanyl-hex-5-en-l-ol (Z-8) (Scheme 2.6, entry
2). PMHS (0.3 mL, 5 mmol) was added to a solution of S-hexyn-l-ol (2) (0.11 mL, 1.0
mmol), Cy3SnCl (1.3 mL, 5 mmol), aqueous KF (580 mg, 10 mol; 3 mL H20), and
AIBN (50 mg) in THF (5 mL). The solution was stirred at 80 °C for 16 hours well after
all the alkyne had been consumed. The solution was then cooled to room temperature and
NaOH (1N) was added and the resulting mixture stirred for 1 hour. The solution was then
extracted with ether and the combined organic phase washed with saturated KF and
water. The organics were dried over MgS04, filtered, and concentrated in vacuo.
Purification by column chromatography on silica gel [EtOAc/hexane 5/95, 1% TBA]
afforded (Z)-6-tricyclohexylstannanyl-hex-S-en—1-ol (Z-8) (341 mg, 73%). IR (CHC13):

3321, 2917, 2845, 1597, 1445 cm'l; 1H NMR (300 MHz, CDC13) 6 6.55 (dt, J= 12.4, 6.9

79

Hz, 1 H), 5.69 (d, J= 12.4 Hz, 1 H), 3.62 (br. s, 2 H), 2.03 (m, 2 H), 1.80 (m, 5 H), 1.65-
1.18 (m, 33 H); 13C NMR (75 MHz, CDCl3) 5 149.1, 126.6, 62.9, 37.6, 324,323,297,
29.3, 27.1, 27.0, 26.0; HRMS (c1) m/z 467.2352 [(M+CH4) calcd for C13H43Sn0

467.2340].

 

SDCY3
W011

E-8 Z-8

W
(2)/3811 OH

 

Preparation of (E)-6-tricyclohexylstannanyl-hex-S-en-l-ol (E-8) and (2)-6-
tricyclobexyIstannanyl-bex-S-en-l-ol (Z-8) (Scheme 2.7, entry 3). PMHS (0.3 mL, 5
mmol) was added to a solution of 5-hexyn-1-ol (0.11 mL, 1.0 mmol), Cy3SnCl (1.3 mL, 5
mmol), aqueous KF (580 mg, 10 mol; 3 mL H20), and AIBN (50 mg) in THF (5 mL).
The solution was stirred at 80 °C for 16 hours well after all the alkyne had been
consumed. The solution was then cooled to room temperature and NaOH (1N) was added
and the resulting mixture stirred for 1 hour. The solution was then extracted with ether
and the combined organic phase washed with saturated KF and water. The organics were
dried over MgSO4, filtered, and concentrated in vacuo to afford a E/Z ratio of 1:4
determined by 1H NMR. Purification by column chromatography on silica gel
[EtOAc/hexane 5/95] afforded of (E)-6-tricyclohexylstannanyl-hex-5-en-l-ol (E8) and
(Z)-6-tricyclohexylstannanyl-hex-5-en-1-ol (Z-8) (289 mg, 62%). IR (CC14): 3337, 1597,
1445 cm]; (E) 1H NMR (300 MHz, CDC13) 5 5.90 (dt, J= 18.9, 5.9 Hz, 1 H), 5.72 (d, J=
18.9 Hz, 1 H), 3.62 (br. s, 2 H), 2.03 (m, 2 H), 1.80 (m, 5 H), 1.65-1.18 (m, 33 H); l3C
NMR (75 MHz, CDC13) 5 149.8, 126.0, 62.7, 37.6, 32.4, 32.3, 29.7, 29.3, 27.1, 27.0,

26.0; HRMS (CI) m/z 454.2264 [(M+ NH4-H204’). calcd. for C24H46NSn 454.2262]

80

Procedure for the kinetic experiments using Pd2dba3 / AsPh; as catalyst. (Schemes
2.8 / 2.9 / 2.11). Pd2dba3 (4.5 mg, 0.005 mmol) was dissolved in THF (0.7 mL) and
AsPh3 (8.5 mg, 0.02 mmol) was added. The reaction was stirred for 20 minutes in order
to preform the catalyst. Deuterated benzene was added (0.05 mL) as well as anisole (0.2
mmol) followed by the stannane (0.2 mmol). The electrophile (0.4 mmol) was added and
the reaction was stirred at 50 °C. The reaction was followed by 1H NMR every 5 minutes
for 1 hour, then every 10 minutes for another hour, then every 30 minutes for 3 more
hours.

Procedure for the kinetic experiments using Pd(PPh3)4 as catalyst. (Schemes 2.12).
Pd(PPh3)4 (4.5 mg, 0.005 mmol) was dissolved in THF (0.7 mL) and stirred for 20
minutes in order to complete the dissolution of the catalyst. Deuterated benzene was
added (0.05 mL) as well as anisole (0.2 mmol) followed by the stannane (0.2 mmol).
Then the electrophile was added and the solution stirred at 50 °C, the reaction was
followed by 1H NMR every 5 minutes for 1 hour, then every 10 minutes for another
hours, then every 30 minutes for 3 more hours.

Note on the Use of Microwave Ovens. The microwave used was a kitchen oven with no
control of pressure and temperature. This means that over pressure could build within the
reactor tube and explosion could follow. Experiments should be conducted behind a blast
shield and in the hood. Furthermore, in order to minimize the risks of explosion, Teflon
coated o-rings should be used as seals and the tube itself should not be scrubbed with
metals brushes as to avoid scratches that might create a weak point in the glass. Teflon

tubes can also be used as they will expand but not explode.

81

 

OH

20

 

 

Representative procedure for the hydrostannation/cross-coupling of alkynes using
(Bu3Sn)2O/PMHS under thermal conditions. Preparation of (1E,3E)-1-(4-phenyl-
buta-l,3-dienyl)-cyclohexanol (20) (Scheme 3.5, entry 1). (Bugsn)20 (1.8 mL, 3.6
mmol), PMHS (0.43 mL, 7.2 mmol), l-ethynyl-cyclohexanol (19) (372 mg, 3 mmol),
bromostryrene (0.39 mL, 3.1 mmol), and (PPh3)2PdC12 (42 mg, 0.06 mmol) were added
successively to a mixture of THF/H20 (10 mL, 1:1) and the solution was heated at 80 °C
until completed by TLC (approximately 6 hours). The solution was then cooled, and
ammonium hydroxide (1 mL) was added and the reaction stirred for 30 minutes. The
solution was extracted with ether, and the combined organic phases washed with water
and brine. The solution was then dried over MgSO4, filtered, and concentrated in vacuo.
The product was purified by column chromatography over silica gel [EtOAc/hexanes
10/90] to afford (1E,3E)-1-(4-phenyl-buta—l,3-dienyl)-cyclohexanol (20) (355 mg, 52%)
as a clear oil. 1H NMR (300 MHz, CDC13) 5 7.19-7.38 (m, 5 H), 6.75 (dd, J = 15.4, 10.4
Hz, 1 H), 6.53 (d, J= 15.4 Hz, 1 H), 6.42 (dd, J= 15.4, 10.4 Hz, 1 H), 5.92 (d, J= 15.4
Hz, 1 H), 1.21-1.77 (m, 10 H); ”c NMR (75 MHz, CDC13) 5 141.7, 137.3, 132.0, 128.8,
128.5, 127.6, 127.4, 126.2, 71.6, 37.8, 25.4, 22.0. Spectroscopic data were consistent with

those previously reported.20

82

 

HO
QMX
21

Preparation of (3E, 5E)-2methyl-6-phenyl-hexa-3,5-dien-2-ol (21) (Scheme 3.5, entry

 

2). The above procedure was performed with (BugSn)20 (1.8 mL, 3.6 mmol), PMHS
(0.43 mL, 7.2 mmol), 2-methyl-3-butyn-2-ol (l) (0.29 mL, 3 mmol) and (PPh3)2PdCl2
(42 mg, 0.06 mmol) in DMF (10 mL). After column chromatography on silica gel
[EtOAc/hexanes 10/90] (3E, 5E)-2-methyl-6-phenyl-hexa-3,5-dien-2-ol (21) (368 mg,
65%) was obtained as a yellow oil. 1H NMR (300 MHz, CDC13) 5 1.31 (s, 3 H), 5.86 (d,
J= 15.4 Hz, 1 H), 6.38 (ddd, J= 15.4, 10.4, 0.6 Hz, 1 H), 6.53 (d, J= 15.7 Hz, 1 H), 6.76
(ddd, J = 15.7, 10.4, 0.6 Hz, 1 H), 7.16-7.39 (m, 5 H); 13c NMR (75 MHz, CDC13)5
140.8, 137.2, 131.9, 128.6, 128.5, 127.8, 127.3, 126.2, 77.0, 35.2, 27.4, 8.3.

Spectroscopic data were consistent with those previously reported.20

 

fl

0H

20

 

 

Representative procedure for the hydrostannation/cross-coupling of alkynes using
(Bu3Sn)2O/PMHS under microwave irradiations. Preparation of (lE,3E)-l-(4-
phenyl-buta-l,3-dienyl)-cyclobexanol (20) (Scheme 3.5, entry 1). (Bu3Sn)20 (1.8 mL,
3.6 mmol), PMHS (0.43 mL, 7.2 mmol), l-ethynyl-cyclohexanol (19) (372 mg, 3 mmol),
bromostryrene (0.39 mL, 3.1 mmol), and (PPh3)2PdCl2 (42 mg, 0.06 mmol) were added
successively to a mixture of THF/H20 (10 mL, 1:1). The reaction was placed in the
middle of the microwave oven and the reaction was irradiated at 140 W for 25 minutes

(done in 5 intervals of 5 minutes). During each interval, the reactor was air cooled to

83

room temperature and checked by TLC. After the reaction was over, the solution was
cooled and ammonium hydroxide (1 mL) was added and the reaction stirred for 30
minutes. The solution was extracted with ether, and the combined organic phases washed
with water and brine. The solution was then dried over MgSO4, filtered, and concentrated
in vacuo. The product was purified by column chromatography over silica gel
[EtOAc/hexanes 10/90] to afford (lE,3E)-1-(4-pheny1-buta-1,3-dienyl)-cyclohexanol

(20) (170 mg, 26%) as a clear oil. For spectroscopic data see page 82.

HO
W
21

Preparation of (3E, 5E)-2methyl-6-phenyl-hexa-3,5-dien-2-ol (21) (Scheme 3.5, entry

 

 

2). The representative procedure was performed with (Bu3Sn)20 (1.8 mL, 3.6 mmol),
PMHS (0.43 mL, 7.2 mmol), 2-methyl-3-butyn-2-ol (l) (0.29 mL, 3 mmol) and
(PPh3)2PdCl2 (42 mg, 0.06 mmol) in DMF (10 mL). After column chromatography on
silica gel [EtOAc/hexanes 10/90] (3E, 5E)-2-methyl-6-phenyl-hexa-3,5-dien—2-ol (21)

(368 mg, 65%) was obtained as a yellow oil. For spectroscopic data see page 83.

[Me3Sn/3\><OH ]

 

 

Control for the thermal hydrostannation. Preparation of (E)- 2-methyl-4-
trimethylstannanyl-but-3-en-2-ol (3) (Scheme 3.6, entry 1). Pd2dba3 (9 mg, 0.01
mmol) and AsPh3 (12 mg, 0.04 mmol) were dissolved in DMF (10 mL) and stirred for 30
minutes. Then 2-methyl-3-butyn-2-ol (1) (0.10 mL, 1 mmol) was added followed by
trimethyltin fluoride (180 mg, 1.2 mmol), PMHS (0.1 mL, 1 mmol) and TBAF (1M

solution in THF, 1 drop). The reaction was stirred at 80 °C for 2 hours. The reaction was

84

then quenched at room temperature with NaOH (1N) and the reaction stirred for 30
minutes. The solution was extracted with ether and the combined organic extract washed
with water and brine. The organics were then dried over MgSO4, filtered, and
concentrated in vacuo. The product was purified by column chromatography on silica gel
[EtOAc/hexanes 9:1 with 1% TEA] to afford 2-methyl-4-trimethylstannanyl—but-3-en-2-

ol (3) (250 mg, 80%) as a yellow oil. For spectroscopic data see page 76.

[Me3 Sn/iXOH I

Microwave assisted hydrostannation. Preparation of (E)-2-methyl-4-

 

trimethylstannanyI-but-3-en-2-ol (3) (Scheme 3.6, entry 2). In a Pyrex pressure tube,
Pd2dba3 (9 mg, 0.01 mmol) and AsPh3 (12 mg, 0.04 mmol) were dissolved in DMF (10
mL) and stirred for 30 minutes. Then 2-methyl-3-butyn-2-ol (1) (0.10 mL, 1 mmol) was
added followed by trimethyltin fluoride (180 mg, 1.2 mmol), PMHS (0.1 mL, 1 mmol)
and TBAF (1M solution in THF, 1 drop) and the stir bar was removed. The pressure tube
was placed in a glass holder in the middle of the microwave and the experiment was
performed without rotation of the rotating plate. The reaction was irradiated at 140 W for
3 minutes. The reaction was then quenched at room temperature with NaOH (1N) and the
mixture stirred for 30 minutes. The solution was extracted with ether and the combined
organic extract washed with water and brine. The solution was then dried over MgSO4,
filtered, and concentrated in vacuo. The product was purified by column chromatography
on silica gel [EtOAc/hexanes 10/90 with 1% TEA] to afford 2-methyl-4-
trimethylstannanyl-but-3-en-2-ol (3) (190 mg, 76%) as a yellow oil. For spectroscopic

data see page 76.

85

 

H0
Q/WX
21

Representative procedure for the microwave assisted Stille cross-coupling.

 

Preparation of (3E, 5E)-2-methyl-6-phenyl-hexa-3,5-dien-2-ol (21) (Scheme 3.7,
entry 1). In a Pyrex pressure tube, Pd2dba3 (9 mg, 0.01 mmol) and AsPh3 (12 mg, 0.04
mmol) were dissolved in a 1:1 mixture of DMF and THF (10 mL total) and stirred for 30
minutes. 2-Methyl-4-trimethylstannanyl-but-3-en-2-ol (3) (250 mg, 1 mmol) was then
added followed by B-bromostyrene (0.26 mL, 2 mmol). The pressure tube was placed in a
glass holder in the middle of the microwave and the experiment was performed without
rotation of the rotating plate. The stir bar was removed, and the reaction was irradiated at
70 W for 3 minutes. The solution was then cooled in air for 10 minutes and a TLC
sample taken. The solution was then heated again at 70 W for 3 minutes, cooled in air,
and quenched with NaOH (IN). The resultant mixture was stirred for 30 minutes. The
mixture was then extracted with ether and the combined organic extract washed with
water and a saturated KF solution. The organics were then dried over MgSO4, filtered,
and concentrated in vacuo. The product was purified by column chromatography on silica
gel [EtOAc/hexanes 10/90] to afford (3E, 5E)-2-methyl-6-phenyl-hexa-3,5-dien-2-ol (21)

(62 mg, 33%) as a clear oil. For spectroscopic data see page 83.

W1

Preparation of (3E, 5E)-2-methyl-6-pheny1-hexa-3,5-dien-Z-ol (21) (Scheme 3.6,

 

 

entry 2). Using the representative procedure with Pd2dba3 (9 mg, 0.01 mmol) and AsPh3

(12 mg, 0.04 mmol), 2-methyl-4-trimethylstannanyl-but-3-en-2-ol (3) (250 mg, 1 mmol)

86

and B-bromostyrene (0.26 mL, 2 mmol) in DMF (10 mL) and after purification by
column chromatography on silica gel [EtOAc/hexanes 10/90] (3E, 5E)-2-methyl-6-
phenyl-hexa—3,5-dien-2-ol (21) (75 mg, 40%) was obtained as a clear oil. For

spectroscopic data see page 83.

 

HO
O/N
21

Preparation of (3E, 5E)-2-methyl-6-phenyI-hexa-3,5-dien-2-ol (21) (Scheme 3.9,

 

entry 3). Using the representative procedure with Pd2dba3 (9 mg, 0.01 mmol), trifuryl
phosphine (TFP) (18 mg, 0.08 mmol), 2-methyl-4-trimethylstannanyl-but~3-en-2-ol (3)
(250 mg, 1 mmol) and B-bromostyrene (0.26 mL, 2 mmol) in DMF (10 mL) and with and
after purification by column chromatography on silica gel [EtOAc/hexanes 10/90] (3E,
5E)-2-methyl-6-phenyl-hexa-3,5-dien-2-ol (21) (80 mg, 43%) was obtained as a clear oil.

For spectroscopic data see page 83.

HO Ph
W
23

First microwave-assisted one pot hydrostannation/Stille. Preparation of (3E, 5E)-

 

 

2,6-diphenyl-hexa-3,5-dien-2-ol (23) (Scheme 3.10, entry 1). In a Pyrex pressure tube,
Pd2dba3 (9 mg, 0.01 mmol) and AsPh3 (12 mg, 0.04 mmol) were dissolved in DMF (10
mL) and stirred for 30 minutes. Then 2-phenyl-but-3-yn-2-ol (22) (146 mg, 1 mmol) was
then added followed by trimethyltin fluoride (180 mg, 1.2 mmol), PMHS (0.1 mL, 1
mmol), and TBAF (1M solution in THF, 1 drop). The stir bar was removed and the
reaction vessel was placed in the center of the microwave. The solution was irradiated at

70 W for 3 minutes without rotation. The reaction was then cooled by placing the vessel

87

in a water bath at room temperature for 2 minutes. B-Bromostyrene (0.26 mL, 2 mmol)
was then added and the reaction was irradiated for two more 5 minute intervals. The
irradiation was stopped and the reaction cooled down and checked by TLC between the
two intervals. The reaction was then quenched with NaOH (1N) and the reaction stirred
for 30 minutes. The solution was extracted with ether and the combined organic extract
washed with water and a saturated KF solution. The organics were then dried over
MgSO4, filtered, and concentrated in vacuo. The product was purified by column
chromatography on silica gel [EtOAc/hexanes 10/90] to afford (3E, 5E)-2,6-diphenyl-
hexa-3,5-dien-2-ol (23) (110 mg, 44%) as a yellow oil. Spectroscopic data were

consistent with those previously reported.20

HO
W
21

Preparation of (3E, 5E)-2-methyl-6-phenyl-hexa-3,5-dien-2-ol (21) (Scheme 3.10,

 

 

entry 2). Applying the representative procedure to Pd2dba3 (9 mg, 0.01 mmol) and AsPh3
(12 mg, 0.04 mmol), 2-methyl-3-butyn-2-ol (1) (0.10 mL, 1 mmol), trimethyltin fluoride
(180 mg, 1.2 mmol), B-bromostyrene (0.26 mL, 2 mmol) in DMF (10 mL) and after
column chromatography on silica gel [EtOAc/hexanes 10/90] afforded (3E, 5E)-2-
methyl-6-phenyl-hexa-3,5-dien-2-ol (21) (49 mg, 26%) as a yellow oil. For spectroscopic

data see page 83.

88

 

H Ph
\ \
23

Control experiment for the initial one pot hydrostannation/Stille under thermal

 

conditions. Preparation of (3E, 5E)-2,6-diphenyl-hexa-3,5-dien-2-ol (23) (Scheme
3.8, entry 3). Pd2dba3 (9 mg, 0.01 mmol) and AsPh3 (12 mg, 0.04 mmol) were dissolved
in DMF (10 mL) and stirred for 30 minutes. Then 2-pheny1-but-3-yn-2-ol (22) (146 mg, 1
mmol) was then added followed by trimethyltin fluoride (180 mg, 1.2 mmol), PMHS (0.1
mL, 1 mmol) and TBAF (1M solution in THF, 1 drop) and the reaction stirred at 80 °C
for 2 hours. B-Bromostyrene (0.26 mL, 2 mmol) was then added and the reaction was
stirred for 16 hours. The reaction was then quenched with NaOH (1N) at room
temperature and the resultant mixture was stirred for 30 minutes. The mixture was then
extracted with ether and the combined organic extract washed with water and a sat. KF
solution. The organics were then dried over MgS04, filtered, and concentrated in vacuo.
The product was purified by column chromatography on silica gel [EtOAc/hexanes
10/90] to afford (3E, 5E)-2,6-diphenyl-hexa-3,5-dien-2-ol (23) (95 mg, 38%) as a yellow

oil. For spectroscopic data see page 87.

24

Representative procedure for the first generation microwave assisted

 

 

hydrostannation/Stille cross-coupling. Prepapration of (E)-2-methyl-4-phenyl-but—3-
en-Z-ol (24) (Scheme 3.11). In a Pyrex pressure tube, Pd2dba3 (9 mg, 0.01 mmol) and
AsPh3 (12 mg, 0.04 mmol) were dissolved in THF (10 mL) and stirred for 30 minutes. 2-

Methyl-3-butyn-2-ol (1) (0.1 mL, 1 mmol) was then added followed by Bu3SnCl (0.33

89

mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20 (1 mL), and
catalytic TBAF (1 M solution in THF, 1 drop). The stir bar was removed and the reaction
vessel was placed in the center of the microwave. The solution was irradiated at 140 W
for 3 minutes without rotation. The reaction was then cooled by placing the vessel in a
water bath at room temperature for 2 minutes. Bromobenzene (0.16 mL, 1.5 mmol) was
added as well as another portion of the premixed catalyst in THF (1 mL, Pd2dba3/AsPh3:
0.01/0.04 mmol) and the solution irradiated at 140 W for 5 minutes. The solution was
cooled and again checked by TLC. Another aliquot of preformed catalyst in THF was
added (1 mL, Pd2dba3/AsPh3: 0.01/0.04 mmol) followed by another irradiation at 140 W
for 5 minutes. The reaction was cooled and quenched at room temperature with NaOH
(1N) and extracted with ether. The combined organic phases were washed with water and
a sat. KF solution. The organics were dried over MgSO4, filtered, and concentrated in
vacuo. The product was purified by column chromatography on silica gel
[EtOAc/hexanes 10/90] to afford to afford (E)-2-methyl-4-phenyl-but-3-en-2-ol (24) (97

mg, 60%) as a yellow oil. Spectroscopic data were consistent with those previously

General procedure for the microwave-assisted palladium catalyzed one-pot

reported.7O

 

 

hydrostannation/Stille coupling. Preparation of (E)—2-methyl-4-phenyI-but-3-en-2-
o] (24) (Scheme 3.13, entry 1). In a Pyrex pressure tube, Pd(PPh3)4 (12 mg, 0.01 mmol)
was dissolved in THF (10 mL). 2-Methyl-3-butyn-2-ol (1) (0.1 mL, 1 mmol) was then

added followed by BU3SnC1 (0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174

90

mg, 3.0 mmol), H20 (1 mL), and catalytic TBAF (1M solution in THF, 1 drop). The stir
bar was removed and the reaction vessel was placed in the center of the microwave. The
solution was irradiated at 140 W for 3 minutes without rotation. The reaction was then
cooled by placing the vessel in a water bath at room temperature for 2 minutes.
Bromobenzene (0.16 mL, 1.5 mmol) was added as well as another portion of Pd(PPh3)4
(12 mg, 0.01 mmol). The solution was again irradiated at 140 W for another 5 minutes.
The solution was cooled again and checked by TLC and another aliquot of Pd(PPh3)4 (12
mg, 0.01 mmol) was added and the solution irradiated at 140 W for 5 minutes. After
cooling of the reaction, TLC showed it to be completed. The reaction was quenched at
room temperature with NaOH (1N), stirred for 30 minutes, and extracted with ether. The
combined organic phases were washed with water and a sat. KF solution. The solution
was dried over MgS04, filtered, and concentrated in vacuo. The product was purified by
column chromatography on silica gel [EtOAc/hexanes 1:9] to afford to afford (E)-2-
methyl-4—phenyl-but-3-en-2-ol (24) (153 mg, 94%). For spectroscopic data, see page 90.

W0”

31

 

 

Preparation of (E)-2-methyl-S-phenyl-pent-3-en-2-ol (31) (Scheme 3.13, entry 2).
Applying the representative conditions with Pd(PPh3)4 (12 mg, 0.01 mmol), Bu3SnCl
(0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20 (1 mL),
THF (10 mL), 2-methyl-3-butyn-2-ol (1) (0.10 mL, 1.0 mmol) and benzyl bromide (0.18
mL, 1.5 mmol) and after chromatography on silica gel [EtOAc/hexanes 10/90] afforded
(E)-2-methyl-5-phenyl-pent-3-en-2-ol (31) (180 mg, 90%) as a thick yellow oil.

Spectroscopic data were consistent with those previously reported.71

91

 

96]

Preparation of (E)-2-(3,3-dimethyl-but-l-enyl)-phenol (32) (Scheme 3.13, entry 3).

 

Applying the representative conditions with Pd(PPh3)4 (12 mg, 0.01 mmol), Bu;SnCl
(0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20 (1 mL),
THF (10 mL), 3,3-dimethyl-butyne (25) (0.12 mL, 1 mmol) and 2-bromophenol (0.39
mL, 1.5 mmol) and after chromatography on silica gel [pentane] afforded (E)-2-(3,3-
dimethyl-but-1-eny1)-phenol (32) (120 mg, 86%) as an oil. Spectroscopic data were

consistent with those previously reported.72

1W]

Preparation of (E,E)-(5,5-dimethyl-hexa-1,3-dienyl)-benzene (33) (Scheme 3.13,

 

 

entry 4). Applying the representative conditions with Pd(PPh3)4 (12 mg, 0.01 mmol),
Bu3SnCl (0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20
(1 mL), THF (10 mL), 3,3-dimethyl-butyne (25) (0.12 mL, 1 mmol) and E-bromostyrene
(0.19 mL, 1.5 mmol) and after chromatography on silica gel [pentane] afforded (E,E)-
(5,5-dimethy1-hexa-1,3-dieny1)-benzene (33) (169 mg, 91%) as an oil. Spectroscopic

data were consistent with those previously reported.20

59)

Preparation of (B-l-styryl-cyclohexanol (34) (Scheme 3.13, entry 5). Applying the

 

 

representative conditions with Pd(PPh3)4 (12 mg, 0.01 mmol), BugSnCl (0.33 mL, 1.2

92

mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20 (1 mL), THF (10 mL),
l-ethynyl-l-cyclohexanol (19) 0.124 g, 1 mmol) and bromobenzene (0.16 mL, 1.5 mmol)
and after chromatography on silica gel [EtOAc/hexanes 10/90] to afford of (E)—1-styry1-
cyclohexane] (34) (115 mg, 57%) as an oil. Spectroscopic data were consistent with

those previously reported.73

 

Et W131

 

Preparation of (E)-l,1-diethyl-3-phenyl-allylamine (35) (Scheme 3.13, entry 6).
Applying the representative conditions with Pd(PPh3)4 (12 mg, 0.01 mmol), Bu3SnCl
(0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20 (1 mL),
THF (10 mL), 1,1-diethylpropargylamine (26) (0.11 g, 1 mmol) and bromobenzene (0.16
mL, 1.5 mmol) and after chromatography on silica gel [EtOAc/pentane 1/1] afforded (E)-
1,1-diethyl-3-phenyl-allylamine (35) (170 mg, 90%) as an oil. 1H NMR (300 MHz,
CDCl3) 5 7.17-7.42 (m, 5H), 6.47 (d, J= 16.2 Hz, 1 H), 6.16 (d, J= 16.2 Hz, 1 H), 1.56
(qd, J= 2.5, 7.4 Hz, 4 H), 1.33 (br s, 2 H), 0.91 (d, J= 7.4 Hz, 3 H), 0.88 (d, J= 7.4 Hz, 3
H); 13C NMR (75 MHz, CDC13) 5 137.7, 137.4, 128.5, 127.3, 127.0, 126.1, 56.3, 34.1,

8.0. Spectroscopic data were consistent with those previously reported.74

 

\Et Et

 

Preparation of (2E,4E)-l,1-diethyl-5-phenyl-penta-2,4-dienylamine (36) (Scheme
3.13, entry 7). Applying the above conditions with Pd(PPh3)4 (12 mg, 0.01 mmol),
Bu3SnCl (0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20

(1 mL), THF (10 mL), 1,1-diethy1propargylamine (26) (0.11 g, 1 mmol) and (E)-B-

93

bromostyrene (0.19 mL, 1.5 mmol), but only irradiating in the presence of the
electrophile for 5 minute, gave the product which was purified by column
chromatography on silica gel [EtOAc/pentane 1:1] to afford (2E,4E)-1,1-diethyl-5-
phenyl-penta-2,4-dienylamine (36) (175 mg, 81%) as an oil. 1H NMR (30 MHz, CDC13)
5 7.15-7.38 (m, 5 H), 6.78 (dd, J= 15.6, 10.3 Hz, 1 H), 6.49 (d, J= 15.7 Hz, 1 H), 6.28
(dd, J= 15.4, 10.4 Hz, 1 H), 5.74 (d, J= 15.4 Hz, 1 H), 1.48 (q, J= 7.4 Hz, 4 H), 1.33 (br
s, 2 H), 0.84 (t, J = 7.4 Hz, 6 H); 13C NMR (75 MHz, CD013) 5 142.4, 137.5, 130.9,

129.1, 128.6, 128.1, 127.1, 126.1, 56.3, 34.0, 8.1. Spectroscopic data were consistent with

W
0“ c0213:
37

Preparation of (2Z,4E)-6-hydroxy-3,6,8-trimethyl-nona-2,4-dienoic acid ethyl ester

those previously reported.74

 

 

(37) (Scheme 3.13, entry 8). Applying the representative conditions with Pd(PPh3)4 (12
mg, 0.01 mmol), Bu3SnCl (0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174
mg, 3.0 mmol), H20 (1 mL), THF (10 mL), 3,5-dimethyl-but-1-yn-3-ol (27) (0.15 mL, 1
mmol) and Z-ethyl-3-iodo-2-butenoate (41) (0.36 g, 1.5 mmol; prepared according to
Chalcat, J. C. C. R. Acad. Sc. Paris (Serie C) 1971, 763-765), but only irradiating in the
presence of the electrophile for 5 minutes, gave a product that was purified by column
chromatography on silica gel [EtOAc/pentane 1:1] to afford (2Z,4E)-6-hydroxy—3,6,8-
t1imethyl-nona-2,4-dienoic acid ethyl ester (37) (169 mg, 81%) as an oil. IR (neat) 3472,
1697, 1638, 1603, 1234, 1157 cm"; 1H NMR (300 MHz, CDCl3) 5 7.66 (d, J= 16.2 Hz,
1 H), 6.15 (d, J=16.2 Hz, 1 H), 5.65 (s, 1 H), 4.13 (q, J= 7.1 Hz, 2 H), 1.97 (d, J= 1.2

Hz, 3 H), 1.88 (br s, 1 H), 1.72 (t, J= 6.6 Hz, 1 H), 1.50 (dd, J= 5.8, 2.2 Hz, 2 H), 1.32

94

(s, 3 H), 1.24 (1, J= 7.1 Hz, 3 H), 0.91 (d, J= 6.8 Hz, 3 H), 0.88 (d, J= 6.8 Hz, 3 H); 13c
NMR (75 MHz, coc13) 5 166.2, 150.4, 144.6, 124.0, 117.3, 73.7, 59.7, 51.1, 28.6, 24.5,
24.3, 21.0, 14.2; LRMS (E1) m/z 223.4 (M+—0H), 197.3, 183.2, 139.2, 137.2, 109.1

(100), 95.1.

 

W]

Preparation of (5E,7E)-8-phenyl-octa-5,7-dien-4-oI (38) (Scheme 3.13, entry 9).

 

Applying the representative conditions with Pd(PPh3)4 (12 mg, 0.01 mmol), Bu38nCl
(0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20 (1 mL),
THF (10 mL), 1-hexyn-3-ol (28) (0.12 mL, 1 mmol) and (EMS-bromostyrene (0.19 mL,
1.5 mmol) and after chromatography on silica gel [EtOAc/pentane 10/90] afforded
(5E,7E)-8-phenyl-octa-5,7-dien-4-ol (38) (112 mg, 55%) as an oil. 1H NMR (300 MHz,
CDCl3) 5 7.16-7.39 (m, 5 H), 6.76 (ddd, J= 15.7, 10.4, 0.6 Hz, 1 H), 6.53 (d, J= 15.7
Hz, 1 H), 6.38 (ddd, J= 15.4, 10.4, 0.6 Hz, 1 H), 5.86 (d, J= 15.4 Hz, 1 H), 1.60 (q, J=
7.4 Hz, 2 H), 1.31(s, 3 H), 0.90 (t, J= 7.4 Hz, 3 H); l3C NMR (75 MHz, CDC13) 5 140.8,
137.2, 131.9, 128.6, 128.5, 127.8, 127.3, 126.2, 77.0, 35.2, 27.4, 8.3. Spectroscopic data

matches those previously reported.74

 

WOH Ph M
P“ W011 Ph 0H
18

E-16 Z-16

Preparation of (E+Z) 6-phenyl-hex-5-en-l-ol (16) and 5-pheny1-hex-5-en-1-ol (18)
(Scheme 3.13, entry 10). Applying the representative conditions with Pd(PPh3)4 ( 12

mg, 0.01 mmol), Bu3SnCl (0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174

95

mg, 3.0 mmol), H20 (1 mL), THF (10 mL), 5-hexyn-1-ol (2) (0.11 mL, 1 mmol) and
bromobenzene (0.16 mL, 1.5 mmol) and after chromatography on silica gel
[EtOAc/pentane 10/90] afforded a 14:1.6:1 (determined by 1H NMR) mixture of (E)-6-
phenyl-hex-S-en- 1 -ol (E-16),(Z)-6-phenyl-hex-5-en-1 -ol (Z-16) and S-phenyl-hex-S-en-l -
01 (18) (90 mg, 57%). Spectroscopic data were consistent with those previously

reported. ”’76

 

1.03%]

 

Preparation of (E)-(4-methoxyphenyl)-2-phenylethylene (39) (Scheme 3.13, entry
11). Applying the representative conditions with Pd(PPh3)4 (12 mg, 0.01 mmol),
Bu3SnCl (0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20
(1 mL), THF (10 mL), phenyl acetylene (29) (0.1 mL, 1 mmol) and p-bromoanisole (0.19
mL, 1.5 mmol) and after chromatography on silica gel [pentane] afforded (E)-(4-
methoxyphenyl)-2-phenylethylene (39) (180 mg, 86%) as a white solid. Spectroscopic

and physical data were consistent with those previously reported. 77

1mm)

Preparation of (E)-3-phenyl-acrylic acid methyl ester (40) (Scheme 3.13, entry 12).

 

 

Applying the representative conditions with Pd(PPh3)4 (12 mg, 0.01 mmol), Bu3SnC1
(0.33 mL, 1.2 mmol), PMHS (0.1 mL, 1.5 mmol), KF (174 mg, 3.0 mmol), H20 (1 mL),
THF (10 mL), methyl propiolate (30) (0.08 mL, 1 mmol) and bromobenzene (0.16 mL,

1.5 mmol) and after chromatography on silica gel [EtOAc/pentane 1:99] afforded (E)-3-

96

phenyl-acrylic acid methyl ester (40) (130 mg, 80%) as an oil. The product was identical

to an authentic sample (Aldrich).

 

1 _ CO2H I __ c0251

41a 41

 

Preparation of (Z)- 3-iodo-but-2-enoic acid ethyl ester (41) and (Z)- 3-iodo-but-2-
enoic acid (41a). Ethyl butanoate (10.4 mL, 88 mmol) was dissolved in water (12 mL)
and H1 (47% in H20, 24 mL, 88 mmol) was added. The reaction was stirred at 80 °C for
16 hours. The mixture was then separated between HCl (1N) and ethyl acetate. The
aqueous phase was further extracted with EtOAc. The combined organic phases were
washed with a 10% solution on Na2S203 and brine, dried over MgS04, filtered, and
concentrated in vacuo. We obtained a white solid corresponding to (Z)- 3-iodo-but-2-
enoic acid (41a) (5.8 g, 31%) and a clear oil corresponding to (Z)-3-iodo-but-2-enoic acid

ethyl ester (41) (8.1 g, 38%). Spectroscopic data matched those previously reported.78

General procedure for the one-pot free radical hydrostannation/palladium catalyzed

 

 

Stille coupling (Method A). Preparation of (E)-2-methyl-4-phenyl-but-3-en-2-ol (24)
(Scheme 3.15, entry 1). To a Pyrex pressure tube containing 5 mL THF were added
AIBN (2 mg), 2-methyl-3-butyn-2-ol (1) (0.10 mL, 1 mmol), Bu3SnCl (0.33 mL, 1.2
mmol), PMHS (90 mg, 1.5 mmol), KF (0.1743 g, 3.0 mmol), 1 mL H20, and catalytic
TBAF (1M solution in THF, 1 drop). The reaction was closed, placed in a 250 mL
beaker set in the center of a domestic microwave (glass turntable removed) and heated for

3 minutes at 140 W (20% power setting on a 700 W microwave oven). Afier being

97

allowed to cool by placing the vessel in a water bath at room temperature, Pd(PPh3)4 (12
mg, 0.01 mmol) and bromobenzene (0.16 mL, 1.5 mmol) were added and the sealed tube
was irradiated at 140 W for 5 minutes. The reaction was cooled by placing the vessel in a
water bath at room temperature and a third portion of Pd(PPh3)4 (12 mg, 0.01 mmol) was
added and the sealed tube was again irradiated at 140 W for another 5 minutes. The
reaction was cooled by placing the vessel in a water bath at room temperature and the
reaction was poured into 10% ammonium hydroxide (25 mL), ether was added (25 mL)
and the mixture stirred for 30 min. The phases were separated and the organics were
combined, washed with brine, dried over MgSO4, filtered, and concentrated. The
resulting residue was purified by flash chromatography [silica gel; 90:10 pentane/EtOAc,
1% TBA] to afford a 20: 1:1 mixture of (E)-2-methyl-4-pheny1-but-3-en-2-ol (E-24), (Z)-
2-methyl-4-phenyl-but-3-en-2-ol (Z-24), and 2-methy1-3-pheny1-but-3-en-2-ol (int-24)79

(140 mg, 86%). For spectroscopic data see page 90.

MeO 39

Preparation of (E)-(4-methoxyphenyl)-2-phenylethylene (39) (Scheme 3.15, entry 2).

 

 

Applying the representative conditions to phenyl acetylene (29) (0.1 mL, 1 mmol) and p-
bromoanisole (0.19 mL, 1.5 mmol) gave a residue, which was purified by column
chromatography on silica gel [pentane] to afford (E)-(4-methoxyphenyl)-2-
phenylethylene (39) (178 mg, 85%) as an oil. Spectroscopic data were consistent with

those previously reported.77

98

 

24

General procedure for the one-pot free radical hydrostannation/palladium catalyzed

 

Stille coupling (Method B). Preparation of (E)-2-methyl-4-phenyl-but-3-en-2-ol (24)
(Scheme 3.15, entry 5). To a thick walled Pyrex tube containing 5 mL THF were added
AIBN (2 mg), 2-methyl-3-butyn-2-ol (l) (0.10 mL, 1 mmol), Bu3SnH (0.32 mL, 1.2
mol), 1 mL H20, and catalytic TBAF (1 drop of a 1M THF solution). The reaction was
closed, placed in a 250 mL beaker placed in the center of a domestic microwave (glass
turntable removed) and heated for 3 minutes at 140 W. After being allowed to cool in
water at room temperature for 2 min, Pd(PPh3)4 (12 mg, 0.01 mmol) and bromobenzene
(0.16 mL, 1.5 mmol) were added and the sealed tube was irradiated at 140 W for 5
minutes. After cooling, the reaction was checked by TLC before a third portion of
Pd(PPh3)4 (12 mg, 0.01 mmol) was added and the reaction was again irradiated at 140 W
for another 5 minutes. After cooling the reaction to room temperature, TLC showed the
reaction to be complete. The reaction was then poured into 10% ammonium hydroxide
(25 mL), ether was added (25 mL and the mixture stirred for 30 min. The phases were
separated and the organics were combined, washed with brine, dried over MgS04,
filtered, and concentrated. The resulting residue was purified by column chromatography
on silica gel [EtOAc/pentane 1/99] to afford a 23:1 (E/Z) mixture of 3-methyl-1-pheny1-

but-1-en—3-ol (24) (128 mg, 79%). For spectroscopic data see page 90.

99

 

WOH Ph M
P“ W011 Ph 011
18

E-l6 z-16
Preparation of (E+Z) 6-pheny1-hex-5-en-l-ol (l6) and S-phenyl-hex-S-en-l-ol (18)
(Scheme 3.15, entry 3). Applying the representative conditions to 5-hexyn-1-ol (2) (0.11
mL, 1 mmol) and bromobenzene (0.16 mL, 1.5 mmol) gave a residue that was purified by
column chromatography on silica gel [EtOAc/pentane 1/99] to afford a 31 :7:1 mixture of
(E)-6-phenyl-hex-5-en-l-ol (E—16), (Z)-6-pheny1-hex-5-en-1-ol (Z-16), and S-phenyl-hex-
5-en-1-ol (18) (84 mg, 48%). Spectroscopic data were consistent with those previously

reported.74

 

1h 12
\ 0H
Wm M011 Ph 011 ]

5-42 242 int-42
Preparation of (5)-4-phenyl-but-3-en-l-ol (42) (Scheme 3.15, entry 4). Applying the
representative conditions to 3-butyn-1-ol (0.07 mL, 1 mmol) and bromobenzene (0.16
mL, 1.5 mmol) gave a residue that was purified by column chromatography on silica gel
[EtOAc/pentane 1:99] to afford a 27:4:1 E/Z/Int mixture of (E)-l-pheny1-but—1-en-4-ol
(19.42),80 (Z)-1-phenyl-but-l-en-4-ol (2.42),80 and 2-phenyl-but-1-en-4-ol (int-42)“ (65

mg, 46%). Spectroscopic data obtained were consistent with those previously reported. 74

OH
8113811“ BU3SH\=_><OH BU3sn/U>< ]
HO

E-4 Z-4 int-4

 

 

Procedure for the determination of the equilibration process of the hydrostannation
in the preparation of (E) and (Z) 2-methyl-4-tributylstannanyl-but-3-en-2-ol (4) and
2-methyl-3-tributylstannanyl-but—3-en-2-ol (int-4) (Scheme 3.16). To a thick walled

Pyrex tube containing 5 mL THF were added AIBN (2 mg), 2-methyl-3-butyn-2-ol (1)

100

(0.10 mL, 1 mmol), Bu3SnH (0.32 mL, 1.2 mol), 1 mL H20, and catalytic TBAF (1
drop of a 1M THF solution). The reaction was closed, placed in a 250 mL beaker placed
in the center of a domestic microwave (glass turntable removed) and heated for 3 minutes
at 140 W (20% power setting on a 700 W microwave oven). After being cooled by
placing the reaction vessel into chilled water, a sample was taken for NMR analysis and
the tube wass heated for another 5 minute interval at 140 W. The process was repeated
for a total reaction time of 18 minutes. The ratios were determined by lH-NMR

measuring the ratios of the olefinic protons.

Cross-over experiment on (E)-2-methyl-4-pheny1but-3-en-2-ol (24) (Scheme 3.18). In

 

 

a Pyrex pressure tube, Pd(PPh3)4 (12 mg, 0.01 mmol) was dissolved in THF:H20 (10 mL,
9:1). Then (E)-2-methy1-4-pheny1but-3-en-2-ol (24) (162 mg, 1 mmol) was added
followed by p-bromotoluene (0.12 mL, 1 mmol). The tube was sealed and the reaction
irradiated at 140 W for 5 minutes. After cooling the reaction to room temperature it was
poured into 10% ammonium hydroxide (25 mL), ether was added (25 mL) and the
mixture stirred for 30 min. The phases were separated and the organics were combined,
washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue
was purified by column chromatography on silica gel [EtOAc/pentane 10/90] to afford

(E)-2-methy1-4-phenylbut-3-en-2-ol (24) only. For spectroscopic data see page 90.

101

 

Ph
Ph/\>(0H W0“ ]

E-24 Z-24

Procedure for the microwave assisted cross coupling of pure Z-vinylstannane with
bromobenzene. Preparation of (E) and (2)-2-methy1—4-phenylbut-3-en-2-ol (24)
(Scheme 3.19, reaction 1). Pd(PPh3)4 (23 mg, 0.02 mmol) was placed in a Pyrex
pressure tube containing THF (5 mL) and water (1 mL). Bromobenzene (0.16 mL, 1.5
mmol) and (Z)-4-(tributylstannyl)-2-methylbut-3-en-2-ol (Z-4) (375 mg, 1 mmol) were
added and the tube was sealed. The sealed tube was then irradiated in a microwave for a
total time of 10 min at 140 W. The reaction was then extracted with ether and the phases
were separated. The organics were dried over MgS04, filtered, and concentrated. The
product was purified by column chromatography [EtOAc/pentane 1:9] to afford a 1:1.72
(E/Z) mixture of 2-methy1-4-phenylbut-3-en-2-ol (24) (110 mg, 68%) as an oil.

Spectroscopic data were consistent with those previously reported.82

Procedure for the microwave assisted cross coupling of pure (E)-viny1stannane with

 

 

bromobenzene. Preparation of (E)-2-methyI-4-phenylbut-3-en-2-ol (81) (Scheme
3.19, reaction 2). Applying the representative conditions using (E)-4-(tributylstannyl)-2-
methylbut-3-en-2-ol (E—4) (375 mg, 1 mmol) and after column chromatography on silica
gel [EtOAc/pentane 10/90] afforded a (E)-2-methyl-4-phenylbut-3-en-2-ol (24) (106 mg,

65%) as an oil. For spectroscopic data see page 90.

102

 

[ BU3Ge/\43<0H ]

 

Representative procedure for the formation of tributylgermanes. Preparation of
(E)-2-methyl-4-tributylgermanyl-but-3-en-2-ol (49) (Scheme 4.8, entry 1). Pd(PPh3)4
(30 mg, 0.03 mmol) is dissolved in THF (10 mL), 2-methy1-but-3-yn-2-ol (l) (0.1 mL, 1
mmol) is then added followed by tributylgermanium hydride (0.3 mL, 1.2 mmol). The
reaction is stirred at room temperature for 8 hours and then sodium hydroxide (1N) is
added. The mixture is stirred for 30 minutes then extracted with ether. The combined
organic extracts are washed with brine, dried with MgSO4, filtered, and concentrated in
vavuo. The product was chromatographed on silica gel [dichloromethane] to afford (E)-2-
methyl-4-tributylgermanyl-but-3-en-2-ol (49) (300 mg, 91%) as a yellow oil. IR (neat):
3368, 1617 cm". 1H NMR (300 MHz, c0013) 5 6.05 (d, J= 18.7 Hz, 1 H), 5.88 (d, J=
18.7 Hz, 1 H), 1.75 (s, 1 H), 1.40-1.20 (m, 18 H), 0.90-0.62 (m, 15 H); l3C NMR (75
MHz, CDC13) 5 152.4, 122.6, 71.9, 29.3, 27.2, 26.3, 13.6, 12.6; LRMS (E1) [M+: 324]:
312, 273 (96), 217 (100). Spectroscopic data were consistent with those previously

reported.34b

 

/W\/OH
Bu3Ge \ BU3GCJk/V\OH

E—SO int-50

 

Preparation of (E)-6-tributylgermanyl-hex-S-en-l-ol (E-50) and 5-tributylgermanyl-
hex-S-en-l-ol (int-50) (Scheme 4.8, entry 2). Applying the representative conditions
with Pd(PPh3)4 (30 mg, 0.03 mmol), tributylgermanium hydride (0.3 mL, 1.2 mol), 6-
hexynol (2) (0.11 mL, 1 mmol) gave a 4:1 E/int. mixture determined by ‘H NMR.

Purification by column chromatography on silica gel [dichloromethane] afforded a 4:1

103

mixture of (E)-6-tributylgermanyl-hex~5~en-1-ol (E-50) and 5-tributylgermanyl-hex-5-
en-1-61 (int-50) in a (220 mg, 64%) as a yellow oil. 1H NMR (300 MHz, c0013) 5 (E)
5.89 (dt, J= 18.4, 6.0 Hz, 1 H), 5.70 (dt, J= 18.4, 1.4 Hz, 1 H), 3.62 (t, J= 6.3 Hz, 2 H),
2.22 (s, 1 H), 2.22-2.10 (m, 2 H), 1.60-1.20 (m, 16 H), 0.96-0.66 (m, 15 H). (Int.) 5.56
(dt, J: 2.6, 1.3 Hz, 1 H), 5.14 (dt, J: 2.6, 1.3 Hz, 1 H), 3.62 (t, J= 6.3 Hz, 2 H), 2.22 (s,
1 H), 2.22-2.10 (m, 2 H), 1.60-1.20 (m, 16 H), 0.96-0.66 (m, 15 H); 13C NMR (75 MHz,
CDC13) 5 (int) 152.3, (E) 145.5, (E) 127.7, (int) 122.6, (E+int) 62.6, 36.3, 32.1, 27.3,
27.3, 26.5, 26.4, 25.0, 24.7, 13.7, 13.6, 12.8, 12.3; HRMS (131) m/z 345.2213 [(M+H)
calcd. for C18H390e0 345.2213].

Bu3GeWOH Mon
BU3GC

E-Sl int-51

 

 

Preparation of (E)-5-tributylgermanyl-pent-4-en-l-ol (E-Sl) and 4-
tributylgermanyl-pent-4-en-l-ol (int-51) (Scheme 4.8, entry 3). Applying the
representative conditions with Pd(PPh3)4 (30 mg, 0.03 mmol), tributylgermanium hydride
(0.3 mL, 1.2 mmol), 5-pentynol (43) (126 mg, 1 mmol) gave a 3.911 E/int. mixture
determined by 1H NMR. Purification by column chromatography on silica gel
[dichloromethane] afforded a 3.9:1 mixture of (E)-5-tributylgennany1-pent-4-en-1-ol (E-
51) and 4-tributy1germanyl-pent-4-en-1-ol (int-51) (245 mg, 74%) as yellow oils. IR
(neat): 3327, 2957, 2924, 2856, 1614, 1464 cm"; 'H NMR (300 MHz, CDCl3) (E) 5 5.92
(dt, J= 18.1, 6.6 Hz, 1 H), 5.75 (d, J= 18.1 Hz, 1 H), 3.65 (t, J= 6.0 Hz, 2 H), 2.20 (q, J
= 7.1 Hz, 2 H), 1.76 (s, 1 H), 1.70 (q, J= 6.6 Hz, 2 H), 1.30 (m, 13 H), 0.90 (m, 14 H),
(int) 5 5.60 (s, 1 H), 5,12 (s, 1 H), 3.65 (t, J= 6.0 Hz, 2 H), 2.20 (q, J= 7.1 Hz, 2 H), 1.76

(s, 1 H), 1.70 (q, J = 6.6 Hz, 2 H), 1.30 (m, 13 H), 0.90 (m, 14 H); 13c NMR (75 MHz,

104

CDC13) (E+int) 5 145.0, 128.3, 62.4, 32.9, 31.7, 27.3, 27.2, 26.4, 13.7, 12.7; HRMS (EI)

m/z 331.2059 [(M+H) calcd for C17H37Ge0 331.2062].

Bu30e’ \\E ;OH
52

Preparation of (E)-1-(2-tributylgermanyl-vinyl)-cyclohexanol (52) (Scheme 4.8,

 

 

entry 4). Applying the representative conditions with Pd(PPh3)4 (30 mg, 0.03 mmol),
tributylgermanium hydride (0.3 mL, 1.2 mmol), 1-ethyny1-cyclohexanol (19) (124 mg,
1.0 mmol) afforded afier column chromatography on silica gel [dichloromethane] (E)-1-
(2-tributylgermany1-vinyl)-cyclohexanol (52) (110 mg, 30%) as a yellow oil. IR (neat):
3370, 2957, 2926, 2855, 1612, 1464 cm"; ‘H NMR (300 MHz, CDC13) 5 6.00 (d, J =
18.6 Hz, 1 H), 5.90 (d, J= 18.6 Hz, 1 H), 1.50 (m, 9 H), 1.28 (m, 14 H), 0.90-0.60 (m, 15
H) ; l3C NMR (75 MHz, CDC13) 5 152.3, 123.5, 72.5, 37.5, 27.3, 26.4, 25.5, 22.1, 13.7,

12.7; HRMS (EI) m/z 369.2229 [(M-H) calcd for C20H3gGe0 369.2217]:

[MM ]

 

 

Preparation of (E)-tributyl-(3,3-dimethyl-but-l-eny1)-germane (53) (Scheme 4.8,
entry 5). Applying the representative conditions with Pd(PPh3)4 (30 mg, 0.03 mmol),
tributylgermanium hydride (0.3 mL, 1.2 mmol), 3,3-dimethyl-but-1-yne (25) (0.12 mL,
1.0 mmol) afforded after column chromatography on silica gel [dichloromethane] (E)-
tributyl-(3,3-dimethy1-but-1-enyl)—germane (53) (235 mg, 73%) as a yellow oil. IR (neat):
1608, 1464 cm"; 'H NMR (300 MHz, CDC13) 5 5.93 (d, J= 18.8 Hz, 1 H), 5.61 (d, J=

18.8 Hz, 1 H), 1.36 (m, 13 H), 1.02 (s, 9 H), 0.91-0.80 (m, 14 H); 13c NMR (75 MHz,

105

CDC13) 5 156.4, 120.0, 35.1, 29.1, 27.3, 26.4, 13.7, 12.8; HRMS (E1) m/z 327.2116 [(M-

H) calcd for C13H37Ge0 327.2110].

M J]\/\
Bu3Ge BU3 Ge

E-54 int-54

 

 

Preparation of (E)-tributyl-hex-1-eny1-germane (E-54) and tributyl-(l-methylene-
pentyl)-germane (int-54) (Scheme 4.8, entry 6). Applying the representative conditions
with Pd(PPh3)4 (30 mg, 0.03 mmol), tributylgermanium hydride (0.3 mL, 1.2 mmol),
pentyne (44) (0.12 mL, 1 mmol) afforded a 3.7:] E/int mixture determined by 1H NMR.
Purification by column chromatography on silica gel [dichloromethane] afforded a 3.7:]
mixture of (E)-tributyl-hex-1-enyl-germane (E-54) and tributyl-(1-methy1ene-pentyl)-
germane (int-54) (244 mg, 78%) as yellow oils. IR (neat): 2986, 1874, 1614, 1464 cm'].
1H NMR (300 MHz, CDC13) (E) 5 5.93 (dt, J= 18.1, 6.0 Hz, 1 H), 5.72 (d, J= 18.1 Hz, 1
H), 2.14 (m, 2 H), 1.30 (m, 14 H), 0.90 (m, 18 H); (int) 5 5.58 (d, J= 1.1 Hz, 1 H), 5.16
(d, J= 1.1 Hz, 1 H), 2.14 (m, 2 H), 1.30 (m, 14 H), 0.90 (m, 18 H); 13C NMR (75 MHz,
CDCl;) 5 151.6 (int), 145.6 (B), 127.1 (E), 121.8 (int), 38.6, 27.1, 26.2, 21.7, 13.4, 13.2,

12.5, 12.1. HRMS (EI) m/z 313.1947 [(M-H) calcd for CansGe 313.1954].

 

M JJ\/
Bu 3Ge OH BU3Ge OH
E-55 int-55

 

Preparation of (E)-3-tributylgermanyl-prop-Z-en-l-ol (E—55) and 2-
tributylgermanyl-prop-2-en-1-ol (int-55) (Scheme 4.8, entry 7). Applying the
representative conditions with Pd(PPh3)4 (30 mg, 0.03 mmol), tributylgermanium hydride
(0.3 mL, 1.2 mmol), propargyl alcohol (45) (0.6 mL, 1 mmol) gave a 1.2:] E/int mixture

determined by 1H NMR. Purification by column chromatography on silica gel

106

[dichloromethane] afforded a 1.2:1 mixture of (E)-3-tributy1germanyl-prop-Z-en—1-ol (E-
55) (126 mg, 42%) 2-tributylgermanyl-prop-2-en-1-ol (int-55) (105 mg, 35%) as yellow
oils. Internal IR (neat): 3316, 2957, 2924, 2872, 2855, 1464 cm'l; 1H NMR (300 MHz,
CDC13) 5 5.81 (d, J= 2.7 Hz, 1 H), 5.25 (d, J= 3.0 Hz, 1 H), 4.30 (s, 2 H), 1.40-1.20 (m,
14 H), 0.90-0.76 (m, 14 H); 13C NMR (75 MHz, CDCl_;) 5 151.4, 120.8, 67.3, 48.7, 27.4,
13.6, 12.5; HRMS (El) m/z 301.1585 [(M-H) calcd for C15H310e0 : 301.1600]; (E)-
isomer IR (neat): 3314, 2957, 2926, 2872, 2855, 1464, 1458 cm"; 1H NMR (300 MHz,
CDC13) 5 6.10 (dt, J= 18.6, 4.4 Hz, 1 H), 6.0 (d, J= 18.6 Hz, 1 H), 4.17 (t, J= 4.5 Hz, 2
H), 1.59 (s, 1 H), 1.40-1.25 (m, 13 H), 0.90-0.70 (m, 14 H); 13c NMR (75 MHz, CDC13)
5 143.8, 128.5, 65.8, 48.7, 27.1, 26.4, 13.8; HRMS (El) m/z 301.1585 [(M-H) calcd for

C|5H31GCO 2 301.1587].

 

Worm) M
B“3Ge \ BU3Ge 0THP

E-56 int-56

 

Preparation of (E)-tributyl-[6-(tetrahydro-pyran-Z-yloxy)-hex-l-enyl]-germane (E-
56) and tributyl-l1-methylene—S-(tetrahydro-pyran-Z-yloxy)-pentyl]-germane (int-
56) (Scheme 4.8, entry 8). Applying the representative conditions with Pd(PPh3)4 (30
mg, 0.03 mmol), tributylgermanium hydride (0.3 mL, 1.2 mmol), 2-hex-5-ynyloxy-
tetrahydro-pyran (46) (330 mg, 1.8 mmol) and tributylgermanium hydride (0.52 mL, 2
mmol) gave a 1.3:1 E/int mixture determined by 1H NMR. Purification by column
chromatography on silica gel [dichloromethane] afforded a 1.3:1 mixture of (E)-tributy1-
[3-(tetrahydro-pyran-2-yloxy)-propenyl]-germane (E-56) and tributyl-[l-(tetrahydro-
pyran-2—yloxymethy1)-vinyl]-gerrnane (int-56) (470 mg, 61%) as yellow oils. 1H NMR

(300 MHz, CDCl3) 5 (E) 5.90 (dt, J= 17.9, 6.7 Hz, 1 H), 5.69 (dt, J= 17.9, 1.3 Hz, 1 H);

107

(1m) 5.54 (m, 1 H), 5.12 (m, 1 H) [E and Int] 4.60 (t, J= 2.7 Hz, 1 H) 3.90-3.84 (m, 1 H),
3.76-3.70 (m, 1 H), 3.50-3.46 (m, 1 H), 3.41-3.36 (m, 1 H), 2.10 (m, 2 H), 1.62-1.40 (m,
10 H), 1.40-1.20 (m, 16 H), 0.90-0.80 (m, 10 H), 0.70 (m, 8 H); HRMS (E1) m/z

429.2800 [(M+H) calcd for C23H47Ge02 : 429.2788].

 

M
BU3Ge OTHP Bu3GcJ\/OTHP
15-57 int-57

 

Preparation of (E)-tributyl-[3-(tetrahydro-pyran-Z-yloxy)-propenyl]-germane (E-
57) and tributyl-[1-(tetrahydro-pyran-Z-yloxymethy1)-viny1]-germane (int-57)
(Scheme 4.8, entry 9). Applying the representative conditions with Pd(PPh3)4 (30 mg,
0.03 mmol), tributylgermanium hydride (0.3 mL, 1.2 mmol), 2-prop-2-ynyloxy-
tetrahydro-pyran (47) (280 mg, 2 mmol) tributylgermanium hydride (0.52 mL, 2 mmol)
gave a 3:1 E/Z mixture determined by lH NMR. Purification by column chromatography
on silica gel [dichloromethane] afforded a 3.0:] mixture of (E)-tributyl-[3-(tetrahydro-
pyran-2-yloxy)-propenyl]-germane (E-57) (362 mg, 47%) and tributyl-[l-(tetrahydro-
pyran-2-yloxymethyl)-viny1]-germane (int-57) (120 mg, 15%) as yellow oils. Internal :
IR (neat): 2957, 2928, 2872, 2855, 1466 cm'l; 1H NMR (300 MHz, CDC13) 5 5.81 (d, J =
2.7 Hz, 1 H), 5.25 (d, J= 3 Hz, 1 H), 4.60 (t, J= 2.5 Hz, 1 H), 4.30 (dt, J= 13.2, 1.3 Hz,
1 H), 4.02 (dt, J= 13.2, 1.9 Hz, 1 H), 3.90-3.80 (m, 1 H), 3.50-3.40 (m, 1 H), 1.90-1.80
(m, 1 H), 1.74-1.70 (m, 1 H), 1.65-1.50 (m, 4 H), 1.37-1.27 (m, 13 H), 0.90-0.76 (m, 14
H); 13C NMR (75 MHz, CDC13) 5 148.5, 122.6, 97.8, 71.8, 61.8, 30.5, 27.2, 26.5, 25.5,
19.3, 13.7, 12.8; HRMS (EI) m/z 387.231 [(M+H): calcd for C17H4oGe02 387.23]; (E) IR
(neat): 2957.25, 2926.32, 2872.4, 2855, 1618, 1466 cm"; ‘H NMR (300 MHz, CDC13) 5

6.01 (m, 2 H), 4.60 (m, 1 H), 4.27-4.23 (m, 1 H), 4.04-4.00 (m, 1 H), 3.90-3.80 (m, 1 H),

108

3.50-3.40 (m, 1 H), 1.90-1.80 (m, 1 H), 1.75-1.70 (m, 1 H), 1.65-1.50 (m, 4 H), 1.37-1.27
(m, 13 H), 0.90-0.76 (m, 14 H); 13C NMR (75 MHz, CDCl3) 5 141.5, 130.8, 98.0, 70.2,
62.5, 48.9, 30.8, 27.5, 26.7, 25.7, 19.8, 13.9, 13.0; HRMS (EI) m/z 387.2310 [(M+H):

calcd for C20H41G602 387.2318].

 

[ ///\OTHP ]
47

 

Preparation of 2-prop-2-ynyloxy-tetrahydro-pyran (47). Propargyl alcohol (35 mL,
600 mmol) was dissolved into CH2C12 (500 mL). DHP (46 mL, 500 mmol) and TsOH
(9.51 g, 50 mmol) were then added. After stirring for 20 h at 25 °C, the reaction was
poured into sat. aq. NaHC03 and then was extracted with CH2C12. The combined
organics were washed with brine, dried (MgSO4), filtered, and concentrated. The
resulting residue was purified by distillation [65 °C at 10 mmHg] to afford tetrahydro-2-
(prop-2-ynyloxy)—2H-pyran (47) (54.01 g, 77%) as a clear liquid. Spectral data were

consistent with a commercial sample.

 

0THP
M ]

 

Preparation of 2-hex-5-ynyloxy-tetrahydro-pyran (46). Hexynol (2) (0.66 mL, 6
mmol) was dissolved into CH2C12 (5 mL). DHP (0.46 mL, 5 mmol) and TsOH (95 mg,
0.5 mmol) were then added. After stirring for 20 h at 25 °C, the reaction was poured into
sat. aq. NaHCO3 and then was extracted with CH2C12. The combined organics were
washed with brine, dried (MgS04), filtered, and concentrated. The resulting residue was
purified by column chromatography on silica gel [dichloromethane] to afford 2-hex-5-
ynyloxy-tetrahydro-pyran (46) (336 mg, 37%) as a clear liquid. 1H NMR (300 MHz,

CDC13) 5 5.20 (s, 0.2 H), 4.45 (t, J= 3.2 Hz, 1 H), 3.76-3.60 (m, 2 H), 3.41-3.25 (m, 2

109

H), 2.13-2.01 (m, 2 H), 1.84 (t, J = 2.6 Hz, 1 H), 1.70-1.38 (m, 10 H); l3‘c NMR (75
MHz, CDC13) 5 98.4, 84.0, 68.2, 66.6, 61.9, 30.4, 28.6, 25.2, 25.1, 19.3, 18.0; HRMS (EI)

m/z 183.1377 [(M+H): calcd for CHH1902 183.1385].

 

 

Bu3oe/\/\0H
555

General conditions for the deprotection of the THP protecting group. Preparation of
(E)-3-tributylgermanyl-prop-Z-en-l-ol (E-55). (5)-Tributyl-[3-(tetrahydro-pyran-2-
yloxy)-propenyl]-germane (E-56) (190 mg, 0.5 mmol) was dissolved in methanol (SmL)
and a few drops of concentrated HCl were added. The mixture was stirred at room
temperature for 3 hours at which time the reaction was completed. The solvent was
removed in vacuo and the residue dissolved in dichloromethane. The organic phase was
washed with water and brine and dried over MgS04, filtered, and concentrated in vacuo
to give (E)-3-tributylgermanyl-prop-2-en-l-ol (E-55) (128 mg, 85%) as a clear oil. IR
(neat): 3314, 2957, 2926, 2872, 2855, 1464, 1458 cm"; 'H NMR (300 MHz, c0013) 5
6.10 (dt, J= 18.6, 4.4 Hz, 1 H), 6.0 (d, J= 18.6 Hz, 1 H), 4.17 (t, J= 4.5 Hz, 2 H), 1.59
(s, 1 H), 1.40-1.25 (m, 13 H), 0.90-0.70 (m, 14 H); 13C NMR (75 MHz, CDC13) 5 143.8,
128.5, 65.8, 48.7, 27.1, 26.4, 13.8; HRMS (El) m/z 301.1585 [(M-H) calcd for

C15H3lGeO : 301.1587].

 

int-55

 

Preparation of 2-tributy1germanyl-prop-Z-en-1-ol (int-55). Applying the above
procedure to tributyl-[1-(tetrahydro-pyran-2-yloxymethyl)-vinyl]-germane (int-56) (190
mg, 0.5 mmol), afforded 2-tributy1germanyl-prop-2-en-l-ol (int-55) (72mg, 47%) as a

clear 011. IR (neat): 3316, 2957, 2924, 2872, 2855, 1464 cm"; 1H NMR (300 MHz,

110

CDC13) 5 5.81 (d, J: 2.7 Hz, 1 H), 5.25 (d, J: 3.0 Hz, 1 H), 4.30 (s, 2 H), 1.40-1.20 (m,
14 H), 0.90-0.76 (m, 14 H); 13c NMR (75 MHz, CDC13) 5 151.4, 120.8, 67.3, 48.7, 27.4,

13.6, 12.5; HRMS (EI) m/z 301.1585 [(M-H) calcd for C15H3lGe0 : 301.1587].

 

BU3GeWOH
E-SO

Preparation of (E)-5-tributylgermanyl-hex-S-en-1-ol (E-50). Applying the above
procedure to tributyl-[6-(tetrahydro-pyran-2-yloxy)-hex-1-enyl]-germane (E—55) (214
mg, 0.5 mmol), afforded 2-t1ibuty1germany1-prop-2-en-1-ol (E-50) (113 mg, 65%) as a
clear oil. 1H NMR (300 MHz, CDC13) 5 5.89 (dt, J = 18.4, 6.0 Hz, 1 H), 5.70 (dt, J =
18.4, 1.4 Hz, 1 H), 3.62 (t, J = 6.3 Hz, 2 H), 2.22 (s, 1 H), 2.22-2.10 (m, 2 H), 1.60-1.20
(m, 16 H), 0.96-0.66 (m, 15 H); 13c NMR (75 MHz, coc13) 5 145.5, 127.7, 62.6, 36.3,
32.1, 27.3, 26.5, 25.0, 13.6, 12.8; HRMS (E1) m/z 345.2213 [(M+H) calcd. for

C13H39GCO 345.2213].

 

int-50

 

Preparation of 5-tributylgermanyl-hex-S-en-l-ol (int-50). Applying the representative
procedure to tributyl-[1-methylene-5-(tetrahydro-pyran-2-yloxy)-pentyl]-germane (int-
55) (214 mg, 0.5 mmol), afforded 2-tributylgermanyl-prop-2-en-1-ol (int-50) (83mg,
48%) as a clear oil. 1H NMR (300 MHz, CDC13) 5 5.56 (dt, J = 2.6, 1.3 Hz, 1 H), 5.14
(dt, J = 2.6, 1.3 Hz, 1 H), 3.62 (t, J = 6.3 Hz, 2 H), 2.22 (s, 1 H), 2.22-2.10 (m, 2 H),
1.60-1.20 (m, 16 H), 0.96-0.66 (m, 15 H). 13'C NMR (75 MHz, CDC13) 5 152.3, 122.6,
62.6, 37.3, 32.2, 27.3, 26.4, 24.7, 13.7, 12.3; HRMS (E1) m/z 345.2213 [(M+H) calcd. for

C13H390e0 345.2213].

111

 

[ n/xon]

 

Preparation of (E)-4-iodo-2-methyl-but-3-en-2-ol (59) (Scheme 4.9). (E)-2-Methyl-4-
tributylgermanyl-but-3-en-2-ol (49) (63 mg, 0.2 mmol) and iodide (50 mg, 0.2 mmol)
were dissolved in dichloromethane (10 mL) and stirred at 25 °C for 90 minutes. A
solution of sodium thiosulfate was added to the reaction and the product was extracted
with ether. The organic phase was washed with brine, dried over MgS04, filtered, and
concentrated in vacuo to afford (E)-4-iodo-2-methy1-but-3-en-2-ol and unreacted (E)-2-
methyl—4-tributylgermanyl-but-3-en-2-ol (59) (85 mg, 30% weight of product, 60%).

Spectroscopic data were consistent with the previously reported product.83

Ph3Ge/\><OH ]
60

 

 

Representative procedure for the formation of triphenylgermanes. Preparation of
(E)-2-methyI-4-triphenylgermanyl-but-3-en-2-ol (60) (Scheme 4.11, entry 1).
Pd(PPh3)4 (20 mg, 0.02 mmol) was dissolved in THF (10 mL). 2-methy1-but-3-yn-2-ol
(l) (0.1 mL, 1 mmol) was then added followed by triphenylgermanium hydride (306 mg,
1.0 mmol). The reaction was stirred at room temperature for 8 hours and then sodium
hydroxide (1N) was added. The mixture was stirred for 30 minutes and the product was
extracted with ether. The organic extracts were washed with brine, dried with MgS04,
filtered, and concentrated in vacuo. The product was chromatographed on silica gel
[dichloromethane] to afford 2-methyl-4-tripheny1gerrnanyl-but-3-en-2-ol (60) (355 mg,
91%) as a yellow oil. 1H NMR (300 MHz, CDCl3) 5 7.69-7.65 (m, 6 H), 7.51-7.46 (m, 9

H), 6.59 (d, J: 18.3 Hz, 1 H), 6.75 (d, J= 18.3 Hz, 1 H), 1.96 (s, 1 H), 1.48 (8,6 H). '3C

112

NMR (75 MHz, CDCl3) 5 156.7, 136.4, 134.9, 128.9, 128.1, 119.2, 72.1, 29.4;

Spectroscopic data were consistent with those previously reported.34b

/\/\/\/0H M
”‘306 \ Ph3Ge 0H

E-61 int-61

 

 

Preparation of (E)-6-triphenylgermanyl-hex-S-en-l-ol (E-61) and 5-
tributylgermanyl-hex-S-en-l-ol (int-61) (Scheme 4.11, entry 2). Applying the
representative conditions with Pd(PPh3)4 (20 mg), triphenylgermanium hydride (306 mg,
1.0 mmol) and 6-hexynol (2) (0.11 mL, 1 mmol) gave a 4:1 E/int mixture determined by
lH NMR. Purification by column chromatography on silica gel [dichloromethane] afford
a 4.0:] mixture of 6-tributy1germanyl-hex-5-en-1-ol (E61) and 5-triphenylgermanyl-hex-
5-en-1-ol (int-61) (254 mg, 63%) as a yellow oil. lH NMR (300 MHz, CDCl3) 5 (E) 7.65-
7.2 (m, 15 H), 6.31 (d, J= 18.4 Hz, 1 H), 6.20 (dt, J= 18.4, 5.2 Hz, 1 H), 3.70 (t, J= 5.8
Hz, 2 H), 2.44-2.28 (m, 2 H), 1.72-1.45 (m, 4 H). (int) 7.65-7.2 (m, 15 H), 6.00 (m, 1 H),
5.51 (m, 1 H), 3.52 (t, J = 6.0 Hz, 2 H), 2.44-2.28 (m, 2 H), 1.72-1.45 (m, 4 H).

Spectroscopic data were consistent with those previously reported. 34"

Representative procedure for the initial Stille type cross-coupling. Preparation of
(Z)-2-methyl-4-phenyl-but-3-en-2-ol (24) (Scheme 4.12, entry 1). Pd2dba3 (18 mg, 0.02
mmol) was dissolved in NMP (5 mL) and AsPh3 (25 mg, 0.08 mmol) was added. The
mixture was stirred for 30 minutes. (E)-2-Methyl-4-tributy1germanyl-but-3-en-2-ol (49)
(33 mg, 0.1 mmol) was then added followed by phenyl bromide (0.2 mL, 0.2 mmol) and

the reaction was stirred at 70 °C for 48 hours. Then NaOH (1N) was added and the

113

reaction stirred for 30 minutes. The mixture was extracted with ether and the organic
phases were washed with water and brine, dried over MgS04, filtered, and concentrated
in vacuo. The product was purified by column chromatography [EtOAc/hexanes: 20/80]
to afford (Z)-2-methyl-4-phenyl-but-3-en-2-ol (24) (4.5 mg, 28%) as a clear oil.

Spectroscopic data were consistant with those previously reported.70

[ Ph30e/\><0H J
60

 

 

Preparation of (E)-2-methyl-4-triphenylgermanyl-but-3-en-2-ol (59) (Scheme 4.12,
entry 2). Pd2dba3 (18 mg, 0.02 mmol) was dissolved in NMP (5 mL) and AsPh3 (25 mg,
0.08 mmol) was added and the mixture stirred for 30 minutes. (E)-2-Methyl-4-
triphenylgermanyl-but-3-en-2-ol (60) (39 mg, 0.1 mmol) was then added followed by
phenyl bromide (0.2 mL, 0.2 mmol) and the reaction was heated to 70 °C for 48 hours.
Then NaOH (1N) was added and the reaction stirred for 30 minutes. The mixture was
extracted with ether and the organic phases were washed with water and brine, dried over
MgS04, filtered, and concentrated in vacuo. The product was purified by column
chromatography [EtOAc/hexanes : 8/2] to afford (E)-2-methyl-4-triphenylgerrnanyl-but-
3-en-2-ol (59) (23 mg, 70%) as a yellow oil. For spectroscopic data see page 109.

Method for the screening of Stille type catalysts (Scheme 4.15). The palladium source
(10 mol%) and the ligand (40 mol%) were dissolved in the selected solvent and allowed
to stir for 30 minute. When an additive was needed (20 mol%) it was added at this time
and the solution allowed to stir for another 10 minutes. The germane (0.1 mmol) was then
added followed by phenyl iodide (0.2 mmol). The reaction was stirred at 60 °C for 16
hours and then quenched at room temperature with saturated ammonium hydroxide and

extracted with ether. The combined organic phases were washed with water and brine,

114

dried over MgS04, filtered, and concentrated in vacuo. The organic phase was dissolved
in deuterated chloroform, with methanol (0.1 mmol) as an internal standard and the yield
was measured by 1H NMR.

Method for the screening of Heck type catalysts (Scheme 4.16). The additive (0.1
mmol) and the base (0.25 mmol) were dissolved and stirred for 15 minutes in the solvent.
The germane (0.1 mmol), the ligand (20 mol%), and phenyl iodide (0.2 mmol) were
added and the mixture stirred for 15 minutes. Then palladium acetate (2.5 mg, 0.01
mmol) was added and the reaction was stirred at 60 °C for 16 hours. The reaction was
quenched at room temperature with saturated ammonium hydroxide and extracted with
ether. The combined organic fractions were washed with water and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The solution was dissolved in deuterated
chloroform, with methanol (0.1 mmol) as an internal standard and the yield was
measured by ‘H NMR.

Method for the screening of temperature of reaction (Scheme 4.17). TBABr (32 mg,
0.1 mmol) and K2C03 (35 mg, 0.25 mmol) were dissolved and stirred for 15 minutes in a
mixture of acetonitrile and water (9:1). (E)-2-Methyl-4-tributylgermanyl-but-3-en-2-ol
(49) (33 mg, 0.1 mmol), triphenyl phosphine (9 mg, 0.04 mmol), and phenyl iodide (0.1
mL, 0.2 mmol) were added and the mixture stirred for 15 minutes. Then palladium
acetate (5 mg, 0.02 mmol) was added and the reaction was stirred at various temperatures
for 16 hours. The reaction was quenched at room temperature with saturated ammonium
hydroxide and extracted with ether. The combined organic fractions were washed with

water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The solution was

115

dissolved in deuterated chloroform, with methanol (0.1 mmol) as an internal standard and
the yield was measured by 1H NMR.

Method for the screening of catalyst loading (Scheme 4.18). TBABr (32 mg, 0.1
mmol) and K2C03 (35 mg, 0.25 mmol) were dissolved and stirred for 15 minutes in a
mixture of acetonitrile and water (9:1). (E)-2-Methyl-4-tributy1germanyl-but-3-en-2-ol
(49) (33 mg, 0.1 mmol), triphenyl phosphine (twice the amount of palladimn), and phenyl
iodide (0.2 mmol) were added and the mixture stirred for 15 minutes. Then palladium
acetate was added and the reaction was stirred at 60 °C for 16 hours. It was then
quenched at room temperature at room temperature with saturated ammonium hydroxide,
extracted with ether, and washed with water and brine. The solution was dried over
MgSO4, filtered, and the solvent was concentrated in vacuo. The solution was dissolved
in deuterated chloroform, and methanol (0.1 mmol) was added as an internal standard and

the yield was measured by 1H NMR.

 

Representative conditions A for Stille cross-coupling. Preparation of (Z)-2-methy1-4-
phenyl-but-3-en-2-ol (24) (Scheme 4.19, entry 1). Pd2dba3 (18 mg, 0.02 mmol) and
AsPh3 (24 mg, 0.08 mmol) were dissolved in NMP (SmL) and that mixture stirred for 30
minutes. (E)-2-Methyl-4-tributylgermanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol) was
added followed by phenyl iodide (0.1 mL, 0.2 mmol). The reaction was stirred at 70 °C
for 48 hours. The mixture was cooled, quenched at room temperature with saturated
ammonium hydroxide, and extracted with ether. The organic fractions were washed with

water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was

116

 

 

purified by column chromatography on silica gel [hexane/EtOAc: 9/ 1] to give (2)-2-
methyl-4-phenyl-but-3-en-2-ol (24) as a yellowish oil (5 mg, 30%). Spectroscopic data

were consistant with those previously reported.70

Representative conditions B for Stille cross-coupling. Preparation of (Z)-2-methyI-4-
phenyl-but-3-en-2-ol (24) (Scheme 4.19, entry 1). Pd(0Ac)2 (5 mg, 0.02 mmol) and
AsPh3 (24 mg, 0.08 mmol) were dissolved in NMP (5 mL) and that mixture stirred for 30
minutes. (E)-2-Methy1-4-tributy1germanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol) was
added followed by phenyl iodide (0.1 mL, 0.2 mmol). The reaction was stirred at 70 °C
for 48 hours. The mixture was cooled, quenched at room temperature with saturated
ammonium hydroxide, and extracted with ether. The organic fractions were washed with
water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was
purified by column chromatography on silica gel [hexane/EtOAc: 9/ 1] to give (2)-2-
methyl-4-phenyl-but-3-en-2-ol (24) as a yellowish oil (4 mg, 25%). Spectroscopic data

were consistant with those previously reported.70

 

Representative conditions C Heck cross-coupling. Preparation of (Z)-2-methyI-4-
phenyl-but-3-en-2-ol (24) (Scheme 4.19, entry 1). TBABr (32 mg, 0.1 mmol) and
K2C03 (35 mg, 0.25 mmol) were dissolved in a mixture of acetonitrile and water (9:1, 2
mL) and stirred for 15 minutes. (E)-2-Methy1-4-tributylgermanyl-but-3-en-2-ol (49) (33

mg, 0.1 mmol), triphenyl phosphine (9 mg, 0.04 mmol), and phenyl iodide (0.1 mL, 0.2

117

mmol) were added and the mixture stirred for 15 minutes. Then Pd(0Ac)2 (5 mg, 0.02
mmol) was added and the reaction was stirred at 70 °C for 16 hours. The mixture was
cooled, quenched at room temperature with saturated ammonium hydroxide, and
extracted with ether. The organic fractions were washed with water and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The product was purified by column
chromatography on silica gel [hexane/EtOAc: 9/ 1] to give (Z)-2-methy1-4-pheny1-but-3-
en—2-ol (24) as a yellowish oil. (8 mg, 47%). Spectroscopic data were consistant with

those previously reported.70

Preparation of (Z)-2-methyl-4-phenyl-but-3-en-2-ol (24) (Scheme 4.19, entry 2).
Applying conditions A with Pd2dba3 (18 mg, 0.02 mmol), AsPh3 (24 mg, 0.08 mmol),
(E)-2-methyl-4-tributylgennanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol), and phenyl
bromide (0.1 mL, 0.2 mmol) afforded (Z)-2-methyl-4-phenyl-but-3-en-2-ol (24) as a
yellowish oil (45 mg, 28%). Spectroscopic data were consistant with those previously

reported.70

 

Preparation of (Z)-2-methyl-4-phenyl-but-3-en-2-ol (24) (Scheme 4.19, entry 2).
Applying conditions B with Pd(0Ac)2 (5 mg, 0.02 mmol), AsPh3 (24 mg, 0.08 mmol),
(E)-2-methyl-4-tributy1germanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol) and phenyl
bromide afforded (Z)-2-methyl-4-phenyl-but-3-en-2-ol (24) as a yellowish oil (4.2 mg ,

28%). Spectroscopic data were consistant with those previously reported.70

118

Preparation of (Z)-2-methyl-4-phenyl-but-3-en-2-ol (24) (Scheme 4.19, entry 2).
Applying conditions C with TBABr (32 mg, 0.1 mmol), K2C03 (35 mg, 0.25 mmol),
triphenyl phosphine (9 mg, 0.04 mmol), Pd(0Ac)2 (5 mg, 0.02 mmol), (E)-2-methy1-4-
tributylgermanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol) and phenyl bromide afforded (Z)-
2-methyl-4-phenyl-but-3-en-2-ol (24) as a yellowish oil (4.1 mg, 26%). Spectroscopic

data were consistant with those previously reported.70
Me0 OH
/
10

Preparation of (Z)-4-(4-methoxy-phenyl)-2-methyl-but-3-en-2-ol (10) (Scheme 4.19,

 

 

entry 3). Applying conditions A with Pd2dba3 ( 18 mg, 0.02 mmol), AsPh3 (24 mg, 0.08
mmol), (E)-2-methyl-4-tributylgerrnanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol) and p-

bromoanisole (0.25 mL, 0.2 mmol) afforded no product.
MeO
U)”
10 ]

Preparation of (2)-4-(4-methoxy-phenyl)-2-methyl-but-3-en-2-ol (10) (Scheme 4.19,

 

 

entry 3). Applying conditions C with TBABr (32 mg, 0.1 mmol), K2C03 (35 mg, 0.25
mmol), triphenyl phosphine (9 mg, 0.04 mmol), Pd(0Ac)2 (5 mg, 0.02 mmol), (E)-2-
methyl-4-tn'butylgermanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol), and p-bromoanisole
(0.25 mL, 0.2 mmol) afforded (Z)-4-(4-methoxy-pheny1)-2-methyl-but-3-en-2-ol (10) (5

mg, 27%). 'H NMR (300 MHz, CDC13) 5 7.31 (d, J= 7.9 Hz, 2 H), 6.85 (d, J: 7.9 Hz, 2

119

H), 6.38 (d, J = 12.4 Hz, 1 H), 5.69 (d, J = 12.4 Hz, 1 H), 3.80 (s, 3 H), 1.37 (s, 6 H).

Spectroscopic data were consistent with those previously reported.84

 

fl

0

OH
/

11

 

 

 

Prepation of (Z)-1-[4-(3-hydroxy-3-methyl-but-1-enyl)-pheny1]-ethanone (11)
(Scheme 4.19, entry 4). Applying conditions B with Pd(0Ac)2 (5 mg, 0.02 mmol),
AsPh3 (24 mg, 0.08 mmol), (E)-2-methyl-4-tributylgennanyl-but-3-en-2-ol (49) (33 mg,
0.1 mmol), and p-bromo acetophenone (40 mg, 0.2 mmol) afforded (Z)-4-(4-methoxy-
phenyl)-2-methy1-but-3-en-2-ol (11) (6 mg, 31%). 1H NMR (300 MHz, CDCl3) 5 7.90 (d,
J= 8.2 Hz, 2 H), 7.47 (d, J= 8.2 Hz, 2 H), 6.45 (d, J= 13.1 Hz, 1 H), 5.83 (d, J= 13.1
Hz, 1 H), 2.60 (s, 3 H), 1.38 (s, 1 H), 2.66 (s, 6 H); 13C NMR (75 MHz, CDC13) 5 197.5,
140.4, 135.0, 129.1, 127.5, 126.7, 71.6, 30.7, 29.5, 26.2; HRMS (E1) m/z 204.1151
[(M+): calc. for C13H1602 204.1150]. Spectroscopic data were consistent with those

previously reported.85

 

[o 8

OH
/

11

 

 

 

Prepation of (Z)-l-[4-(3-hydroxy-3-methyl-but-l-enyl)-phenyl]-ethanone (11)
(Scheme 4.19, entry 4). Applying conditions C with TBABr (32 mg, 0.1 mmol), K2C03
(35 mg, 0.25 mmol), triphenyl phosphine (9 mg, 0.04 mmol), Pd(0Ac)2 (5 mg, 0.02
mmol), (E)-2-methyl-4-tributylgermanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol), and p-
bromo acetophenone (40 mg, 0.2 mmol) afforded (Z)-4-(4-methoxy-phenyl)-2-methy1-

but-3-en-2-ol (11) (12 mg, 61%). See above for spectroscopic data.

120

 

Representative procedure for the cross-coupling of tributyl germanes. Preparation

 

of (Z)-2-methyl-4-p-tolyl-but-3-en-2-ol (62) (Scheme 4.20, entry 3). TBABr (32 mg,
0.1 mmol) and K2C03 (35 mg, 0.25 mmol) were dissolved in a mixture of acetonitrile and
water (9:1) and stirred for 15 minutes. (E)-2-Methyl-4-tributylgermanyl-but—3-en-2-ol
(49) (33 mg, 0.1 mmol), triphenyl phosphine (9 mg, 0.04 mmol), and phenyl iodide (0.2
mmol) were added and the mixture stirred for 15 minutes. Then Pd(0Ac)2 (5 mg, 0.02
mmol) was added and the reaction was stirred at 70 °C for 16 hours. It was then
quenched at room temperature with saturated ammonium choride, extracted with ether,
and washed with water and brine. The solution was dried over MgSO4, filtered, and the
solvent was concentrated in vacuo. The solution was purified by column chromatography
on silica gel [hexane/EtOAc : 9/ 1] to give (Z)-2-methyl-4-phenyl-but-3-en-2-ol (62) as a
yellowish oil (7 mg, 41%). lH NMR (300 MHz, CDC13) 5 7.24 (d, J = 9 Hz, 2 H), 7.12
(d, J= 9 Hz, 2 H), 6.42 (d, J= 13 Hz, 1 H), 5.72 (d, J= 13 Hz, 1 H), 2.33 (s, 3 H), 1.60
(s, 1 H), 1.36 (s, 6 H); 13C NMR (75 MHz, CDC13) 5 139.2, 136.8, 134.7, 129.1, 128.9,
128.1, 72.2, 31.4, 21.3. LRMS (M+: 176.1): 176.0, 161.1, 105 (100), 43.3. Spectroscopic

data were consistent with those reported in the literature.86

121

 

fl

0 0
Me0 OH MeO
/ / OH
Z-63 E-63

Preparation of (Z)-4-(3-hydroxy-3-methyl-but-1-enyl)-benzoic acid methyl ester (Z-

 

 

 

63) and (E)-4-(3-hydroxy-3-methy1-but-l-eny1)-benzoic acid methyl ester (E-63)
(Scheme 4.20, entry 6). Applying the representative conditions with TBABr (32 mg, 0.1
mmol), K2C03 (35 mg, 0.25 mmol), triphenyl phosphine (9 mg, 0.04 mmol), Pd(0Ac)2 (5
mg, 0.02 mmol), (E)-2-methyl-4-tributylgermanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol),
and 4-bromo-benzoic acid methyl ester (42 mg, 0.2 mmol) afforded a 4.7:1 mixture of
Z/E determined by 1H NMR. Purification by column chromatography on silica gel
[EtOAc/hexanes: 1/9] afforded a 4.7:] mixture of (2)-4-(3-hydroxy-3-methyl-but-1-
enyl)-benzoic acid methyl ester (Z-63) and (E)-4-(3-hydroxy-3-methyl-but-1-enyl)-
benzoic acid methyl ester (int-63) (15 mg, 68%) as a yellow oil. IR (neat): 3491, 2972,
2930, 1722, 1606 cm"; (E) 'H NMR (300 MHz, CDC13) 5 8.00 (d, J: 6.6 Hz, 2 H), 7.45
(d, J= 6.6 Hz, 2 H) 6.80 (dd, J= 15.7, 16.1 Hz, 2 H), 3.93 (s, 3 H), 1.46 (s, 6 H). (Z) 1H
NMR (300 MHz, CDC13) 5 8.00 (d, J = 8.3 Hz, 2 H), 7.44 (d, J = 8.3 Hz, 2 H), 6.45 (d, J
= 12.4 Hz, 1 H), 5.83 (d, J= 12.4 Hz, 1 H), 3.92 (s, 3 H), 1.38 (s, 6 H); 13C NMR (75
MHz, CDC13) 5 (Z) 166.9, 142.5, 140.6, 129.2, 129.1, 129.0, 127.1, 72.0, 52.0, 31.0;

LRMS (M+: 220.11): 220.2, 205.2 (100), 178.2, 173.1, 149.0, 91.1, 59.0.

122

 

fi

02N OH 02N

Z-64 E-64

 

 

 

Preparation of (2)-2-methyl-4-(4-nitro-phenyl)-but-3-en-2-ol (Z-64) and (E)-2-
methyl-4-(4-nitro-phenyl)-but—3-en-2-ol (E-64) (Scheme 4.20, entry 7). Applying the
representative conditions with TBABr (32 mg, 0.1 mmol), K2C03 (35 mg, 0.25 mmol),
triphenyl phosphine (9 mg, 0.04 mmol), Pd(0Ac)2 (5 mg, 0.02 mmol), (E)-2-methyl-4-
tributylgermanyl-but-3-en-2-ol (49) (33 mg, 0.1 mmol), and 4-bromo-nitro benzene (40
mg, 0.2 mmo) afforded a 4.621 mixture of Z/E products determined by 1H NMR.
Purification by column chromatography on silica gel [EtOAc/hexanes: 1/9] afforded a
4.6:] mixture of (Z)-4-(3-hydroxy-3-methyl-but-1-enyl)-benzoic acid methyl ester (Z-64)
and (E)-4-(3-hydroxy-3-methyl-but-1-enyl)-benzoic acid methyl ester (E-64) (11.5 mg,
56%). IR (neat): 1595, 1516, 1342 cm]; (E) 1H NMR (300 MHz, CDC13) 5 8.19 (d, J=
8.8 Hz, 2 H), 7.51 (d, J= 8.8 Hz, 2 H) 6.64 (dd, J= 8.9, 16.0 Hz, 2 H), 1.46 (s, 6 H). (Z)
lH NMR (300 MHz, CDC13) 5 8.19 (d, J= 8.8 Hz, 2 H), 7.51 (d, J= 8.8 Hz, 2 H), 6.32
(d, J = 12.8 Hz, 1 H), 5.82 (d, J = 12.8 Hz, 1 H), 1.46 (s, 6 H). l3C NMR (75 MHz,
CDCl;;) 5 (Z) 146.4, 144.5, 141.6, 130.2, 126.1, 122.9, 72.1, 31.0; HRMS (E1) m/z

207.0900 [(M+) calcd. for C ”H13N03 207.0895].

0
OH
/

65

 

 

 

Preparation of (Z)-l-{4-[2-(1-hydroxy-cyclohexyI)-vinyl]-phenyl}-ethanone (65)
(Scheme 4.20, entry 12). Applying the representative conditions with TBABr (32 mg,

0.1 mmol), K2C03 (35 mg, 0.25 mmol), triphenyl phosphine (9 mg, 0.04 mmol),

123

Pd(0Ac)2 (5 mg, 0.02 mmol), (E)-1-(2-tributylgermanyl-vinyl)-cyclohexanol (52) (37
mg, 0.1 mmol), and p-bromo acetophenone (40 mg, 0.2 mmol) afforded (Z)-4-(3-
hydroxy-3-methy1-but-1-enyl)-benzoic acid methyl ester (65) (15 mg, 61%). IR (neat):
3466, 2930, 2855, 1680, 1603 cm'l. 'H NMR (300 MHz, CDCl3) 5 7.90 (d, J= 8.3 Hz, 2
H), 7.52 (d, J= 8.3 Hz, 2 H), 6.49 (d, J= 12.5 Hz, 1 H), 5.80 (d, J= 12.5 Hz, 1 H), 2.60
(s, 3 H), 1.70- 1.20 (m, 10 H). l3C NMR (75 MHz, CDCl;;) 5 197.4, 142.6, 140.0, 135.0,
129.2, 127.6, 127.6, 72.5, 38.4, 26.0, 24.9, 21.6; HRMS m/z 244.1464 [(M+) calcd. for

C 16H2002 244.1463].

 

int-67 E-67 Z-67

 

 

Preparation of 1-[4-(4-hydroxy-l-methylene-butyl)-phenyl]-ethanone (int-67) (E)-l-
[4-(5-hydroxy-pent-1-enyl)-pheny1]-ethanone (E-67) and (Z)-1-[4-(5-hydroxy-pent-1-
enyl)-phenyl]-ethanone (Z-67) (Scheme 4.21, entry 3). Applying the representative
conditions with TBABr (32 mg, 0.1 mmol), K2C03 (35 mg, 0.25 mmol), triphenyl
phosphine (9 mg, 0.04 mmol), Pd(0Ac)2 (5 mg, 0.02 mmol), (E)-5-tributy1germanyl-
pent-4-en-1-ol and 4-tributylgermanyl-pent-4-en-1-ol (51) (3.9:1 ratio, 33 mg, 0.1 mmol),
and p-bromo acetophenone (40 mg, 0.2 mmol) afforded a 4:1 :20 Z/E/int. ratio determined
by 1H NMR of 1-[4-(4-hydroxy-1-methy1ene-buty1)-phenyl]-ethanone (int-67) (E)-1-[4-
(S-hydroxy-pent-1-enyl)-pheny1]-ethanone (EM) and (Z)-1-[4-(5-hydroxy-pent-1-enyl)-
phenyl]-ethanone (Z-67) (10 mg, 49%). 1H NMR (300 MHz, CDC13) 5 (Z) 6.50 (d, J =
11.5 Hz, 1 H), 5.80 (dt, J = 11.5, 7.7 Hz, 1 H) (int) 5.40 (s, 1 H), 5.20 (s, 1 H), (Z+int)

3.70 (t, J = 6.0 Hz, 3 H), 2.62 (m, 2 H), 2.61 (s, 3 H), 1.76 (m, 2 H), 1.46 (br. s, 1 H);

124

HRMS (E1) m/z 204.1142 [(M+) calcd. for C13H1602 204.1150]. Spectroscopic data

were consistent with those previously published. 87

 

int-16 E-16 Z-16

Preparation of 5-phenyl-hex-5-en-1-ol (int-l6), (li')-6-phenyl-hex-5-en-1-ol (E-16)
and (Z)- 6-phenyl-hex-5-en-l-ol (Z-16) (Scheme 4.21, entry 4). Applying the
representative procedure with TBABr (32 mg, 0.1 mmol), K2C03 (35 mg, 0.25 mmol),
triphenyl phosphine (9 mg, 0.04 mmol), Pd(0Ac)2 (5 mg, 0.02 mmol), (E)-6-
tributylgermanyl-hex-S-en-l-ol and 5-tributy1germany1-hex-5-en-1-ol (50) (4:1 E/Z, 34
mg, 0.1 mmol) afforded a 5.2:] :19 Z/E/Int mixture determined by 1H NMR of S-phenyl-
hex-S-en-l-ol (int-18), (E)- 6-phenyl-hex-5-en-1-ol (E-l8) and (Z)- 6-pheny1-hex-5-en-1-

ol (Z-18) (6 mg, 35%). For spectroscopic data see page 96.

 

—.

int-68 B68 0 Z-68

 

 

 

Preparation of l-[4-(4-hydroxy-1-methy1ene-penty1)-phenyl]-ethanone (int-69) (E)-
1-[4-(5-hydroxy-hex-1-enyl)-phenyl]-ethanone (E-69) and (2)-1-[4-(5-hydroxy-hex-l-
enyl)-phenyl]-ethanone (Z-69) (Scheme 4.21, entries 5 and 6). Applying the
representative procedure with TBABr (32 mg, 0.1 mmol), K2C03 (35 mg, 0.25 mmol),
triphenyl phosphine (9 mg, 0.04 mmol), Pd(0Ac)2 (5 mg, 0.02 mmol), (E)-6-
tributylgermanyl-hex-S-en-1-ol and 5-tributylgermanyl-hex-5-en-1-ol (50) (4:1 E/Z, 34
mg, 0.1 mmol,) and p-bromo acetophenone (40 mg, 0.2 mmol) afforded a 5.2:1:19

Z/E/Int mixture determined by 1H NMR of 1-[4-(4-hydroxy-1-methy1ene-pentyl)-

125

phenyl]-ethanone (int-69) (E)-1-[4-(5-hydroxy-hex-1-enyl)-phenyl]-ethanone (E-69) and
(Z)-1-[4-(5-hydroxy-hex-l-enyl)-phenyl]-ethanone (Z—69) (7 mg, 42%).1H NMR (300
MHz, CDCl3) 5 (E) 7.87 (d, J= 8.4 Hz, 2 H), 7.39 (d, J= 8.4 Hz, 2 H), 6.42 (d, J= 15.9
Hz, 1 H), 6.35 (dt, J= 15.9, 6.6 Hz, 1 H) (Z) 7.90 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4
Hz, 2 H), 6.44 (d, J= 11.5 Hz, 1 H), 5.77 (dt, J= 11.5, 5.8 Hz, 1 H), 3.67 (t, J= 6.1 Hz, 2
H) (int) 7.90 (d, J= 8.4 Hz, 2 H), 7.46 (d, J= 8.4 Hz, 2 H), 5.36 (s, 1 H), 5.17 (s, 1 H),
3.62 (t, J= 6.6 Hz, 2 H), 2.58 (s, 3 H), 2.54 (m, 2 H), 1.68-1.49 (m, 4 H), 1.20 (br s, 1 H);
13C NMR (75 MHz, CDC13) 5 197.6, 147.4, 145.9, 135.9, 128.4, 128.2, 126.2, 114.4,

62.6, 34.8, 32.2, 24.3; LRMS (M+: 176.1): 176.0, 161.1, 133.2 (100)

 

.—

OTHP \ 4OTHP 4 0THP
4
O O

int-69 E-69 Z-69

 

 

Preparation of 1-{4-[l-methylene-S-(tetrahydro-pyran-2-yloxy)-pentyl]-pheny1}-
ethanone (int-69), (E)-l-{4-[6-(tetrahydro-pyran-Z-yloxy)-hex-l-enyl]-pheny1}-
ethanone (E-69) an (Z)- 1-{4-[6-(tetrahydro-pyran-2-yloxy)-hex-1-enyl]-phenyl}-
ethanone (Z-69) (Scheme 4.21, entries 8 and 9). Applying the representative procedure
with TBABr (32 mg, 0.1 mmol), K2C03 (35 mg, 0.25 mmol), triphenyl phosphine (9 mg,
0.04 mmol), Pd(0Ac)2 (5 mg, 0.02 mmol), (5)-tributyl-[6-(tetrahydro-pyran-2-yloxy)-
hex-1-enyl]-germane (E-56) and tributyl-[1-methylene-5-(tetrahydro-pyran-Z-yloxy)-
pentyl]-germane (int-56) (43 mg, 0.1 mmol), and p-bromo acetophenone (40 mg, 0.2
mmol) afforded a 5.2:1 : 19 Z/E/Int mixture determined by 1H NMR of 1-{4-[1-methylene-
5-(tetrahydro-pyran-2-yloxy)-pentyl]-pheny1} -ethanone (int-69), (E)-1 - { 4- [6-(tetrahydro-

pyran-2-yloxy)-hex-1-enyl]-pheny1}-ethanone (E-69) and (Z)— 1-{4-[6-(tetrahydro-pyran-

126

2-yloxy)-hex-1-enyl]-phenyl}-ethanone (Z-69) (41%, determined by 1H NMR with an

internal standard).

 

m,oe—:——3(

OH
71

 

Preparation of 2-methyl-4-tributylgermanyl—but-3-yn-2-ol (71) (Scheme 4.25). 2-
Methyl-but-3-yn-2-ol (l) (0.6 mL, 6 mmol) was dissolved in THF (10 mL) and cooled to
0 °C. A solution of n-butyl lithium (1.6 M in hexanes, 8.8 mL, 12.8 mmol) was added
dropwise to the solution. The mixture was allowed to stir for 10 minutes at which time
tributyl bromo germane (2.0 g, 6 mmol) was added dropwise and the reaction was stirred
at room temperature for 6 hours. The solution was then quenched at room temperature by
a saturated solution of ammonium chloride and extracted with ether. The organic phase
was washed with water and brine, dried over MgS04, filtered, and concentrated in vacuo.
After purification by column chromatography on silica gel [dichloromethane] 2-methyl-
4-tributylgermanyl-but-3-yn-2-ol (71) was obtained as a yellow oil (2.0 g, 98%). 'H
NMR (300 MHz, CDC13) 5 2.07 (s, 1 H), 1.50 (s, 6 H), 1.44-1.30 (m, 13 H), 0.99-0.82
(m, 14 H). 13C NMR (75 MHz, CDC13) 5 111.1, 84.0, 65.4, 31.6, 27.2, 25.9, 13.9, 13.6.

Spectroscopic data were consistent with those previously reported. 34b

[sac-5. ]

Z-49

 

Preparation (2)-2-methyl-4-tributylgermanyl-but-3-en-2-ol (Z-49) (Scheme 4.26).
Cyclohexene (0.6 mL, 6 mmol) in THF (2mL) was added to an ice cold solution of
BH3'DMS (2 M in THF, 1.5 mL, 3 mmol). The solution was stirred for 1 hour while the

temperature was maintained between 0 and 5 °C during which time a white solid

127

precipitates. The reaction was then cooled to -10 °C and 2-methy1-4-tributylgermanyl-
but-3-yn-2-ol (70) (500 mg, 1.5 mmol) in THF (2 mL) was added dropwise. Once the
addition was complete the solution was warmed to 10 °C. The precipitate dissolved and
the reaction was stirred for 30 minutes at 10 °C. Then acetic acid was added (3 mL) and
the reaction was stirred at room temperature for 3 hours. Water was added and the
mixture was extracted with ether. The organic phase was washed with water and brine,
dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by
column chromatography [dichloromethane] to afford (Z)-2-methyl-4-tributylgerrnanyl-
but-3-en-2-ol (Z-49) (317 mg, 63%). 1H NMR (300 MHz, CDC13) 5 6.43 (d, J = 13.6 Hz,
1 H), 5.53 (d, J= 13.6 Hz, 1 H), 1.31 (s, 6 H), 1.40-1.28 (m, 13 H), 0.88-0.82 (m, 14 H);
13C NMR (75 MHz, CDC13) 5 152.9, 124.6, 72.8, 30.6, 27.7, 26.6, 15.4, 13.8.

Spectroscopic data were consistent with those previously reported. 34b

 

Ph
W0“ Pb/\><0H

Z-24 E-24

Preparation of (E)-2-methyl-4-phenyl-but-3-en-2-o1 (E-24) and (Z)-2-methy1-4-
phenyl-but-3-en-2-ol (Z-24) (Scheme 4.27). TBABr (32 mg, 0.1 mmol) and K2C03 (35
mg, 0.25 mmol) were dissolved in a mixture of acetonitrile and water (9:1) and stirred for
15 minutes. (Z)-2-Methy1-4-tributylgermany1-but-3-en-2-ol (Z-49) (33 mg, 0.1 mmol),
triphenyl phosphine (9 mg, 0.04 mmol), and iodo benzene (0.1 mL, 0.2 mmol) were
added and the mixture stirred for 15 minutes. Then palladium acetate (5 mg, 0.02 mmol)
was added and the reaction was stirred at 70 °C for 6 hours. The solution was cooled and
quenched at room temperature with saturated ammonium hydroxide and extracted with

ether. The organic phase was washed with water and brine dried over MgSOa, filtered,

128

and concentrated. Purification by column chromatography on silica gel [hexane / EtOAc :
9/ 1] afforded a 4:5 Z/E mixture determined by 1H NMR (E)-2-methy1-4-phenyl-but-3-en-
2-ol (E-24) and (Z)-2-methy1-4-pheny1-but-3-en-2-ol (Z—24) as a yellowish oil. (7.9 mg,

49%). Spectroscopic data were consistant with those previously reported.70

m WV
0 z-72 0 E72

Preparation of 1-[4-(1-methylene-butyl)-phenyl]-ethanone (int-72) and (Z)- l-(4-

 

O int-72

 

 

pent-l-enyl-phenyl)-ethanone (Z-72), (E)- l-(4-pent-1-enyl-phenyl)-ethanone (E-72)
(Scheme 4.32). TBABr (0.1 mmol) and K2C03 (0.25 mmol) were dissolved in a mixture
of acetonitrile and water (9:1) and stirred for 15 minutes. (E)-Tributyl-hex-1-enyl-
germane (59) and tributyl-(1-methylene-pentyl)-germane (54) (3.721 E/int, 0.1 mmol),
triphenyl phosphine (9 mg, 0.04 mmol), and p-bromo acetophenone (40 mg, 0.2 mmol)
were added and the mixture stirred for 15 minutes. Then palladium acetate was added and
the reaction was stirred at 70 °C for 6 hours. The solution was cooled and quenched at
room temperature with saturated ammonium hydroxide and extracted with ether. The
organic phase was washed with water and brine dried over MgS04, filtered, and
concentrated in vacuo to give a 1:1.1:5 E/Z/Int mixture determined by 1H NMR.
Purification by column chromatography on silica gel [hexane / EtOAc : 9/1] afforded 1-
[4-(1-methylene-buty1)-pheny1]-ethanone (int-72) and (Z)- 1-(4-pent-1-enyl-phenyl)-
ethanone (Z-72), (E)- 1-(4-pent-1-eny1-phenyl)-ethanone (E-72)88 as a yellowish oil. (12
mg, 47%). NMR 1H (300 MHz, CDCl;;) 5 (int) 7.83 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3
Hz, 2H), 5.38 (d, J= 1.2 Hz, 1H), 5.17 (d, J= 1.2 Hz, 1H) 2.62 (s, 3 H), (Z) 7.93 (d, J=

8.6 Hz, 2H), 7.50 (d, J= 8.6 Hz, 2H), 6.45 (d, J= 11.8 Hz, 1H), 5.80 (dt, J: 11.8, 7.8

129

Hz, 1H), 2.61 (s, 3 H), (E+int) 2.51 (t, J= 7.6 Hz, 2 H), 1.50 (s, J= 7.4 Hz, 2 H), 0.94 (t,

J= 7.4 Hz, 3 H).

 

1

0 0

bin

80

 

 

Preparation of 2-Oxo-cyclohexanecarbaldehyde (80) (Scheme 5.15). NaH (490 mg,
20.4 mmol) was suspended in dry ether (80 mL). Ethanol (1.5 mL, 25 mmol) was then
added and after the gas evolution stopped, ethyl forrnate (1.6 mL, 20.4 mmol) and
cyclohexanone (78) (2.1 mL, 20.4 mmol) were added in succession. The reaction was
stirred at room temperature for 18 hours during which time a precipitate was formed. The
slurry was filtered and the filtrate was partitioned between ether and water. The aqueous
phase was acidified and extracted twice with ether. The organic phase was then washed
with brine, dried over MgSO4, filtrated, and concentrated in vacuo. Flashed
chromatography on silica gel [hexanes/ether 8:2] afforded 2-oxo-

cyclohexanecarbaldehyde (80) (1.01 g, 40% yield). Spectroscopic data were consistent

15?]

Preparation of 2-methyl-cyc1ohexanone (79) (Scheme 5.15). Diisopropyl amine (1.8

with those found in the literature.89

 

mL, 13 mmol) was dissolved in THF (30 mL) and the solution was cooled to 0 °C. n-
BuLi (1.6 M in hexane, 8.1 mL, 13 mmol) was added dropwise and the solution stirred
for 35 minutes before being cooled to —78 °C. Cyclohexanone (78) (1.2 g, 10 mmol) in

THF (20 mL) was added dropwise and the solution was stirred for 35 minutes. The

130

solution was cooled to —78 °C and methyl iodide (2.5 mL, 40 mmol) was added in one
portion. The reaction was stirred for 3 hours while being allowed to slowly warm to room
temperature. The reaction was stirred overnight before being quenched with water. The
aqueous phase was extracted with ether and the combined organic phase was washed
with brine and saturated ammonium chloride. The solution was dried with MgSO4,
filtered, and concentrated in vacuo. Purification by column chromatography on silica gel
[dichloromethane] afforded 2-methyl-cyclohexanone (79) (0.8 g, 71%). The product

compared fully to a commercial sample (Aldrich).

 

0

G

81

 

Preparation of l-methyl-7-oxa-bicyclo[4.1.0]heptane (81) (Scheme 5.15). l-Methyl
cyclohexene (5.0 mL, 41.6 mmol) was dissolved in dichloromethane (50 mL) and cooled
to 0 °C. m-Chloro-perbenzoic acid (10.8 g, 62.4 mmol) was added in 3 portions and the
reaction stirred at 0 °C for 2 hours. The mixture was filtered and the filtrate washed with
NaOH (IN). The filtrate was extracted with CH2C12. The organic phase was washed with
water, dried over MgS04, filtered, and distilled (130 °C, 1 atrn) to give 1-methyl-7-oxa-
bicyclo[4.1.0]heptane (81) (3.0 g, 65%). Spectroscopic data were consistent with those

found in the literature.90

 

OTMS

85

Preparation of trimethyl-(Z-methyl-cyclohex-l-enyloxy)-silane (85) (Scheme 5.16). 2-

Methyl-cyclohexanone (5.75 mL, 50 mmol), triethylamine (8.64 mL, 62 mmol) and

131

trimethylsilyl chloride (TMSCl) (7.8 mL, 62 mmol) were dissolved in acetonitrile (62
mL). A solution of sodium iodide (9.3 g, 62 mmol) in acetonitrile (20 mL) was added
dropwise to the solution and the reaction was allowed to stir at room temperature for 16
hours. The mixture was then poured onto ice and extracted with pentane. The organic
phase was washed with ice water, dried over MgSO4, filtered, and concentrated in vacuo
to afford trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane (85) (8.64 g, 96%, 90% pure).

Spectroscopic data were consistent with those previously published.

 

O

U

87

 

Preparation of 2,6-dimethyl-cyclohex-Z-enone (87) (Scheme 5.19). 2,6-Dimethyl
cyclohexanone (86) (23.1 mL, 190 mmol) was suspended in CC14 (150 mL). NBS (35 g,
197 mmol) was added in one portion followed by AIBN (25 mg, catalytic). The reaction
was heated at reflux for 24 hours. When the reaction was complete the solution was
poured on a saturated solution of NaHC03 (300 mL), the solution was extracted with
chloroform and the combined organic phases washed with water, dried over MgSO4,
filtered, and concentrated in vacuo. The product was purified by column chromatography
on silica gel [hexane/ether 8/2] to give 2,6-dimethyl-cyclohex-2-enone (87) (17.7 g, 75%)

as a clear liquid. Spectroscopic data were consistent with those found in the literature.91

l o l
\
We]

 

 

 

Preparation of 6-chloroethynyl-2,6-dimethyl-cyclohex-Z-enone (88) (Scheme 5.19).

n-Butyl lithium (1.6 M in hexanes, 68.7 mL, 110 mmol) was added dropwise at 0 °C to a

132

solution of diisopropyl amine (14 mL, 110 mmol) in THF (500 mL). The solution was
stirred for 30 minutes then cooled to -78 °C and 2,6-dimethy1-cyclohex-2-enone (87)
(12.5 g, 100 mmol) was added followed by HMPA (17.4 mL, 100 mmol). The solution
was stirred at -78 °C for 30 minutes and then tetrachloro ethylene (10.3 mL, 110 mmol)
was added and the reaction allowed to warm to room temperature over a period of 3
hours. The reaction stirred for another hour at room temperature before being poured into
water. The solution was extracted with ether and the combined organic extracts washed
with water, dried over MgSO4, filtered, and concentrated in vacuo. The product was
purified by column chromatography on silica gel [dichloromethane] to afford 6-
chloroethynyl-2,6-dimethyl-cyclohex-2-enone (88) (3.3 g, 18 %). Spectroscopic data

were consistent with those found in the literature.92
0

fig
89

Preparation of 6-ethynyl-2,6-dimethyl-cyclohex-Z-enone (89) (Scheme 5.19). 6-

 

 

Chloroethynyl-2,6-dimethyl-cyclohex-2-enone (88) (500 mg, 2.7 mmol) and copper
powder (870 mg, 13.7 mmol) were suspended in THF (40 mL). Acetic acid (14 mL) was
added and the reaction was stirred at 70 °C for 4 hours. After completion, the reaction
was poured on water and extracted with ether. The combined organic phase is washed
with saturated NH4C1, NaHCO3, and water. The organic phase was then dried over
MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography
[hexanes/ether 9:1] afforded 6-ethynyl-2,6-dimethyl-cyclohex-2-enone (89) (220 mg,
55%) as a clear oil. Spectroscopic data were consistent with those found in the

literature.93

133

 

OH
fig
92

Preparation 6-ethynyl-2,6-dimethyl-cyclohex-Z-enol (92) (Scheme 5.19). 6-Ethynyl-

 

2,6-dimethy1-cyclohex-2-enone (89) (340 mg, 2.3 mmol) was dissolved in dry ether (5
mL) and cooled at 0 °C. Lithium aluminum hydride (27 mg, 0.59 mmol) was added and
the reaction stirred at room temperature for 30 minutes. The solution was then cooled to
0 °C and water was added dropwise. Then a saturated solution of ammonium chloride
was added and the solution extracted with ether. The aqueous phase was acidified with
HCl and extracted with ether. The combined organic phases were washed with HCl (1N),
water and brine, dried over MgSO4, filtrated, and concentrated in vacuo. Purification by
column chromatography [hexanes/ether 8:2] afforded 6-ethynyl-2,6-dimethy1-cyclohex-
2-enol (92) (300 mg, 87%) as a clear liquid. A diastereomeric mixture of 58/42 was
obtained. 1H NMR (300 MH, CDC13) 5 5.50 (m, 1 H), 3.70 (m, 0.58 H), 3.60 (m, 0.42 H),
2.20 (m, 2 H), 2.00 (s, 1 H), 1.76 (s, 3 H), 1.72 (s, l H), 1.54 (m, 2 H), 1.25 (s, 3 H); 13C

NMR (75 MHZ, CDCl3) 5 133.6, 123.3, 87.3, 75.3, 75.3, 37.3, 33.5, 24.2, 23.7, 20.5.

Ac
Q
93

Preparation of acetic acid 6-ethynyl-2,6-dimethyl-cyclohex-Z-enyl ester (93) (Scheme

 

 

5.19). 6-Ethynyl-2,6-dimethyl-cyclohex-2-enol (92) (300 mg, 2 mmol) was dissolved in
pyridine (10 mL) and acetic anhydride is added (3 mL, 30 mmol). The reaction was
stirred at room temperature for 16 hours. The product was extracted with ether, and the

combined organic phases washed with HCl (1N), saturated bicarbonate and brine. The

134

organic phase was then dried over MgSO4, filtered, and concentrated in vacuo to afford a
63/27 diastereoisomeric mixture of 6-ethynyl-2,6-dimethyl-cyclohex-Z-enyl ester (93)
(280 mg, 73%) as a yellow oil. Spectroscopic data of the major isomer: 1H NMR (300

MHz, CDC13) 5 5.50 (m, 1 H), 5.20 (m, 1 H), 2.00 (m, 7 H), 1.50 (m, 4 H), 1.10 (m, 3 H).

 

r 1
OH
\
mm
90

 

 

 

Preparation 6-chloroethynyl-Z,6-dimethyl-cyclohex-Z-enol (90) (Scheme 5.19). 2,6-
Dimethyl-cyclohex-2-enone (9.1 g, 50 mmol) was dissolved in benzene (200 mL) and
cooled to 0 °C. DIBAL (1M in hexanes, 50 mL, 50 mmol) was added dropwise and the
reaction stirred for 1 hour at 0 °C. Methanol (200 mL) was then added and the mixture
stirred for another hour. The solvent was concentrated in vacuo and the residue was
partitioned between ether and a 5% aqueous solution of H2804. The aqueous phase was
extracted with ether and the combined organic phases washed with water and brine, dried
over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography
[hexanes/ether 8:2] afforded 6-chloroethynyl-2,6-dimethyl-cyclohex-2-enol (2 g, 22%) as
a 90/10 cis/trans diastereoisomeric mixture (determined by goesy experiments).(Cis) 1H
NMR (300 MHz, CDCl3) 6 5.50 (m, 1 H), 3.70 (m, 1 H), 2.20 (m, 1 H), 2.00 (m, 1 H),
1.78 (s, 3 H), 1.74 (s, 1 H), 1.56 (m, 2 H), 1.25 (s, 3 H); IR(CC14): 3379, 2235, 1601,

1454 cm-1;LRMS(M+: 184): 184, 171, 169, 155, 149, 83.9 (100).

135

 

OAc

\
We

91

 

 

 

Preparation of acetic acid 6-ethynyl-2,6-dimethyl-cyclohex-2-enyl ester (91) (Scheme
5.19). cis-6-Chloroethynyl-2,6—dimethyl-cyclohex-2-enol (90) (90 mg, 0.48 mmol) was
dissolved in pyridine (2 mL) and acetic anhydride was then added (0.3 mL, 8 mmol). The
reaction was stirred at room temperature for 16 hours. The product was then extracted
with ether, and the combined organic phases washed with HCl (1N), saturated
bicarbonate and brine. The organic phase was dried over MgSO4, filtered, and
concentrated in vacuo. Purification by column chromatography [hexanes/ether 9:1]
afforded cis-6-ethynyl-2,6-dimethyl-cyclohex-2-enyl ester (91) (84 mg, 77%) as a yellow
oil. 1H NMR (300 MHz, CDC13) 5 5.50 (br-s, 1 H), 5.12 (s, 1 H), 2.10 (s, 3 H), 2.30-1.70
(m, 4 H), 1.60 (m, 4 H), 1.10 (s, 3 H). 13C NMR (75 MHz, CDC13) 5 170.9, 130.3, 125.6,

74.9, 72.6, 58.6, 35.8, 31.4, 23.7, 22.3, 20.8, 20.1

 

F

Ac

94 OH

 

 

Cross-coupling experiment. Preparation of acetic acid 6-(3-hydroxy-3-methyl-but-l-
ynyl)-2,6-dimethyl-cyclohex—Z-enyl ester (94) (Scheme 5.20). (E)-2-methyl-4-
trimethylstannanyl-but-3-en-2-ol (4) (190 mg, 0.76 mmol), and LiCl (48 mg, 1.14 mmol)
were added to a solution of 6-ethynyl-2,6-dimethyl-cyclohex-2-enyl ester (91) (84 mg,
0.37 mmol) DMF (2 mL). Pd2(dba)3 (18 mg, 0.02 mmol) was then added and the reaction

was stirred at room temperature for 48 hours. The solution was then paritiond between

136

water and ether. The organic phase was washed with water and brine, dired over MgSO4,
filtered, and concentrated in vacuo. Purification by column chromatography gave 6-(3-
hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-cyclohex-2—enyl ester (94) (25 mg, 37%) as
a 72/28 E/Z mixture and a 79/21 diastereoisomeric mixture. Spectroscopic data of the
major product (E/cis): 1H NMR (300 MHz, CDC13) 6.11 (d, J = 16.0 Hz, 1 H), 5.63 (d, J
= 16.0 Hz, 1 H), 5.56 (br-s, 1 H), 5.14 (s, 1 H), 2.09 (s, 3 H), 1.61 (m, 4 H), 1.30-1.27 (m,
6 H), 1.21-1.17 (m, 3 H); l3C NMR (75 MHz, CDC13) 5 171.1, 149.2, 130.3, 126.1,
125.7, 107.1, 93.9, 75.0, 70.8, 35.7, 31.3, 29.6, 29.3, 23.7, 22.4, 21.0, 20.5; LRMS (M+:

276.37): 276, 261.1, 201.1, 83.9, 42.9 (100).

 

O

U

73

 

 

Preparation of 6-methyl-cyclohex-Z-enone (73) (Scheme 5.21/5.22). To a solution of
diisopropylamine (24 mL, 175 mmol) in THF (100 mL), n-butylLithium (100 mL; 1.6 M
in hexane) was added dropwise at 0 °C and the mixture was stirred at 0 °C for 15
minutes. A solution of 2-cyclohexenone (75) in THF (100 mL) was added dropwise and
the solution was stirred for another 30 minutes. Methyl iodide (60 mL, 1.25 mol) was
then added and a white precipitate rapidly formed. The ice bath was then removed and
the reaction was stirred at room temperature until all the starting material disappeared by
TLC (between 1 and 3 hours). The solution was then filtrated and used directly in the
next step. For isolation purposes we poured the reaction into a saturated solution of
sodium bicarbonate. The solution was extracted with hexanes and the combined extracts

washed with brine, dried over MgSO4 and the solvent was distilled (short path, ) to give

137

6-methyl-cyclohex-2-enone (73) as a colorless oil (3.0 g, 23%). Spectroscopic data

matched those reported in the literature.”

 

OH

95

 

 

Preparation of 6-methyI-cyclohex-2-enol (95) (Scheme 5.21/5.22). After filtering the
solution of 6-methyl-cyclohex-2-enone (73), lithium aluminum hydride (2.8 g, 75 mmol)
was carefully added by small portions, and the reaction was allowed to stir at room
temperature for 10 hours. The reaction was judged complete by TLC and the solution was
cooled to 0 °C. Aqueous NH4Cl was added slowly and once the gas evolution stopped,
more sat NH4Cl (500 mL) was added and the mixture was stirred for 2 hours. The
solution was extracted with ether and the combined organic extracts were washed with
1N HCl solution, water and brine. The organic phase was dried over MgSO4, filtered, and
concentrated in vacuo. Purification by column chromatography on silica gel
[ether/hexanes 10% to 40% ether] gave a 31/69 cis/trans diastereoisomeric mixture of 6-
methyl-cyclohex-2—enol (95) as a pale yellow oil (3.5 g, 25%). Spectroscopic data

matched those reported in the literature.94

 

0A0

96

 

Preparation of acetic acid 6-methyl-cyclohex-2-enyl ester (96) (Scheme 5.23). 6-
Methyl-cyclohex-Z-enol (95) (3.5g, 31 mmol) was dissolved in pyridine (200 mL) and
acetic anhydride (50 mL) was added, followed by a catalytic amount of DMAP. The

solution was stirred for 3 hours, upon which all the starting material had been consumed.

138

The solution was then poured into 1N HCl and the solution was extracted with ether and
the combined organic phase washed with saturated bicarbonate and brine, dried over
MgSO4, filtered, and concentrated in vacuo to afford a 31/69 cis/trans diastereoisomeric
mixture of 6-methyl-cyclohex-2-enyl ester (96) as a yellow oil (3.0 g, 63%).

Spectroscopic data matched those reported in the literature.95

Preparation of vinyltributyltin. Tributyltin chloride (16.25 g, 50 mmol) in THF (100
mL) was added dropwise to a solution of solution of vinylmagnesium bromide (100 mL,
1 M in THF, 100 mmol). The solution was stirred at reflux for 16 hours after which time
ether and ammonium chloride were added. The mixture was stirred for 1 hour. The
aqueous phase was extracted with ether and the precipitate was washed with ether. The
combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo.
Short path distillation afforded vinyltributyltin as a colorless liquid (12.0 g, 76%).
Spectroscopic data matched those reported in the literature.“5

Representative protocol for the cross-coupling screening (Scheme 1.10). szdba3 (1,
3, 5 mol%) and the ligand (4 eq. to Pd) were stirred for 15 minutes in the solvent (2.5
mL). Then 6-methyl-cyclohex-2-enyl ester (50 mg, 0.3 mmol) was added followed by
vinyltributyltin (103 mg, 0.3 mmol) and LiCl (40 mg, 1 mmol) being added last. The

reaction was stirred at room temperature and followed by TLC.

139

BIBLIOGRAPHY

140

BIBLIOGRAPHY

 

(1) For some recent reviews on the Heck reaction: (a) Dounay, A. B.; Overman, L. E.
Chem. Rev. 2003, 103, 2945—2963. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem.
Rev. 2000, 100, 3009—3066. (c) de Meijere, A.; Meyer, F. E. Angew. Chem. Int. Ed.
Eng]. 1994, 33, 2379—241 1.

(2) For a review: Campbell, I. B. Organocopper Reagents, 1994, 217—235.
(3) For a review see: Miyaura, N.; Suzuki, A. Chem Rev. 1995, 95, 2457—2483.

(4) (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771-1780. (b) Stille, J. K. Angew.
Chem. Int. Ed. Engl. 1986, 25, 508—523. (c) Stille, J. K.; Groh, B. L. J. Am. Chem.
Soc. 1987, 109, 813—817. ((1) Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic
Reactions 1997, 50, 1—652.

(5) For recent examples see: (a) Laio, B. Q.; Negishi, E. Heterocycles 2000, 52, 1241—
1249. (b) Nicolaou, K. C.; Murphy, F .; Barluenga, S.; Ohshima, T.; Wei, H.; Xu, J .;
Gray, D. L. F.; Baudoin, O. J. Am. Chem. Soc. 2000, 122, 3830—3838. (c) Williams,
D, R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945—948. (d) Huang, A. X.; Xiong,
Z. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999—10003. (e) White, J. D.;
Hong, J.; Robarge, L. A. J. Am. Chem. Soc. 1999, 121, 6206—6216. (0 Wipf, P.;
Coish, P. D. G. J. Org. Chem. 1999, 64, 5053—5061. (g) Smith, A. B., 111.; Ott, G.
R. J. Am. Chem. Soc. 1998, 120, 3935—3948. (h) Chen, X. T.; Zhou, B. S.;
Bhattacharya, S. K.; Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky, S. J. Angew.
Chem, Int. Ed. Engl. 1998, 37, 789—792.

(6) For recent examples see: (a) Hoepping, A.; Johnson, K. M.; George, C.; Flippen-
Anderson, J.; Kozikowski, A. P. J. Med. Chem. 2000, 43, 2064—2071. (b) Jensen,
M. S.; Yang, C. H.; Hsiao, Y.; Rivera, N.; Wells, K. M.; Chung, J. Y. L.; Yasuda,
N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2000, 2, 1081-1084. (c) Marriere, E.;
Rouden, J .; Tadino, V.; Lasne, M. C. Org. Lett. 2000, 2, 1121—1124. (d) Smaill, J.
B.; Rewcastle, G. W.; Loo, J. A.; Greis, K. D.; Chan, 0. H.; Reyner, E. L.; Lipka,
E.; Showalter, H. D. H.; Vincent, P. W.; Elliott, W. L.; Denny, W. A. J. Med.
Chem. 2000, 43, 1380-1397.

(7) For new methods of reaction activation see ref 6b and the following: (a) Han, X. J .;
Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600—7605. (b) Fugami,
K.; Ohnuma, S.-y.; Kameyama, M.; Saotome, T.; Kosugi, M. Synlett 1999, 63—64.
(c) Fouquet, E.; Rodriguez, A. L. Synlett 1998, 1323—1324. (d) Fouquet, E.;
Pereyre, M.; Rodriguez, A. L. J. Org. Chem. 1997, 62, 5242—5243. (e) Farina, V.
Pure Appl. Chem. 1996, 68, 73—78. (f) Crisp, G. T.; Gebauer, M. G. Tetrahedron
Lett. 1996, 36, 3389—3392. (g) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc.
1996, 118, 2748—2749.

141

 

(8) (a) Genet, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305—317 and
references therein. (b) Rai, R.; Aubrecht, K. B.; Collum, D. B. Tetrahedron Lett.
1995, 36, 3111—3114.

(9) (a) Olofsson, K.; Kim, S.-Y.; Larhed, M.; Curran, D. P.; Hallberg, A. J. Org. Chem.
1999, 64, 4539—4541. (b) Hoshino, M.; Degenkolb, P.; Curran, D. P. J. Org. Chem.
1997, 62, 8341—8349. (c) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118,
2531—2532.

(10) (a) Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978—8985. (b) Flohr, A.
Tetrahedron Lett. 1998, 39, 5177—5180. (c) Quayle, P.; Wang, J. Y.; Xu, J.; Urch,
C. J. Tetrahedron Lett. 1998, 39, 489—492. ((1) Choshi, T.; Yamada, S.; Nobuhiro,
J .; Mihara, Y.; Sugino, 13.; Hibino, S. Heterocycles 1998, 48, 11—14. (e) Shirakawa,
E.; Yoshida, H.; Hiyama, T. Tetrahedron Lett. 1997, 38, 5177—5180. (f) Mateo, C.;
Cardenas, D. J.; Fernandez Rivas. C.; Echavarren. A. M. Chem. Eur. J. 1996, 2,
1596—1606. (g) Farina, V.; Hossain, M. A. Tetrahedron Lett. 1996, 37, 6997—7000.
(h) Vicente, J.; Areas, A.; Bautista, D.; Tiripicchio, A.; Camellini, M. T. New J.
Chem. 1996, 20, 345—356.

(11) Farina, V.; Krishnamurthy, V.; Scott, W. J. “The Stille Reaction” John Wiley &
Sons, Inc; New York; 1998

(12) (a) Chemistry of Tin; Smith, P. J ., Ed; Blackie Academic & Professional: New
York, 1998. (b) Davies, A. G. In Organotin Chemistry; VCH: New York, 1997.

(13) (a) Maleczka, R. E., Jr.; Gallagher, W. P. Org. Lett. 2001, 3, 4173—4176. (b)
Gallagher, W. P.; Terstiege, 1.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 2001, 123,
3194-3204. (c) Maleczka, R. E., Jr.; Gallagher, W. P.; Terstiege, I. J. Am. Chem.
Soc. 2000, 122, 384—385.

(14) On oxidative addition: (a) Amatore, C.; Jutland, A.; Suarez, A. J. Am. Chem. Soc.
1993, 115, 9531—9541. (b) Amatore, C.; Pfluger, F.; Organometallics 1990, 9,
2276—2282. And references cited therein.

(15) On reductive elimination: (a) Ozawa, F.; Fujimori, M.; Yamamoto, T.; Yamamoto,
A. Organometallics 1986, 5, 2144—2149. (b) Tatsumi, K, Hoffman, R.; Yamamoto,
A.; Stille, J. K. Bull. Chem. Soc. Jpn. 1981, 54, 1857—1867.

(16) Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129—6137.

(17) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585—9595.

(18) (a) Liebeskind, L. S.; F engl, R. W. J. Org. Chem 1990, 55, 5359—5364. (b) Farina,

V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59,
5905—591 1. (c) Casado, A. L.; Espinet, P. Organometallics 2003, 22, 1305—1309.

142

 

(l9) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem. 1993, 58, 5434—
5444.

(20) Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 1998, 63, 9622—9623.

(21) Betzer, J .-F.; Delaloge, F; Muller, B.; Pancrazi, A.; Prunet, J. J. Org. Chem. 1997,
62, 7768—7780.

(22) Rice, M. B.; Whitehead, S. L.; Horvath, C. M.; Muchnij, J. A.; Maleczka, R. E., Jr.
Synthesis 2001, 10, 1495-1504.

(23) Perreux, L.; Loupy, A Tetrahedron 2001, 5 7, 9199—9223.

(24) Mingos, D. M. P.; Baghurst, D. R. In Microwave Enhanced Chemistry, Kingston, H.
M., Haswell, S. J ., Eds; American Chemical Society: Washington, DC, 1997; pp.
4—7.

(25) (a) Bond, G. ; Moyes, R. B.; Pollington, J. D.; Whan, D. A. Chem Ind. 1991, 686—
687. (b) Baghurst, D. R.; Mingos, D. M. P. J. Chem. Soc., Chem. Commun. 1992,
674—677.

(26) Loupy, A.; Perreux, L.; Liagre, M.; Burle, K.; Moneuse, M. Pure Appl. Chem. 2001,
73, 161—166.

(27) (a) Ingersoll, A. W.; Brown, J. H.; Kim, C. K.; Beauchamp, W. D.; Jennings, G. J.
Am. Chem. Soc. 1936, 58, 1808—1811. (b) Loupy, A.; Monteux, D.; Petit, A.;
Aizpurua, J. M.; Dominguez, E. ; Palomo, C. Tetrahedron Lett. 1996, 37, 8177—
8180.

(28) (a) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582-9584. (b) Larhed, M.;
Hoshino, M.; Hadida, S.; Curran, D.P.; Hallberg, A. J. Org. Chem. 1997, 62, 5583—
5587.

(29) Villemin, D.; Cailot, F. Tetrahedron Lett. 2001, 42, 639—642.
(30) Hayashi, K.; Iyoda, J .; Shiiara, I. J. J. Organomet. Chem. 1967, 10, 81—94.

(31) (a) Zapf, A.; Beller, M. Chem. Eur. J. 2000, 6, 1830-1833. (b) Albisson, D. A.;
Bedford, R. B.; Lawrence, S. E.; Scully, P. N. J. Chem. Soc, Chem. Commun.
1998, 2095—2096.

(32) Busacca, C. A.; Swestock, J .; Johnson, R. E.; Bailey, T. R.; Musza, L.; Rodger, C.
A. J. Org. Chem. 1994, 59, 7553—7556.

(33) (a) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang, Q; Nolan, S. P. J.

Organomet. Chem. 2002, 653, 69-82. (b) Hiyama, T. J. Organomet. Chem. 2002,
653, 58-61. (c)

143

 

(34) (a) Corriu, R. J. P.; Moreau, J. J. E. J. Organomet. Chem. 1972, 40, 55-72. (b)
Corriu, R. J. P.; Moreau, J. J. E. J. Organomet. Chem. 1972, 40, 73-96.

(35) Iserloch, U.; Curran, D. P. J. Org. Chem. 1998, 63, 4711-4716.

(36) Mukai, C.; Kozaka, T.; Suzuki, Y.; Kim, I. J. Tetrahedron Lett. 2002, 43, 8575-
8578.

(3 7) Widendorf, R. A.; Vadehra, A.; Cheruvu, P. K. Organometallics 1999, 18, 4614-
4618.

(3 8) Kosugi, M.; Tanii, T.; Tanaka, Y.; Yohida, A. ; Fugami K. ; Kameyama, M. ;
Migita, T. J. Organomet. Chem. 1996, 508, 255-257.

(39) Ikenaga, K.; Matsumoto, S.; Kikukawa, K; Matsuda, T. Chem. Lett. 1990, 185-188.

(40) David-Quillot, F .; Thibonnet, J .; Marsacq, D.; Abarbri, M.; Duchene, A.
Tetrahedron Lett. 2000, 41, 9981-9984.

(41) (a) F aller, J. W.; Kultyshev, R. G. Organometallics 2002, 21, 5911-5918. (b) F aller,
J. W.; Kultyshev, R. G.; Parr, J. Tetrahedron Lett. 2003, 44, 451-453.

(42) (a) Nakamura, T.; Yorimitsu, H.; Shinokubo, H. Oshima, K. Synlett 1999, 9, 1415-
1416. (b) Nakamura, T.; Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett.
2002, 4, 3165-3167.

(43) (a) Furukawa, N.; Kourogi, N. Seki, Y. Organometallics 1999, 18, 3764-3767. (b)
Ichinose, Y.; Oda, H.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1987, 60,
3468-3470.

(44) Oda, H.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1984, 25, 3221-
3224.

(45) (a) Jeffery, T. Tetrahedron Lett. 1994, 35, 3051—3054. (b) Jeffery, T. Tetrahedron
1996, 52, 10113—10130.

(46) Karabelas, K.; Hallberg, A. J. Org. Chem. 1986, 51, 5286-5290.
(47) Huang, X.; Liang, C-G. Synth. Commun. 2000, 30, 1903-1909.
(48) Private communication with Pr. Duchénes of results not yet published (July 2001).

(49) (a) Crisp, G. T.; Link, P. T. Tetrahedron 1994, 50, 3213—3234. (b) Sagelstein, B. E. ;
Butler, T. W.; Chenard, B. L. J. Org. Chem. 1995, 60, 12—13.

(50) D’Auria, M. V.; Debitus, C.; Paloma, L. G.; Minale, L.; Zampella, A. J. Am. Chem.
Soc. 1994, 116, 6658—6663.

144

 

(51) (a) Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2003, 68, 3838-3843. (b) Roush, W.
R.; Hertel, L.; Schnaderbeck, M. J .; Yakelis, N. A. Tetrahedron Lett. 2002, 43,
4885—4887. (c) Solsona, J. G.; Romea, P., Urpi, F. Org. Lett. 2003, 5, 4681—4684.
(d) Yu, W.; Zhang, Y.; Jin, Z. Org. Lett. 2001, 3, 1447—1450.

(52) (a) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Haltennan, R. L. J.
Am. Chem. Soc. 1990, 112, 6339—6348. (b) Roush, W. R.; Palkowitz, A. D. J. Am.
Chem. Soc. 1990, 112, 6348—6359.

(53) Solsona, J. G.; Romea, P.; Urpi, F.; Vilarrasa, J. Org. Lett. 2003, 5, 519-522.

(54) Roush, W. R.; Champoux, J. A.; Peterson, B. C. Tetrahedron Lett. 1996, 37, 8989—
8992.

(55) Del Valle, L.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990, 55, 3019-3023.

(56) (a) Sheffy, F. K.; Godschalx, J. P.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 4833-
4840. (b) Kurosawa, H.; Ogoshi, S.; Kawasaki, Y.; Murai, S.; Miyoshi, M; Ikeda, I.
J. Am. Chem. Soc. 1990, 112, 2813-2814. (c) Kurosawa, H.; Kajimura, H.; Ogoshi,
S.; Yoneda, H.; Miki, K.; Kasai, N.; Murai, S.; Ikeda, I. J. Am. Chem. Soc. 1992,
114, 8417-8424.

(57) Castano, A. M.; Echavarren, A. M. Tetrahedron Lett. 1996, 3 7, 6587—6590.

(58) Kurosawa, H.; Ogoshi, S.; Kawasaki, Y.; Murai, S.; Miyoshi, M.; Ikeda, I. J. Am.
Chem. Soc. 1990, 112, 2813—2814.

(59) (a) Genet, J. P.; Balabane, M.; Backvall, J. E.; Nystrom, J. E. Tetrahedron Lett.
1983, 24, 2745—2748. (b) Genet, J. P.; Balabane, M.; Legras, Y. Tetrahedron Lett.
1982, 23, 331-334.

(60) Krafft, M. E.; Wilson, A. M.; Fu, Z.; Procter, M. J .; Dasse, O. A. J. Org. Chem.
1998, 63, 1748—1749.

(61) (a) Asao, N.; Asano, T.; Ohishi, T.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122,
4817—4818. (b) Asao, N.; Ohishi, T.; Sato, K.; Yamamoto, Y. Tetrahedron 2002,
58, 8195—8203.

(62) Goyal, S. C.; Gupta, S. M. Ann Chim. 1977, 2, 57-59.

(63) Cory, R. M.; Chan, D. M. T.; Naguib, Y. M. A.; Rastall, M. H.; Renneboog, R. M. J.
Org. Chem. 1980, 45, 1852-1863.

(64) For example: (a) Mereyla, H. B.; Frei, B. Helv. Chim. Act. 1986, 69, 415-18. (b)
Meguro, M.; Asao, N.; Yamamoto, Y. J. Chem. Soc., Perkin Trans. 1 1994, 18,
2597-2601. (c) Begley, M. J .; Ladlow, M.; Pattenden, G. J. Chem. Soc, Perkin
Trans. 1 1988, 5, 1095-1106.

145

 

(65) (a) Kende, A. S.; Fludzinski, P.; Hill, J. H.; Swenson, W.; Clardy, J. J. Am. Chem.
Soc. 1984, 106, 3551-3562. (b) Kende, A. S.; F ludzinski, P. Tetrahedron Lett.
1982, 23, 2369—2372. (c) Kende, A. S.; Fludzinski, P. Tetrahedron Lett. 1982, 23,
2373-2376. (d) Kende, A. S.; Fludzinski, P. Chem. Comm. 1982, 455-456.

(66) Reginato, G.; Mordini, A.; Caracciolo, M. J. Org. Chem. 1997, 62, 6187—6192.
(67) Echavaren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478-5486.
(68) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982, 47, 404-408.

(69) (a) Shanna, S.; Oehlschlger, A. C. J. Org. Chem. 1989, 54, 5064-5073. (b)
Maleczka, R. E.; Terrell, L. R.; Clark, D. H. ; Whitehead, S. L.; Gallagher, W. P.;
Terstiege, I. J. Org. Chem. 1999, 64, 5958-5965.

(70) Marko, I. E.; Leung, C. W. J. Am. Chem. Soc. 1994, 116, 371-372.

(71) Reich, H. J .; Shah, S. K.; Chow, F. J. Am. Chem. Soc. 1979, 101, 6648-6656.
(72) Russell, G. A.; Kim, B. H.; Kulkarni, S. V. J. Org. Chem. 1989, 54, 3768-3770.

(73) Chiacchio, U; Liguori, A.; Romeo, G.; Sindona, G.; Uccella, N. Heterocycles 1993,
36, 799-817.

(74) (a) Maleczka, R. E., Jr.; Lavis, J. M.; Clark, D. H.; Gallagher, W. P. Org. Lett. 2000,
2, 3655-3658. (b) Gallagher, W. P., Ph.D. Dissertation, Michigan State University,
2003.

(75) Shrestha, K. S.; Honda, K.; Asami, M.; Inoue, S. Bull Chem. Soc. Jpn. 1999, 72, 73-
83.

(76) Pearson, W. H.; Szura, D. P.; Postich, M. J. J. Am. Chem. Soc. 1992, 114, 1329-
1345.

(77) Majima, T.; Tojo, S.; Ishida, A.; Takamuku, S. J. Org. Chem. 1996, 61, 7793-7800.
(78) Chalcat, J. C. C. R. Acad. Sc. Paris (Serie C) 1971, 763-765.
(79) Yu, W.-Y.; Bensimon, C.; Alper, H. Chem. Eur. J. 1997, 3, 417-423.

(80) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120,
11943-11952.

(81) Maercker, A.; Weber, K. Liebigs Ann. Chem. 1972, 756, 20-32.
(82) Marko, I. E.; Leung, C. W. J. Am. Chem. Soc. 1994, 116, 371-372.

(83) Morril, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031-6034.

146

 

(84) (a) Buono-Core, G. E.; Screbler, R.; Aros, F.; Verdugo, J. C. Boletin de la Sociedad
Chilena de Quimica, 1995, 40, 219-220. (b) Pandey, G.; Krishna, A. J. Org. Chem.
1988, 53, 2364-2365.

(85) Chalk, A.; Mangennis, S. A. J. Org. Chem. 1976, 41, 1206-1209.

(86) Prakash, G. K.; Krishnamurthy, V. V.; Olah, G. A.; Farnum, D. G. J. Am. Chem.
Soc. 1985, 107, 3928-3935.

(87) Denmark, S. Wang, Z. Org. Lett. 2001, 3, 1073-1076.
(88) Berthiol, F.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2003, 44, 1221-1225.
(89) Barna, J .; Robinson, M. J. T. Tetrahedron Lett. 1979, 16, 1455-1458.

(90) Kaneda, K., Itoh, T., Fujiwara, Y.; Teranishi, S. Bull. Chem. Soc. Jpn. 1973, 46,
3810-3814.

(91) Reich, H. J.; Reich, 1. L.; Renga, J. J. Am. Chem. Soc. 1973 95, 5813-5815.

(92) Kende, A. S.; Benechie, M.; Curran, D. P.; Fludzinski, P.; Swenson, W.’ Clardy, J.
Tetrahedron Lett. 1979, 19, 4513-4516.

(93) Kende, A. S.; Fludinski, P. Tetrahedron Lett. 1982, 23, 2373-2376.
(94) Liotta, D.; Zima, G.; Saindane, M. J. Org. Chem. 1982, 4 7, 1258-167.
(95) Hansson, S.; Heuman, A.; Rein, T.; Aakermark, B. J. Org. Chem. 1990, 55, 975-984.

(96) Seyferth, D.; Stone, F. G. A. J. Am. Chem. Soc. 1957, 79, 515-517.

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