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THESlS

j Illllllllllll|||l||lilllllllllllllllllllllll‘llllllllllllllll

3 1293 020604

This is to certify that the

thesis entitled

A Regioselectivity Study of Hydrostannylation
Reactions on Terminal Alkynes with Oxygen
Functionalities in Close Proximity

presented by

Michael Burton Rice

has been accepted towards fulfillment
of the requirements for

M. S. degree in Cheml Stry

 

Major profe r

Date October 11, 1999

 

0-7639 MS U is an Affirmative Action/Equal Opportunity Institution

 

 

PLACE IN RETURN BOX to remove this checkout from your record.
TO AVOID FINES return on or before date due.
MAY BE RECALLED with earlier due date if requested.

 

DATE DUE DATE DUE DATE DUE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

11/00 cIClRCIDatoDuopfis-pu

 

A REGIOSELECTIVITY STUDY or HYDROSTANNYLATION REACTIONS ON
TERMINAL ALKYNES WITH OXYGEN FUNCTIONALITIES IN CLOSE
PROXIMITY
By

Michael Burton Rice

A THESIS
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
MASTER OF SCIENCE
Department of Chemistry

1999

ABSTRACT
A REGIOSELECTIVITY STUDY OF HYDROSTANNYLATION REACTIONS ON
TERMINAL ALKYNES WITH OXYGEN FUNCTIONALITIES IN CLOSE
PROXIMITY
By

Michael Burton Rice

Vinyl stannanes hold an important place in organic synthesis. They can
be used in a variety of roles and their preparation has been the topic of many
studies. One means Of preparing a vinyl stannane is to hydrostannate an
alkyne. This process can be catalyzed by palladium, as first demonstrated by
Oshima and coworkers.‘ A high degree Of regioselectivity is almost always
desired in these transformations, and this warrants the need for a systematic
study on what structural features can influence the regiochemical outcome of
the reaction. In this study a variety Of terminal alkynes were subjected to Pd(0)
mediated hydrostannylation conditions with either a hydroxyl, methoxy, or
acetate functional group in close proximity. it was shown here that the oxygen
functionalities enhance formation of the internal stannane, either by polarization
Of the carbon-carbon triple bond2 or via palladacycle intermediacy.3 Among the
functional groups studied it was observed that the acetate functional group had

a greater directing effect then either the hydroxy or methoxy group.

DEDICATION

For my grandfather
who taught me to work hard
and that I could accomplish anything.

ACKNOWLEDGMENTS

I would like to acknowledge my adviser, Dr. Robert E Maleczka Jr., with
out his advise and guidance none of this would be possible. By seeing me for
who I am and giving me good advice, I was able to make an extremely difficult
career Choice that has led me in the right direction. I would also like to thank the
members of Dr. Maleczka’s group for helping me throughout my studies.

I would also like to take this time to thank my family, especially Raymond,

who throughout my life has given me inspiration and support in my endeavors.

iv

TABLE OF CONTENTS

LIST OF FIGURES

INTRODUCTION
Methods of Preparing Vinyl Stannanes

RESULT & DISCUSSION

Aliphatic Series
Alcohol Series
Hydrostannylation Of Alcohols
Oxygen Directed} vs. Stearic Hindrance

Methyl Ether Series
Preparation Of Methyl Ethers
Hydrostannylation of Methyl Ethers
Acetates Series
Preparation Of Acetates
Hydrostannylation of Acetates
One Pot Hydrostannylation/Stille—Cross Coupling
Information Provided
Control Study
FUTURE WORK
SUMMARY AND CONCLUSIONS
EXPERIMENTAL
SPECTRA

BIBLIOGRAPHY

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
Figure 16
Figure 17
Figure 18
Figure 19

Figure 20

LIST OF FIGURES

Vinyl Stannane Structure

Examples of Pd(0) Cross-Couplings

Formation of Vinyl Stannanes via Transmetallation
Metallometallation of Terminal Alkynes

Mechanism of Radical Mediated Hydrostannylation
Examples of Pd(0) Hydrostannylations Reported in the Literature
Mechanism of Pd(O) Mediated Hydrostannylation

Formation of an Allylic Stannane via an Allene Intermediate.
One Pot Hydrostannylation/Stine Cross-Coupling

Pd(0) Mediated Hydrostannylation

Contrasting Regioselectivity Examples

Hydrostannylations Of Aliphatic Alkynes

Oxygen Directed Hydrostannylations

Pancrazi’s Proposed Palladacycle lntennediate

Possible Palladacycles for Terminal Alkynols
Hydrostannylation of oc-Substituted Alkynes

Preparation of the Methyl Ether Series

Methoxy Ether Oxygen Directed Hydrostannylations
Preparation of the Acetate Series

Acetate Oxygen Directed Hydrostannylations

vi

Figure 21 Two Step Hydrostannylation/StiIIe-Cross Coupling

Figure 22 Future Series

PMHS
NMR
OAC
OH

TBAF
THF

THP

LIST OF ABBREVIATION

potassium fluoride
polymethylhydrosiloxane
nuclear magnetic resonance
acetate

hydroxyl

round bottom
tetrabutylammonium fluoride
tetrahydrofuran
tetrahydropyranyl

halide

viii

INTRODUCTION

Figure 1. Vinyl Stannane Stmcture.

Nita”

1

The formation of carbon-carbon bonds is central to the art Of organic
synthesis. Vinyl stannanes have been widely used for this purpose, a new
carbon-carbon bond can be formed by the coupling of a variety of electrophiles
with vinyl stannanes. The substrates that can act as electrophiles include
carbonyl compounds, enones, acyl chlorides, vinyl, aryI, allyl, and benzyl
halides and triflates.‘ Typically these couplings are mediated by catalytic
amounts of palladium, as the examples in Figure 2 Show. Such conditions are

mild and allow for a large array of functional groups to be present in both the

Figure 2. Examples of Pd(0) Cross-Couplings.

\ "a” Para)
M + ' > / /
/ I THF. 40°C, 70%

 

 

 

2 3 4
PhCH Pd P CI
Mme + A“, 2 <th = w
3 HMPA. 65°C. 92.5% Mac
5 a 7
Br PhCH Pd P /
©/\ + fish”, 2 ( ”1:920 : G/v
HMPA,65°C,100%
a 9 1o

electrophilic and nucleophilic substrates. Also the coupled products are often
formed in good yields and almost always with retention of the olefin geometry.19
Due to the synthetic versatility of vinyl stannanes a variety Of methods have
been developed to prepare them: transmetallation"o with other vinyl metals;
metallometallation22 Of alkynes; hydrostannylation Of alkynes, either via metal

1-11

catalysis or under free radical conditions.‘2"°

Figure 3. Formation of Vinyl Stannanes via Transmetallation.

H LI nBu;
t-BuLI _ Bu SnCI k
\IO’g THF, 0°C ' \O/K 3 E \o

11 12 13

 

 

 

2:
E
t:

ll
:9
5

I

1
in

(E

N

14 15 16

Transmetallation of vinyl metals, in particular lithium, with a tin halide has
proven to be a useful method for the preparation of vinyl stannanes (Figure 3).
These reactions give good regioselectivity and fairly good yields?0 However
this system only works well if the functional groups present in the system are not
sensitive to the basic conditions of the Iithiation. The vinyl lithium precursor can
be formed either. from Iithiation of the corresponding alkene or via halogen
metal exchange with a vinyl halide. TO prepare the vinyl lithium precursor from
an alkene, an alkene is reacted with an alkyl lithium reagent. The alkyl lithium
reagent is very basic and will abstract a suitably acidic proton from the alkene.

Depending on the alkene this may work for or against formation Of the desired

product. For the correct regioisomer to be formed the correct hydrogen has to
be the most acidic proton available. If the regioselectivity is a concern a vinyl
halide of defined geometry could be synthesized prior to halogen metal
exchange.21

In addition to the transmetallation method a variety Of metallometallation
techniques have also been developed which take advantage metals which are
less electropositive than Li and Na. Metallometallation has the added bonus of
providing two synthetic handles on the alkene. Of the bimetallic reagents that
have been developed, the Sn—AI, Sn-Si, and Sn—Cu species are the most
synthetically useful.22 These reagents can form vinyl stannanes in good yields
and in high regioselectivity (Figure 4). The reaction conditions are fairly mild
and insensitive to a variety of functional groups; including OH, OTHP, OAC, and

halides. AS shown in Figure 4, the two possible isomers are the trans and

Figure 4. Metallometallation of Terminal Alkynes.

Shah "BU;
19

ll

11 1a
Bimetallic reagent Conditions Products Ratio
Ellnt.
BUaSnSIMefh 1. Pd(Ph3P)4.THF,A Eonly
2. TBAF, THF/F120, m.
BuasnAIEtg 1. CuCN,Tl-IF. -30°c 91/1
2. H’

1. CuCN, HMPA, -30°C
2. H’

BugSn(R')CuCNLI-z 1. Tg-lsli‘lMeOH. 4010 -30°C

internal vinyl stannanes. This is due to the syn addition of the bimetallic reagent
across the carbon—carbon triple bond. One drawback of this methodology is the
need for 2 to 3 equivalents of the bimetalic reagents, which can lead to
unwanted byproducts. For Sn-Cu and Sn-Al systems, the bimetallic alkene can
not be isolated, but in terms of forming vinyl stannanes this is not important.

Further more the Sn—Cu and Sn—Al reagents can hydrostannate both internal

Figure 5. Mechanism of Radical Mediated Hydrostannylation.

R—E—H 3W9“ i ',—-<_ BUaSnH : _
R 50803 "a":
20 22

 

 

 

 

 

and terminal alkynes. In contrast the Sn—Si reactions are limited to terminal
alkynes were the substituents alpha to the carbon—carbon triple bond are not
sterically demanding.

Though transmetallation and metallometallation are well established
techniques the traditional protocol for forming vinyl stannanes is through the
free radical hydrostannylation of alkynes. This method gives predominately the
cis and trans isomers (Figure 5).“‘“ The cis vinyl stannane is formed initially as
the tin radical attacks the sterically less hindered terminal carbon. The trans

isomer is produced as the major isomer, by running the reaction for longer

periods of time and with excess amounts of tin hydride.‘2'15 This allows the
formation of a second tin radical which under equilibrating conditions can attack
the initially formed cis vinyl stannane to form an unstable ditin radical species
(23). This ditin radical is free to rotate about the carbon—carbon o-bond, thus
elimination of the tributyltin radical will ultimately lead to the formation of the
more thermodynamically stable trans stannane.

Figure 6. Examples of Pd(O) Hydrostannylations Reported in the Literature.

 

 

 

(Pth)PdCI2 \ 0303
Bu 8 H :
///\01 + 3 n THF(41%) BUNCH + JVH
(45:55)
25 26 27 a
H P“ ”3‘”
4. 3113an ( 3")wa : M + H
é THF(85%) Buss H
(0:100)
29 as so 31
Ph P P "B":
///V\ + 8113an ( 3 ) dc" ; 8mm +
THF (98%)
(65:35)
32 as 33 34

Another method to form vinyl stannanes, that is of particular interest to us,
is the hydrostannylation of terminal alkynes mediated by catalytic amounts of
Pd(0). These conditions are very mild and produce vinyl stannanes in good
yields (Figure 6). In the literature there are two mechanisms proposed for
palladium mediated hydrostannylations, the first by Oshima1 in 1987 and the

second by Wada in 1988.5 The only difference between these two mechanisms

Figure 7. Pd(O) Mediated Hydrostannylation Mechanism.

 

 

 

BuasnPdtz— H \
H : 3.13an a
paw) k > a : k : 11—: 55>:
an BuMédfifl B
35 /

Buasn Na'l
37

Figure 8. Formation of an Allylic Stannane via an Allene Intermediate.

90112 n H P n H
9012—: ___. h _’ H dHa H
“W "”13 "Prb H2$nPh3
as as

”1331’ Ibd<11

 

40

is the order in which the hydrogen and the tin moiety add across the carbon-
carbon triple bond (Figure 7). Oshima's work focused on the hydrostannylation
of terminal alkynes and he observed mixtures of terminal and internal isomers
and on some occasions allylic stannanes. Based on the observed products,
Oshima proposed initial addition of the tin moiety to afford intermediate 37. To
further explain the formation of the allylic stannane 40, Oshima proposed the
addition of the tin moiety (Figure 8) can form intermediate 38 where there is the
possibility of B-hydride elimination to allow formation of allene 39. Then the

allene could be reduced by Pde to form an allylic stannane. No spectroscopic

experiments were conducted by Oshima to support this proposal and this was
the only literature report of the formation of allylic stannanes.

Wada’ss mechanism follows more traditional transition metal mediated
chemistry and he proposed the hydride is added first, to afford intermediate 36.
This proposal was supported by Trost’s work2 on the hydrostannylation of
enynes with electron withdrawing group at the alpha position. Trost observed
that the proximal isomer predominated when an electron withdrawing
substituent was present alpha to the olefin of an internal enyne. Trost states
that a reasonable explanation is that the acetylene is polarized by the electron
withdrawing group, so the hydrogen will add to the more electron deficient
carbon. Of these two proposals the later is more accepted in the literature and
will be the one assumed throughout this research. In both mechanistic
pathways the addition of the hydride and tin moiety proceeds in a syn fashion,
explaining why the trans and internal stannanes are the predominate isomers
and very little cis products are ever observed.

Irrespective of the method of formation, vinyl stannanes can be further
elaborated via a variety of chemical transformations. As previously mentioned
one of the most common applications of vinyl stannanes is in palladium cross-
couplings. The Stille cross-coupling of vinyl halides with vinyl stannanes is a
mild method for the stereoselective synthesis of 1,3-dienes, a structural unit
which is often found in natural products and used as synthetic intermediates.”26

In spite of its wide use, this reaction bears some problems. The vinyl halide and

Figure 9. One Pot Hydrostannylation/Stille Cross-Coupling.

*K—(Pa—Sneua R’\Pd\/\
803$“
[Hydrostannylation [ Pd°] [Stlllo-CoupllngJ
e P H
"as"— RRR\—4/XG_R1—Po—x

BU3$rH

 

 

 

 

the vinyl tin compound have to be prepared stereoselectively in separate steps,
prior to their employment in the coupling reaction. Furthermore, some vinyl tins
undergo protodestannylation during chromatographic purification"""3 and
stoichiometric amounts of toxic organotin halides are produced as a byproduct.
Therefore, we viewed the development of a one pot protocol for the
stereoselective generation of vinyl tins and their subsequent cross-coupling,
employing only catalytic amounts of tin, as highly desirable (Figure 9).

Towards this end, Boden et al. have shown that upon the complete
palladium mediated hydrostannylation of 1-bromo alkynes, the addition of a
further quantity of Pd-catalyst and a vinyl bromide could furnish the desired
Stille product.” This procedure represents a means to obviate the isolation of
the vinyl stannane intermediate. However the stepwise nature of the sequence

was inconsistent with our own goal of developing a protocol catalytic in tin in

which all reaction components are present at the beginning of the reaction
sequence.

While the Pd-catalyzed hydrostannylation is a well established synthetic
tool"“-""28 the feasibility of carrying out Pd-catalyzed hydrostannylations in the
presence of a Stille electrophile was by no means assured. We would need to
strike a balance between the catalyst requirements for high yielding
hydrostannylations (strong o-donor ligands such as PPha) and efficient cross-
couplings (weaker o-donor ligands).25 Equally important, was the need to
minimize side reactions, especially the Pd-mediated BUSSRH reduction of vinyl
halides.”30 Finally, understanding the regiochemical consequence of Pd-
catalyzed hydrostannylations remains an important aspect of this
methodology.“-i’3‘25 It is on this last point that this study is focused. We aim to
discover the factors that play a role in the regioselectivity of Pd(0) mediated
hydrostannylations.

Figure 10. Pd(O) Mediated Hydrostannylation.
SnBua Bu3$1

Pd(0 _
r. ) r /=/ + )= + / \
alaSl‘lH R R 80803

R

l

Since the addition of the tin moiety can either occur at the terminus or the
internal carbon (Figure 10) the possibility of the trans, internal, and the cis
isomers are all possible. Literature cases have been reported where the trans

vinyl stannane is the predominate product (Figure 11),‘ but there have also

Figure 11. Contrasting Regioselectivity Examples.

Ph 3 30H "PM
M 835 — (Ph 3P)‘Pd r
(69%) Measl‘

 

8113an
(Ph P)2PdClz
(85%)

   

been examples where the internal vinyl stannane is formed preferentially.31 In
all cases very little if any of the cis isomer is observed. A systematic study of
how oxygen functionalities, in close proximity to the alkyne. affect the
regioselectivity during palladium mediated hydrostannylations has not been
done. Oxygen functionalities were chosen in order to probe the possibility of
coordination of the heteroatom to the Pd center. Coordination to the metal
center could enhance formation of the internal stannane, as shown by Guibé
and coworkers.‘ In fact while this research was being conducted an example of
how an hydroxyl group can direct the tin moiety to the internal carbon via a six
member palladacycle was cited by Pancrazi and co-workers.3 Oxygen
functionalities could also alter the polarization of the carbon-carbon triple bond,
in keeping with the proposal made by Trost.2 In conducting such a study we
also decided to examine substrates that contained oxygen functionalites which

would allow for these situations.

10

Along with Pd-mediated hydrostannylation, traditional free radical

hydrostannylation reactions were also studied. These results allow us to make

a direct regiochemical comparison and provide an alternate route to the vinyl

stannanes, which would be of assistance in securing their structures.

RESULTS & DISCUSSION

ALIPHATIC SERIES

While our goal was to evaluate the influence of oxygen on regiocontrol,

we initially examined a series of aliphatic alkynes to establish for comparison

purposes the effects of related non-polarizing and non-coordinating groups.

While we wished to initially examine aliphatic alkynes of similar chain length to

the oxygenated substrates we would ultimately examine, some allowances for

Figure 12. Hydrostannylations of Aliphatic Alkynes.

 

///\/ 8113an

 

 

Ph P PdClz
gnu-3,11%
41
803an
///V\ (Phapli’daa
THF. 0°C
32
M 8:13an
// (Ph 3P)2Pd012
THF, 0°c
44

80380
8"33"\/\/\ + N

2.2 1

42 43

a
Bu35"\/\/\/ + j\/\/

1 .8 1

33 34

B
WSW + j\/\/\

1 .9 1

45 46

11

practicality had to be made. For example alkynes with less then 4 carbons in
the skeletal chain were too volatile to study. Experimentally, the alkyne was
added to a solution of THF, then catalytic amounts of palladium and an
equivalent of tin hydride were added. The reactions were usually complete
after 45 min., at which time the solvent was removed. The product ratios were
determined by 1H NMR taken of the crude mixture, specifically through the
intergration of the vinylic protons. As the data in Figure 7 shows, a 2:1 ratio of
trans to internal vinyl stannane isomers would appear to be the inherent bias for

these reactions.
ALCOHOL SERIES

With the suggestion of oxygen coordinating to the palladium center, as
proposed by Guibé,‘ it was decided that studying a series of alcohols would

further probe this hypothesis and provide a greater understanding of these

Figure 13. Oxygen Directed Hydrostannylations.

 

SUB“:
8%an M + W + wm
H _ Bu S \ H \
//"’.P - . n ,, .3...
mm W

n = 1 25 Free Radical: 60% 9 47 2 48 1 49
Pd(O) Mediated: 52% 1 27 0 50 1.3 23

n = 2 51 Free Radical: >99% 80 52 19 1 54
Pd(O) Mediated: 69% 1.6 55 0 58 1 57

n = 3 58 Free Radical: 70% 9 59 1 60 0 61
Pd(O) Mediated: 56% 2.5 52 0 33 1 54

n = 4 65 Free Radical: 64% 5.4 68 1 67 0 68
Pd(O) Mediated: 95% 3 39 0 7° 1 71

12

types of hydrostannylations. The variable within this series would be the
relative position of the carbon-carbon triple bond and the hydroxyl function. As
with the aliphatic substrates, Pd(O) mediated hydrostannylations were
performed. For propargyl alcohol (25) a 1:1.3 ratio (Figure 13) of trans to the
internal isomer was observed. Similar results for the hydrostannylation of
propargyl alcohol were reported by Guibé‘ and co-workers, thus establishing
that our techniques were consistent with known procedures. As substrates with
more methylene spacers between the acetylene and the hydroxyl group were
examined, the apparent directing of the tin moiety to the internal position
decreased. Comparing the n = 1 (25) and n = 4 (65) cases the ratio of trans to
internal went from 1:1.3 to 3:1. To explain this trend, it is useful to consider the
work of Pancrazi’sa and coworkers, who have examined the hydrostannylations
of enynes. After subjecting an enyne, such as 72 (shown in Figure 14), to
standard Pd(0) hydrostannylation conditions a 1:7.3 ratio of terminal to internal
vinyl stannanes was observed. This lead Pancrazi to suggest a six member
palladacycle (73) as an intermediate. The existence of palladacycles can also

be applied to the alcohol series. Possible palladacycles for propargyl alcohol

Figure 14. Pancrazi's Proposed Palladacycle Intermediate.

 

 

O H 0 H
8113an I q H
: bk :
I Pd(O) SnBua Sneu3
§
72 73 74

13

Figure 15. Possible Palladacycles for Terminal Alkynols.

Ratios (Ezlnf)

H
I
1:1.3 / {smug
H
n=1 25 78
"=2 51
" 16°1
/ .. #w
H San

78

 

0H

\\,Z

ll
“\
I

(25) and 3-butyn-1-ol (51) are shown in Figure 15. These cyclic intermediates
may explain why the internal isomer is formed in greater yields when the
number of the methylene spacers are small. When n = 1, 2, and 3 the cyclic
intermediates are 4, 5, and 6 membered rings respectively. Work done by
Dieter35 and coworkers suggest that palladcycles that are 4 member rings are
not favored, but 5 and 6 membered rings are. It would then be reasonable to
expect the 5 and 6 membered ring intermediates to give the lowest ratio of trans
to internal stannane, but this is not what is observed. To explain why the ratio of
trans to internal stannane is lowest for the n = 1 case, the electronics of the 7
system must also be considered. It has already been shown that the presence
of an electron withdrawing group alpha to the carbon—carbon triple bond leads
to selective internal isomer production. This is explained by the polarization ‘of
the triple bond. Once polarized, the terminal carbon will be partially positive
which will enhance the addition of the hydride to that position.

With regards to the free radical conditions, the trans isomer is always the

dominant isomer and in the 4-pentyn-1-ol (58) and 5-hexyn-1-ol (65) examples

14

Figure 16. Hydrostannylation of a-Substituted Alkynes.

 

Pd(O) H
///\OH BuaSnH (52%) : Bu:1~¢"/§/\°" + jg:

1 1.3

 

 

25 27 20
}A MD) T A +
// 8113an (86%) Bugs \ "Bus
3 1
79 so 81
H
22 PM» A f<
: +
Bu Snl-l 60% B \
// a ( ) U3 0:
19 1
29 so 31

no internal isomer is observed. In comparing the two methods, they seem
complementary with regards to the trans isomer being predominate under
radical conditions and the internal isomer being available in decent yields via
the Pd(O) conditions.

To get an idea of the strength of the directing effect compared to steric
hindrance, a series of experiments was designed to examine these potentially
competing features (Figure 16). With only one substituent alpha to the carbon-
carbon triple bond, the trans isomer predominates but significant amounts of the
internal stannane are produced. For the disubstituted propargyl alcohol the
trans isomer is formed in a large excess, 19:1. These results agree with the

general consensus in the literature,” that large steric hindrance at the alpha

15

position can overwhelm any directing effects by neighboring oxygen
functionalities.
METHYL ETHER SERIES

The next question was whether the observed directing effect is unique to
hydroxyl oxygens, or can other oxygen containing functionalities such as ethers
or esters influence the regioselectivity. To answer this question, the alcohols
studied previously were converted to the corresponding methyl ethers32 and
then subjected to both free radical and Pd(0) catalyzed hydrostannylation
conditions. To form the methyl ethers, the corresponding alcohols were reacted
with sodium hydride and then exposed to methyl iodide (Figure 17). The
isolation of these compounds were not as trivial as one may suspect, due to

their boiling points being similar to those of the solvents, a prep-GC was used to

Figure 17. Preparation of the Methyl Ether Series.

//H.:OH 2:82,," ; fl“

n=2,3,4

 

purify the methyl ethers. The prep-GC did prove adequate to purify small
amounts of the methyl ethers, but due to time only enough of the material was
isolated to be carried on to the hydrostannylation step. As indicated by the
results shown in Figure 18, the ether series did indeed promote the addition of

the tin moiety to the internal carbon. In fact, there was a greater directing effect

16

Figure 18. Methoxy Ether Oxygen Directed Hydrostannylations.

81:3an "8“3 /
W : Baas/V6.12” * My “ "
l1

 

n80;

mm W
n =1 82 Free Radical: 82% 7.8 83 1.8 84 1 5
Pd(O) Mediated: 81% 5.7 33 1 37 16.7 33
n = 2 89 Free Radical: 50% 19 90 1 91 0 92
Pd(0) Mediated: 77% 6.5 93 1 94 6 6 95
n = 3 96 Free Radical: 46% 20 97 1 98 2 99
Pd(O) Mediated: 81% 1.4 100 0 101 1 101
n = 4 102 Free Radical: 48% 16 103 1 104 1 105
Pd(O) Mediated: 73% 3.5 109 1 107 1.3 103

for the methoxy propargyl substrate than for propargyl alcohol. This may be a
reflection of the availability of the oxygen to coordinate to the Pd center in a
palladacycle intermediate. The hydroxyl functional group will be hindered for
coordination due to hydrogen bonding with the solvent (THF), but this will not be
the case for the methyl ether group. The hindrance caused by hydrogen
bonding will be amplified for the n = 1 case. In this situation the formation of a 4
membered palladacycle intermediate is highly strained, and the hindrance of
any solvation of oxygen will be even more sterically demanding. The ratio of
trans to internal slowly goes to 3:1 as the methoxy group position is extended by
4 methylene spacers (102). The methoxy function did not effect the ratio under
the free radical conditions. The trans isomer is always formed in a fairly high

excess and in ratios similar to the hydroxyl substrates.

17

ACETATE SERIES

Next a new series with acetate functional groups were examined.
Acetates should be able to coordinate to the Pd metal center better than the
hydroxyls or the methoxy ethers already studied. The acetates were
synthesized from the corresponding alcohols by reacting the alkynol with acetic
anhydride and pyridine (Figure 19).32 The acetates also showed a directing
effect, which was larger than that observed for either the hydroxyl groups or the
methyl ethers (Figure 20). Even when there were four methylene spacers (128)
between the acetylene and acetate functionality the ratio of trans to internal

stannane was 1.3:1, where as for the corresponding alcohol (65) it was 3:1 and

Figure 19. Preparation of Acetate Series.

 

Figure 20. Acetate Oxygen Directed Hydrostannylations.

 

Al en’sm = euaMo/lksm K/fie/fix mi

 

lends

nfl 109 Free Radical: 69% 9.7 110 1 111 0 112
Pd(O) Mediated: 94% 1 "3 o I“ 1.3 "5

n=3 116 Free Radical: 75% 18.6 117 1.5 119 1 119
Pd(O) Mediated: 60% 1.4 12° 0 12‘ 1 122

n=4 123 Free Radical: 61% 4 124 1 125 0 128
Pd(O) Mediated: 99% 1.9 ‘27 o ‘2‘ 1 m

18

the for methyl ether (102) 2.7:1 ratio was observed. Thus the acetate exhibited
3 times the directing effect than the hydroxyl and methyl ether substrates. This
result may be due to the increased basicity at the carbonyl oxygen.
Unfortunately direct comparison in the propargyl were impossible due to the fact
that during hydrostannylation under Pd(0) conditions the acetate functionality
would serve as a leaving group and no vinyl stannane could be towed.28

The results of the reactions under the free radical conditions followed the
trend that had been observed in the previous series. The formation of the trans
isomer was always dominates. Hydrostannylation of the propargyl acetate
under free radical did not produce a vinyl stannane as decomposition of starting
material occurred.
ONE POT HYDROSTANNYLATION/STILLE-CROSS COUPLING

Development of our one pot hydrostannylation/St“le-Cross coupling
methodology ran concurrent with this project. The initial results of steric vs.
oxygen directed hydrostannylations helped identify the alkynes to be used for
the one pot study. As the focus of our study was the combination of the
hydrostannylation and cross-coupling reactions, we wished to minimize
complications which could arise from the hydrostannylation step being non-
regioselective. Therefore we chose a-trisubstituted alkynes as our substrates
since they are highly biased towards (E)-vinylstannanes upon Pd-catalyzed
hydrostannylation.3"'3‘

Thus it was observed by others within the group that the reaction of

Buaan with a variety of alkynes in the presence of 1.1 equivalents of B-

19

Figure 21. Two Step Hydrostannylation/StilIe-Cross Coupling.

OH W'

 

 

 

 

 

 

H 313an
(PhaPldeCiz _ Bu as W (PhaPthCh _ \ \
// THF, 0°C (emf THF. rt (45%) r
130 131 132
NH 3,3an NH: PM 2
2 (Phaplzpdcb Ems/w (PhanPdC‘z _ \ \
é THF, ooc (W THF, r.t. (47%) V
133 134 135
a: SnF \
(Ph33P)2PdClz ‘ M pN \ \
/ PMHS,TBAFfi “35 (”'3th =
/ Et20, 0°C (44%) THF, r.t. (41%)
139 137 133

bromostyrene and 0.3 mol% (PPh3)2PdCl2 resulted in formation of the
anticipated 1,3-dienes in yields that were comparable or superior to that of the
stepwise variant. Control reactions were also completed using the traditional
two step method with 3,3—dimethyl-1-butyne (136), 3,5-dimethyl-1-hexyn-3-ol
(130), and 3,3-diethylpropargylamine (133) as shown in Figure 21. As
expected, the high steric hindrance at the alpha position, lead to the trans
stannane being formed as the sole product during the hydrostannylation. The
vinyl tin products from these reactions were then subjected to Stille cross-
couplings (Figure 21).

One problem that plagues Pd(0) mediated hydrostannylations is the
separation of the vinyl stannane from any hexabutylditin byproduct. Since the
polarity of the hexabutylditin and many alkyl vinyl stannanes is very similar their

elution times on a silica gel column is often identical. To avoid this problem a

20

modification to the hydrostannylation conditions were discovered by a coworker
within the group.38 By using slight excess of Buaanl, aqueous KF, and PMHS
to effect the in situ generation of Buaan, the formation of the tin dimer can be
minimized.
FUTURE WORK

To date we have demonstrated that there is a directing effect from oxygen
functionalities which can enhance the formation of internal vinyl stannanes. To
further explore this topic, a series of experiments with functional groups that
could coordinate either better or worse to the palladium metal center need to be
developed. By comparing these extreme cases to the functional groups already

studied, a better handle on the factors that influences internal stannane

Figure 22. Future Series.

u;
313an
N... “M... . E», . W
n "W “03
140 141 143

)2

 

 

139
”05” 8%an M + m ".3
03 t Bus M03 \ + n
n n
/ 11 Slide, Snag
1‘3 1“ 145 1“

formation would be attained. For example, it is known that amino groups bind to
palladium better than do oxygen. If our proposal is correct, using the amino
functionality in a series should show an increased trend in formation of the
internal stannane. Silylethers would be expected to decrease the coordination

due to the steric hindrance around the oxygen atom, resulting in a smaller

21

amount of internal stannane produced. The electronics of the Silylethers would
be similar to that of the methyl ethers so the effect of polariztion would not be a
factor when comparing the two sets of data. Once these two series are studied
a clearer picture into the question of coordination to the palladium center and
the possibility of palladacycles will be available.
SUMMARY AND CONCLUSIONS

To conclude, it has been shown that oxygen functionalities can influence
the regioselectivity of hydrostannylation reactions, with a bias in the direction of
the internal isomer. The degree of this influence does decrease as the oxygen
functionality is moved away from the alkyne and there is a high degree of steric
hindrance at the or position. This directing effect maybe the result of polarization
of the triple bond and/or the formation of palladacycle intermediates. The notion
of polarization of the triple bond explains the large amount of internal vinyl
stannane being formed when the oxygen is alpha to the alkyne. Once the
oxygen functionality is further removed, palladacycle intermediates provide
reasonable explanations for the formation of the internal isomer. It was also
observed that the acetates exhibited 3 times the directing effect as the hydroxyl
or methyl ether functional groups. This information will prove useful in
predicting the expected ratios of Pd(0) mediated hydrostannylations, and may
also assist in the decision as to which methodology to employ when forming
vinyl stannanes.

EXPERIMENTAL

22

Reactions were carried out in oven-dried glassware under nitrogen
atmosphere, unless otherwise noted. All commercial reagents were used
without purification. All solvents were reagent grade. THF was freshly distilled
from sodium/benzophenone from under nitrogen. Benzene was freshly distilled
from calcium hydride under nitrogen. Except as otherwise indicated, all
reactions were magnetically stirred and monitored by thin layer chromatography
with 0.25-mm precoated silica gel plates. Flash chromatography was
performed with silica gel 60 A (particle size 230-400 Mesh ASTM) supplied by
Whatman Inc. The column used in the preparatory gas chromatography was
packed with 20% SE-30 on Chromosorb W-AW-DMCS. Yields refer to
chromatographically and spectroscopically pure compounds, unless otherwise
stated. Infrared spectra were recorded on a Nicolet lR/42 spectrometer. Proton
and carbon NMR spectra were recorded on a Varian Gemini-300 spectrometer.
Chemical shifts are reported relative to the residue peaks of solvent chloroform
(8 7.24 for ‘H and 6 77.0 for ‘30). High-resolution mass spectra were obtained
at either the Michigan State University Mass Spectrometry Service Center with
a JEOL-AX505 mass spectrometer (resolution 7000) or at the Mass
Spectrometry Laboratory of the University of South Carolina, Department of
Chemistry & Biochemistry with a Micromass VG-7OS mass spectrometer.
GC/MS were performed with either a HP-5890 GC/MS fitted with a SPB—20
fused silica column or a Finnigan 4500 fitted with a Restek Rtx-5 column (30
meter by 0.25 mm ID).

Preparation of 5-methoxy-1-pentyne (mbr1-68):

23

Wo/

To a 100 mL RB containing a solution of Mel (8.90 g, 63 mmol) and THF
(50 mL) was added NaH (2.40 g, 55 mmol, 55% dispersion in oil).12 The
reaction was then placed in an oil bath that was preheated to 65 °C. 4-pentyn-
1-oI (3.40 g, 40 mmol) was added dropwise to the reaction mixture. Upon
complete addition the reaction was allowed to stir for 1 hr. At this time a few
milliliters of water were added to destroy any remaining NaH. Then the mixture
was extracted with diethyl ether (3x) and dried over MgSO4. The ether layer
was filtered and then distilled until the distalant was no longer pure ether (~ 30
mL). The remaining mixture was then subjected to preparatory gas
chromoatography. The desired product, a yellowish liquid, had a retention time
of 6 min. when the prep-GC was set at 80°C, ~100 mg was collected. 1H NMR
(300 MHz, CDCI3) 6 1.76 (m, 2 H), 1.92 (t, J = 2.5 Hz, 1 H), 2.26 (dt, J = 2.7 Hz,
7.1 Hz, 2 H), 3.32 (s, 3 H), 3.45 (t, J: 6.3 Hz, 2 H). The spectroscopic data was
consistent with those previously reported in the literature: Jackson, R.;
Perlmutter P.; Smallridge A. Aust. J. Chem. 1988, 41, 251.

Formation of 6-methoxy-1-hexyne (mbr1-26):

\
///\/\/o

To a 100 mL RB containing a solution of Mel (8.57 g, 61 mmol) and THF
(40 mL) was added NaH (2.40 g, 55 mmol, 55% dispersion in oil).12 The
reaction was then placed in an oil bath that was preheated to 65 °C. 5-hexyn-1-

ol (3.90 g, 40 mmol) was added dropwise to the reaction mixture. Upon

24

complete addition the reaction was allowed to stir for 1.5 hr. At this time a few
milliliters of water were added to destroy any remaining NaH. Then the mixture
was extracted with diethyl ether (3x) and dried over MgSO,. The ether layer
was filtered and then distilled until the distalant was no longer pure ether (~ 30
mL). The remaining mixture was then subjected to preparatory gas
chromoatography. The desired product, a yellowish liquid, had a retention time
of 6 min. when the prep-GO was set at 80 °C. ~130 mg was collected. ‘H NMR
(300 MHz, CDCla) 6 1.60 (m, 4 H), 1.90 (t, J = 2.8 Hz, 1 H), 2.18 (dt, J: 2.7 Hz,
6.8 Hz, 2 H), 3.28 (s, 3 H), 3.35 (t, J = 6 Hz, 2 H). The spectroscopic data was
consistent with those previously reported in the literature: Jackson, R.;
Perlmutter P.; Smallridge A. Aust. J. Chem. 1988, 41, 251.

Formation of 3-methoxy-1-hexyne (mbr1-28):

/
%/\/

To a 100 mL RB containing a solution of Mel (4.25 g, 30 mmol) and THF
(20 mL) was added NaH (4.01 g, 97 mmol, 55% dispersion in oil)." The
reaction was then placed in an oil bath that was preheated to 65 °C. 1-hexyn-3-
ol (1.98 g, 40 mmol) was added dropwise to the reaction mixture. Upon
complete addition the reaction was allowed to stir for 1.5 hr. At this time a few
milliliters of water were added to destroy any remaining NaH. Then the mixture
was extracted with diethyl ether (3x) and dried over MgSO,. The ether layer

was filtered and then distilled until the distillate was no longer pure ether (~ 30

25

mL). The remaining mixture was then subjected to preparatory gas
chromoatography. The desired product, a yellowish liquid, had a retention time
of 6 min. when the prep-GO was set at 80 °C. ~100 mg was collected. 1H NMR
(300 MHz, CDCI3) 6 0.91 (t, J: 7.2 Hz, 3 H), 1.47 (m, 2 H), 1.67 (m 2 H), 2.41 (d,
J: 2.2 Hz, 1 H), 3.39 (s, 3 H), 3.92 (dt, J: 2.2 Hz, 6.4 Hz, 1 H).

Formation of 4-aceto-1-butyne (mbr1-43):
O
é/V \g/

To a 50 mL RB containing a solution of pyridine (5.45 g, 69 mmol) and 3-
butyn-1-ol (4.84 g, 69 mmol) was added acetic anhydride (6.92 g, 68 mmol).
Upon complete addition the reaction was allowed to stir for 6 hrs. The reaction
mixture was extracted with diethyl ether and CuSO4 (3x) and dried over M9804.
The organic layer was filtered and then concentrated on a rotavap. The desired
product, a clear liquid, was isolated in a 65 % yield. 1H NMR (300 MHz, CDCIa)
6 1.96 (t, J: 3.8 Hz, 1 H), 2.04 (s, 3 H), 2.48 (dt, J: 2.8 Hz, 6.8 Hz, 2 H), 4.13 (t,
J = 6.8 Hz, 2 H). Preperation of 4-aceto—1-butyne was done similiar as reported
in the literature: Jones, E.; Shen 1.; Whiting M. Chem. Soc. 1950, 230.1

Formation of 5-aceto-1-pentyne (mbr1-63):

Wit

To a 50 mL RB containing a solution of pyridine (5.45 g, 69 mmol) and 4-

petyn-1-ol (5.80 g, 69 mmol) was added acetic anhydride (6.99 g, 68 mmol).

26

Upon complete addition the reaction was allowed to stir for 6 hrs. The reaction
mixture was extracted with diethyl ether and CuSO4 (3x) and dried over MgSO,,.
The organic layer was filtered and then concentrated on a rotavap. The desired
product, a clear liquid, was isolated in a 72 % yield (6.28 g). 1H NMR (300 MHz,
CDCI3) 6 1.82 (m, 2 H), 1.93 (t. J: 2.8 Hz, 1 H), 2.01 (s, 3 H), 2.25 (dt, J: 2.7 Hz,
7.0 Hz 2 H), 4.13 (t, J = 6.3 Hz, 2 H). The spectroscopic data was consistent
with those previously reported in the literature: White J.; Kim T.; Nambu M. J.
Am. Chem. Soc. 1997, 119, 103.

Hydrostannylation of 1-pentyne (Pd(0). mbr1-86):

B
Buss

In a 25 mL RB 5 mL THF, 8 mg (PhaP)2PdCl2 (8 umol), and 68 mg of 1-
pentyne (1 mmol) were added. An ice bath was used to maintain the
temperature of the reaction at 0 °C. Then 0.4 mL BuSSnH (1.5 mmol) was
‘ added slowly. After 45 min. a crude NMR was taken to establish the ratio of
regioisomers, E/lnt/Z 2.2/1/0. 1H NMR (300 MHz, CDCIa) for E; 6 0.87 (m, 20 H),
1.28 (m, 6 H), 1.45 (m, 6 H), 2.08 (m, 2 H), 5.89 (m, 2 H). 1H NMR (300 MHz,
CDCI3) for Int.; 6 0.87 (m, 20 H), 1.28 (m, 6 H), 1.45 (m, 6 H), 2.19 (t, J: 7.1 Hz, 2
H), 5.07 (m, 1 H), 5.63 (m, 1 H).

Hydrostannylation of 1-hexyne (Pd(0). mbr1-69):

DB
Buasw “3 M

8038n

27

In a 25 mL RB 5 mL THF, 5.4 mg (Ph:,P)2PdCl2 (8 umol), and 90 mg of 1-
hexyne (1 mmol) were added. An ice bath was used to maintain the
temperature of the reaction at 0 °C. Then 0.4 mL Buaan (1.5 mmol) was
added slowly. After 1 hr a crude NMR was taken to establish the ratio of
regioisomers, E/lnt/Z 1.8/1/0. 1H NMR (300 MHz, CDCI3) for E; 6 0.87 (m, 20 H),
1.28 (m, 8 H), 1.45 (m, 8 H), 2.11 (q, 2 H), 5.88 (m, 2 H). ‘H NMR (300 MHz,
CDCla) for Int.; 6 0.86 (m, 20 H), 1.28 (m, 8 H), 1.45 (m, 6 H), 2.21 (t, 2 H), 5.06
(m, 1 H), 5.63 (m, 1 H).

Hydrostannylation of 1-heptyne (Pd(0), mbr1-87):

B 038W x M
B u3Sn

In a 25 mL RB 5 mL THF, 5 mg (Ph:,P)2PdCI2 (8 umol), and 96 mg of 1-
heptyne (1 mmol) were added. An ice bath was used to maintain the
temperature of the reaction at 0 °C. Then 0.4 mL BUSSnH (1.5 mmol) was
added slowly. After 45 min. a crude NMR was taken to establish the ratio of
regioisomers, E/Int/Z 1.9/1/0. 1H NMR (300 MHz, CDCIa) for E; 6 0.86 (m, 20 H),
1.28 (m, 8 H), 1.45 (m, 8 H), 2.10 (dq, J: 1.1 Hz, J: 6.9 Hz, 2 H), 5.99 (m, 2 H).
1H NMR (300 MHz, CDCI3) for Int.; 6 0.86 (m, 20 H), 1.28 (m, 8 H), 1.45 (m, 8 H),
2.20 (t, J: 7.4 Hz, 2 H), 5.06 (m, J3” = 66 Hz, 1 H), 5.63 (m, J3" = 142 Hz, 1 H).
The spectroscopic data was consistent with those previously reported in the
literature: Cliff M.; Pyne S. Tetrahedron 1996, 52, 13703-13712.

Hydrostannylation of 4-pentyn-1-ol (Pd(0), mbr1-62):

28

3038 H
B WSW/VG” M H M

803811

In a 25 mL flask 5 mL THF, 5.9 mg (8 umol) (PhaP)2PdCI2 and
0.095 mL (1 mmol) 4-pentyn-1-ol was added. An ice bath was used to maintain
the temperature of the reaction at 0 °C. Then 0.4 mL (1.5 mmol) Bu38nH was
added dropwise. The reaction was stopped after 45 min. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/lntemaI/Z 2.5:1 :0. The
mixture was passed through a silica column using 95.5:0.5 petroleum
ether/ethyl acetate, R, = 0.25. The isolated yield was 56% (210 mg mixture of
the E and internal isomer). IR (neat) 3330, 2960, 2920, 2880, 2860, 1450,
1410, 1380, 1070 cm"; 1H NMR (300 MHz, CDCla) for E: 6 0.86 (m, 15 H), 1.29
(m, 6 H), 1.43 (m, 6 H), 1.66 (m, 2 H), 2.21 (m, 2 H), 3.63 (m, 2 H), 5.92 (m, 2 H)
for Internal: 6 0.86 (m, 15 H), 1.29 (m, 6 H), 1.43 (m, 6 H), 1.66 (m, 2 H), 2.30 (t, J
= 7.4 Hz, 2 H), 3.63 (m, 2 H), 5.11 (m, an = 30.5 Hz, 1 H), 5.69 (m, an = 68.4
Hz, 1 H); 130 NMR (75 MHz, CDCla) for E: 6 148.6, 128.1, 62.4, 34.1, 31.7,
29.1, 27.2, 13.7, 9.3 for internal: 6 154.7, 125.2, 62.4, 37.4, 32.3, 29.1, 27.3,
13.6, 9.5; HRMS (El) m/z 319.1082 [(Mf-Bu); calcd. for C13H270Sn 319.1086].
(radical, mbr1-64)
In a 25 mL flask 5 mL benzene, 9.9 mg (0.08 mmol) AIBN and 0.094 mL
(1 mmol) 4-pentyn-1ol was added. A preheated oil bath was used to maintain
the temperature of the reaction at 80 °C. Then 0.4 mL (1.5 mmol) BuaSnH was
added dropwise. The reaction was stopped after 3.25 hrs. A crude NMR was

taken to establish the ratio of the regioisomers formed, E/lntJZ 9:0:1. The

29

mixture was passed through a silica column using 95.5:0.5 petroleum
ether/ethyl acetate, Rl = 0.20. The isolated yield was 70% (91 mg of the E
isomer and 170 mg mixture of the E and Z isomer). IR (neat) 3310, 2960, 2920,
2870, 2850, 1450, 1390, 1070 cm“; ‘H NMR (300 MHz, CDCla) for E; 6 0.87 (m,
15 H), 1.29 (m, 6 H), 1.44 (m, 6 H), 1.66 (m, 2 H), 2.20 (dt, J = 4.4 Hz, 7.1 Hz 2
H), 3.64 (t, J = 6.3 Hz, 2 H), 5.92 (m, 2 H) for Z; 6 0.87 (m, 15 H), 1.29 (m, 6 H),
1.44 (m, 6 H), 1.66 (m, 2 H), 2.10 (ddt, J: 0.8 Hz, 7.2 Hz, 6.5 Hz, 2 H), 3.64 (t, J
= 6.3 Hz, 2 H), 5.80 (dt, J: 12.4 Hz, 1.1 Hz, 1 H), 6.51 (dt, J = 12.4 Hz, 7.2 Hz, 1
H); 1“C NMR (75 MHz, CDCIa) for E; 6 9.3, 13.7, 27.2, 29.1, 31.7, 34.1, 62.5,
128.2, 148.6for Z; 6 148.6, 128.2, 62.5, 33.3, 32.8, 29.1, 27.3, 13.7, 10.2; HRMS
(El) m/z 319.1090 [(M*-Bu); calcd. for C,3H2.,OSn 319.1086]. The spectroscopic
data was consistent with those previously reported in the literature: Dussault P.;
Eary T. J. Am. Chem. Soc. 1998, 120, 7133-7134 .

Hydrostannylation of 3-methoxy-1-propyne (Pd(0), mbr1-32):

Bu38n /
“MW )\/‘K M

8038n

In a 25 mL flask 5 mL THF, 5.4 mg (8 umol) (Ph:,P)2PdCl2 and 0.084 mL
(1 mmol) 3-methoxy-1-propyne was added. An ice bath was used to maintain
the temperature of the reaction at 0 °C. Then 0.4 mL (1.5 mmol) Buaan was
added dropwise. The reaction was stopped after 45 min. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/lntemaI/Z 2.6:8.1:1.
The mixture was passed through a silica column using 99.5:0.5 petroleum

ether/ethyl acetate, R, = 0.18. The isolated yield was 49% (72.1 mg of the E

30

isomer and 104.3 mg mixture of the Z and internal isomer). IR (neat) 2930,
2910, 2830, 2810, 1405, 1050. 1H NMR (300 MHz, CDCIa) for E: 6 0.87 (m, 15
H), 1.27 (m, 12 H), 1.44 (m, 12 H), 3.32 (s, 3 H), 3.93 (dd, J = 1.4 Hz, 4.9 Hz, 1
H), 6.02 (dt,J= 19.2 Hz, 5.0 Hz, 2 H), 6.20 (dt, J = 18.9 Hz, 1.1 Hz, 1 H) for
lntemal: 6 0.87 (m, 15 H), 1.27 (m, 12 H), 1.44 (m, 12 H), 3.32 (s, 3 H), 4.00 (t, J
= 1.6 Hz), 5.24 (m, J3" = 64.9 Hz, 1 H), 5.83 (m, J8" = 116.7 Hz, 1 H) for Z: 6 0.87
(m, 15 H), 1.27 (m, 12 H), 1.44 (m, 12 H), 3.27 (s, 3 H), 3.89 (dd, J: 5.5 Hz, 1.4
Hz, 2 H), 6.06 (d, J = 13.2 Hz, 1 H), 6.60 (dt, J: 12.9 Hz, 5.5 Hz, 1 H); 13C NMR
75 MHz, CDCIS) for E: 6 144.4, 131.3, 76.3, 57.8, 29.1, 27.3, 13.7, 9.4 for
lntemal: 6 153.0, 124.6, 79.7, 57.7, 29.1, 27.4, 13.7, 9.5 for Z: 6 143.9, 131.8,
75.1, 57.7, 29.1, 27.4, 13.7, 9.5; HRMS (El) m/z 305.0933 [(M"-Bu); calcd. for
C,2H250$n 305.0929].

(radical, mbr1-60)

In a 25 mL flask 10 mL benzene, 11 mg (0.09 mmol) AIBN and .09 mL (1
mmol) 3-methoxy-1-propyne was added. A preheated oil bath was used to
maintain the temperature of the reaction at 80 °C. Then 0.27 mL (1 mmol)
Buaan was added dropwise. The reaction was stopped after 3 hrs. A crude
NMR was taken to establish the ratio of the regioisomers formed, E/Intemal/Z
7.8:1:1.8. The mixture was passed through a silica column using 95:5
petroleum ether/ethyl acetate, Fl, = 0.41. The isolated yield was 82% (48.4 mg
of the E isomer and 248.9 mg mixture of the E, Z, and internal isomer). IR (neat)
2950, 2920, 2870, 2840, 2810, 1450, 1380, 1110, 1100, 1000 cm"; ‘H NMR

(300 MHz, CDCI3) for E: 6 0.86 (m, 15 H), 1.29 (m, 6 H), 1.45 (m, 6 H), 3.31 (s, 3

31

H), 3.92 (dd, J: 1.3 Hz, 5.0 Hz, 2 H), 6.05 (m, 2 H) for lntemal: 6 0.86 (m, 15 H),
1.29 (m, 6 H), 1.45 (m, 6 H), 3.27 (s, 3 H), 4.00 (t, J = 1.5 Hz, 2 H), 5.24 (m, J5" =
62.4 Hz, 1 H), 5.83 (m, J3" = 128.2 Hz, 1 H) for Z 6 0.86 (m, 15 H), 1.29 (m, 12
H), 1.45 (m, 12 H), 3.31 (s, 3 H), 3.87 (dd, J = 1.3 Hz, 5.2 Hz, 2 H), 6.06 (dt, J =
13.2 Hz, 1.4 Hz, 1 H), 6.59 (dt, J = 13.2 Hz, J: 5.5 Hz, 1 H). ”C NMR (75 MHz,
00013) for E: 6 144.4, 131.3, 76.6, 57.8, 29.1, 27.3, 13.7 for lntemal: 6 153.0,
124.6, 79.7, 58.0, 29.1, 27.4, 13.7, 9.5 for Z: 6 143.9, 131.8, 75.1, 58.0, 29.1,
27.4, 13.7, 9.5; HRMS (El) m/z 305.0936 [(M*-Bu); calcd. for C,2H2508n
305.0929]. The spectroscopic data was consistent with those previously
reported in the literature: Verlhac J.; Pereyre M. Tetrahedron 1990, 46, 6399-
6412.

Hydrostannylation of 4-methoxy-1-butyne (Pd(0), mbr1-53):
Buas / O/
BUaSWo/ 0/ 8%an

In a 25 mL flask 5 mL THF, 5.9 mg (8 umol) (Ph:,,P)2PdCl2 and 79 mg (1
mmol) 4-methoxy-1-butyne was added. An ice bath was used to maintain the
temperature of the reaction at 0 °C. Then 0.4 mL (1.5 mmol) BuSSnH was
added dropwise. The reaction was stopped after 50 min. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/Intemal/Z 6.5:6.6:1.
The mixture was passed through a silica column using 99.5:0.5 petroleum
ether/ethyl acetate, R, = 0.11. The isolated yield was 77% (285.3 mg mixture of
the E, Z, and intemal isomer). IR (neat) 2960, 2920, 2860, 2850, 1450, 1360,

1110 cm"; ‘H NMR (300 MHz, 0001,) for E: 6 0.86 (m. 15 H). 1.28 (m. 12 H).

32

1.45 (m, 12 H), 2.40 (m, 2 H), 3.30 (s, 3 H), 3.41 (t, J=6.9 Hz, 2 H), 5.93 (m, 2 H)
for lntemal: 6 0.86 (m, 15 H), 1.28 (m, 12 H), 1.45 (m, 12 H), 2.49 (t, J: 6.6 Hz, 2
H), 3.30 (s, 3 H), 3.37 (t, J: 6.9 Hz, 2 H), 5.16 (m, J9, = 60 Hz, 1 H), 5.72 (m, J3"
= 136 Hz, 1 H); 13C NMR (75 MHz, CDCIS) for E: 6145.1, 129.8, 72.6, 41.3, 29.1,
27.4, 13.7, 9.7 for lntemal: 6 151.6, 126.6, 72.2, 58.5, 29.3, 27.3, 13.7, 9.5;
HRMS (El) m/z 319.1088 [(M*-Bu); calcd. for C,3H2,OSn 319.1086].
Preparation/hydrostannylation of 4-methoxy-1-butyne (mbr1-90)

To a 50 mL RB containing a solution of Mel (709 mg, 5 mmol) and
benzene (25 mL) was added NaH (117 mg, 5.1 mmol). A preheated oil bath
was used to maintain the temperature of the reaction at 80 °C. 3-butyn-1-ol
(350 mg, 5 mmol) was added dropwise to the reaction mixture. After the
reaction had stirred for 3 hr, catalytic amount of AIBN (40 mg) was added. Then
Bu38nH (2.5 mL, 5.5 mmol) was added drop wise. The reaction was stopped
after stirring for an additional 3.5 hours. The reaction mixture was concentrated
and a crude NMR was taken to establish the ratio of the regioisomers,
E/lntemaVZ 15/0/1. Then the reaction was purified by flash column
chromotography using 9:1 hexanes/ethyl acetate, Rl = 0.57. The observation
was made that a large portion of the original alcohol was not converted to the
methyl ether (~1.2 9), so there was a substantial amount of alkynol vinyl
stannane formed. 0.94 g of the trans isomer was isolated (50 % yield) with trace
amounts of the cis isomer being present. IR (neat) 2950, 2910, 2870, 2850,
1420, 1100 cm“; 1H NMR (300 MHz, CDCI3) for E: 6 0.86 (m, 15 H), 1.28 (m, 6

H). 1-45 (m, 6 H), 2.39 (m, 2 H), 3.31 (s, 3 H), 3.41 (t, J: 7.0 Hz, 2 H), 5.95 (m, 2

33

H). ‘30 NMR (75 MHz, 0001,) for E: 5 144.7, 131.9, 61.5, 41.2, 29.1, 27.3, 13.7,

9.5; HRMS (El) m/z 319.1097 [(M*-Bu); calcd. for C13H2.,OSn 319.1086].

Hydrostannylation of 5-methoxy-1-pentyne (Pd(0), mbr1-73):
Buas
/ \
BuasW\ MO\ Boas!‘/\/\/°

In a 25 mL flask 5 mL THF, 7.1 mg (0.1 mmol) (PhaP)2PdC|2 and 120 mg
(1.2 mmol) 4-methoxy-1-butyne was added. An ice bath was used to maintain
the temperature of the reaction at 0 °C. Then 0.6 mL (2.2 mmol) Buaan was
added dropwise. The reaction was stopped after 45 min. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/IntemaI/Z 1.4:1:0. The
mixture was passed through a silica column using 95:5 petroleum ether/ethyl
acetate, R, = 0.75. The isolated yield was 81% (316.3 mg mixture of the E and
internal isomer). IR (neat) 2960, 2920, 2870, 2850, 1450, 1110 cm“; ‘H NMR
(300 MHz, CDCla) for E: 6 0.86 (m, 15 H), 1.28 (m, 12 H), 1.44 (m, 12 H) 1.65 (m,
2 H), 2.16 (dt, J = 4.6 Hz, 7.7 Hz, 2 H), 3.30 (s, 3 H), 3.35 (t, J = 6.6 Hz, 2 H), 5.89
(m, 2 H) for lntemal: 6 0.86 (m, 15 H), 1.28 (m, 12 H), 1.44 (m, 12 H) 1.65 (m, 2
H), 2.26 (t, J=7.5 Hz, 2 H), 3.30 (s, 3 H), 3.35 (t, J = 6.6 Hz, 2 H), 5.09 (m, J =
62.0 Hz, 1 H), 5.66 (m, Js,,= 138.6 Hz, 1 H); “C NMR (75 MHz, CDCIS) for E: 6
148.6, 127.8, 72.2, 58.5, 34.1, 29.1, 27.2, 13.7, 9.3 for lntemal: 6 154.6, 125.0,
72.3, 58.5, 37.4, 29.1, 27.3, 13.7, 9.5; HRMS (El) m/z 333.1246 [(M"-Bu); calcd.
for C,,H2,OSn 333.1243].

(radlcal, mbr1-71):

34

In a 25 mL flask 5 mL benzene, 9 mg (0.078 mmol) AIBN and 100 mg (1
mmol) 5-methoxy-1-pentyne was added. A preheated oil bath was used to
maintain the temperature of the reaction at 80 °C. Then 0.4 mL (1.5 mmol)
Buaan was added dropwise. The reaction was stopped after 3 hrs. A crude
NMR was taken to establish the ratio of the regioisomers formed, E/lntJZ 10:1:1.
The mixture was passed through a silica column using 95:5 petroleum
ether/ethyl acetate, R, = 0.40. The isolated yield was 46% (69 mg of the E
isomer and 110 mg mixture of the E, Z, and internal isomer). IR (neat) 2960,
2920, 2870, 2850, 1460, 1110 cm". 1H NMR (300 MHZ, CDCIa) for E: 6 0.86 (m,
15 H), 1.29 (m, 12 H), 1.45 (m, 12 H) 1.66 (m, 2 H), 2.16 (m, 2 H), 3.30 (s, 3 H),
3.35 (t, J = 6.6 Hz, 2 H), 5.90 (m, 2 H) for lntemal: 6 0.86 (m, 15 H), 1.29 (m, 12
H), 1.45 (m, 12 H) 1.66 (m, 2 H), 2.06 (m, 2 H), 3.30 (s, 3 H), 3.35 (t, J: 6.6 Hz, 2
H), 5.10 (m, J3" = 61.0 Hz), 5.66 (m, J5" = 144.2 Hz) for Z: 6 0.86 (m, 15 H), 1.29
(m, 12 H), 1.45 (m, 12 H) 1.66 (m, 2 H), 2.27 (m, 2 H), 3.30 (s, 3 H), 3.35 (t, J =
6.6 Hz, 2 H), 5.780 (dt, 12.4 Hz, 1.1 Hz, 1 H), 6.48 (dt, J = 12.4 Hz, 7.2 Hz, 2 H).
13C NMR (75 MHz, CDCIa) for E: 6 148.6, 127.8, 72.2, 58.5, 34.2, 29.1, 28.8,
27.3, 13.7, 9.4 for Z: 6 148.3, 128.3, 72.2, 58.5, 34.2, 29.1, 27.3, 13.7, 9.4;
HRMS (El) m/z 333.1249 [(M-Bu); calcd. for C1 4H2,,OSn 333.1243].

Hydrostannylation of 6-methoxy-1-hexyne (Pd(0), mbr1-27):

BUaSKA/W/ O/ BUSSM

In a 25 mL flask 5 mL THF, 4.1 mg (5 umol) (PhaP)2PdCl2 and 113 mg (1

mmol) 6-methoxy-1-hexyne was added. An ice bath was used to maintain the

35

temperature of the reaction at 0 °C. Then 0.54 mL (1.9 mmol) Buaan was
added dropwise. The reaction was stopped after 35 min. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/lntemal/Z 6.2:3:1. The
mixture was passed through a silica column using 99:1 petroleum ether/ethyl
acetate, RI = 0.10. The isolated yield was 73% (294.8 mg mixture of the E, Z
and internal isomer). IR (neat) 2980, 2960, 2930, 2920, 1210, 1150; ‘H NMR
(300 MHz, CDCIS) for E: 6 (m, 15 H), 1.28 (m, 12 H), 1.43 (m, 12 H), 1.56 (m, 4
H), 2.12 (dt, J: 4.9 Hz, 7.1 Hz, 2 H), 3.30 (s, 3 H), 3.35 (t, J = 6.5 Hz, 2 H), 5.87
(m, 2 H) for lntemal: 6 (m, 15 H), 1.28 (m, 12 H), 1.43 (m, 12 H), 1.56 (m, 4 H),
2.33 (t, J = 7.4 Hz, 2 H), 3.30 (s, 3 H), 3.34 (t, J = 6.6 Hz, 2 H), 5.08 (m, J3” = 62
Hz, 1 H), 5.64 (m, J3" = 140.2 Hz, 1 H). 13C NMR (75 MHz, CDCIa) for E: 6 149.0,
127.3, 72.7, 41.0, 29.1, 27.3, 13.8, 9.4 for lntemal: 6 155.0, 124.8, 72.6, 58.5,
29.2, 27.4, 13.8, 9.6; HRMS (El) m/z 347.1397 [(M*-Bu); calcd. C,5H3,OSn
347.1400].
(radical, mbr1-22):

In a 50 mL flask 16 mL benzene, 8.2 mg (0.07 mmol) AIBN and 100 mg
(1 mmol) 6-methoxy-1-hexyne was added. A preheated oil bath was used to
maintain the temperature of the reaction at 80 °C. Then 0.4 mL (1.5 mmol)
Buaan was added dropwise. After 3 hrs 8 mg (0.07 mmol) AIBN and 0.05 mL
(0.1 pmol) 3113an was added, and the reaction was stopped 1.5 hrs later. A
crude NMR was taken to establish the ratio of the regioisomers formed, E/IntJZ
10:0:1. The mixture was passed through a silica column using 99:1 petroleum

ether/ethyl acetate, R, = 0.10. The isolated yield was 48% (87.4 mg mixture of

36

the E and Z isomer). IR (neat) 2980, 2970, 2930, 2920, 1210, 1050; 1H NMR
(300 MHz, CDCIa) for E; 6 0.86 (m, 15 H), 1.28 (m, 12 H), 1.43 (m, 12 H), 1.56
(m, 2 H), 2.13 (dt, 4.7 Hz, 7.1 Hz, 2 H), 3.31 (s, 3 H), 3.35 (t, J = 6.6 Hz, 2 H),
5.87 (m, 2 H) for Z; 6 0.86 (m, 15 H), 1.28 (m, 12H), 1.43 (m, 12 H), 1.56 (m, 2 H),
2.03 (dt, 7.3 Hz, 7.2 Hz, 2 H), 3.31 (s, 3 H), 3.35 (t, J = 6.6 Hz, 2H), 5.87 (d, 12.4
Hz, 1 H), 6.47 (dt, J: 12.4 Hz, 7.2 Hz, 1 H).

Hydrostannylation of 4-aceto-1-butyne (Pd(0), mbr1-55):

O
B 038 O
Buaswoi Wok auasmk

In a 25 mL flask 5 mL THF, 5.5 mg (7.8 pmol) (Ph:,P)2PdCI2 and 112 mg
(1 mmol) 4-aceto-1-butyne was added. An ice bath was used to maintain the
temperature of the reaction at 0 °C. Then 0.4 mL (1.5 mmol) BUSSnH was
added dropwise. The reaction was stopped after 45 min. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/IntemaI/Z 1:1.4:0. The
mixture was passed through a silica column using 99.5:0.5 petroleum
ether/ethyl acetate, R, = 0.06. The isolated yield was 94% (380.6 mg mixture of
the E and internal isomer). IR (neat) 2960, 2920, 2880, 2850,1730, 1450,
1380, 1350, 1220, 1020 cm"; 1H NMR (300 MHz, CDCIa) for E: 6 .086 (m, 15 H),
1.28 (m, 12 H), 1.44 (m, 12 H), 2.01 (s, 3 H) 2.43 (ddt, J: 0.8 Hz, 5.8 Hz, 6.9 Hz,
2 H), 4.06 (t, J: 6.8 Hz, 2 H), 5.91 (m, 2 H) for lntemal: 6.086 (m, 15 H), 1.28 (m,
12 H), 1.44 (m, 12 H), 2.01 (s, 3 H), 2.52 (t, J: 6.8 Hz, 2 H), 4.09 (t, J = 6.9 Hz, 2

H), 5.19 (m, .18, = 50.4 Hz, 1 H), 5.73 (m, .15, = 133.4 Hz, 1 H); 130 NMR (75 MHz

37

CDCIa) for E: 6 171.0, 143.8, 131.3, 63.5, 36.8, 29.0, 13.7, 9.3 for lntemal: 6
171.0, 150.3, 127.7, 64.0, 39.7, 27.3, 21.0, 13.7, 9.5; HRMS (El) m/z 347.1032
[(M"-bu); calcd. for C,,H27028n 347.1036].

(radical, mbr1-57):

In a 50 mL flask 15 mL benzene, 12 mg (0.1 mmol) AIBN and 112 mg (1
mmol) 4-aceto-1-butyne was added. A preheated oil bath was used to maintain
the temperature of the reaction at 80 °C. Then 0.27 mL (1 mmol) Buaan was
added dropwise. The reaction was stopped after 3 hrs. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/IntemaI/Z 9.7:0:1. The
mixture was passed through a silica column using 95:5 petroleum ether/ethyl
acetate, R, = 0.62. The isolated yield was 69% (280 mg mixture of the E and Z
isomer). IR (neat) 2950, 2920, 2870, 2840, 1740, 1450, 1380, 1350, 1210,
1020 cm“; 1H NMR (300 MHz, CDCIa) for E: 6 0.85 (m, 15 H), 1.28 (m, 12 H),
1.44 (m, 12 H), 2.01 (s, 3 H), 2.42 (ddt, J: 0.8 Hz, 6.0 Hz, 6.9 Hz, 2 H), 4.09 (t, J
= 6.8 Hz, 2 H), 5.95 (m, 2 H) for Z‘ 6 0.85 (m, 15 H), 1.28 (m, 12 H), 1.44 (m, 12
H), 2.01 (s, 3 H), 2.33 (ddt, J: 1.1 Hz, 6.8 Hz, 6.9 Hz, 2 H), 4.07 (t, J = 6.8 Hz, 2
H), 5.92 (dt, J=12.7 Hz, 1.1 Hz, 1 H), 6.44 (dt, J = 12.7 Hz, 6.9 Hz, 1 H); “C
NMR (75 MHz, CDCIa) for E: 6 171.1, 143.8, 131.3, 63.6, 36.8, 29.0, 27.2, 20.9,
13.7, 9.3 for Z: 6 171.0, 143.7, 131.8, 63.8, 36.0, 29.0, 27.2, 20.9, 13.7, 9.3;
HRMS (El) m/z 347.1036 [(M*-bu); calcd. for C,,,H2,OZSn 347.1036].

Hydrostannylation of 5-aceto-1-pentyne (Pd(0), mbr1-66):

38

WSW? til/Jr emf/VT

In a 25 mL flask 5 mL THF, 8 mg (11 umol) (PhaP)2PdCI2 and 129 mg (1
mmol) 5-aceto-1-pentyne was added. An ice bath was used to maintain the
temperature of the reaction at 0 °C. Then 0.4 mL (1.5 mmol) Bu38nH was
added dropwise. The reaction was stopped after 50 min. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/lntemaI/Z 1.4:1:0. The
mixture was passed through a silica column using 99.5:0.5 petroleum
ether/ethyl acetate, R, = 0.12. The isolated yield was 60% (250 mg mixture of
the E and internal isomer). IR (neat) 2950, 2910, 2890, 2830, 1730, 1450,
1370, 1230, 1050; 1H NMR (300 MHz, CD013) for E: 6 0.86 (m, 15 H), 1.29 (m,
12 H), 1.45 (m, 12 H), 1.70 (m, 2 H), 2.03 (s, 3 H), 2.17 (m, 2 H), 4.04 (t, J: 6.6
Hz, 2 H), 5.90 (m, 2 H) for lntemal: 60.86 (m, 15 H), 1.29 (m, 12 H), 1.45 (m, 12
H), 1.70 (m, 2 H), 2.03 (s, 3 H), 2.27 (t, J = 7.7 Hz, H), 4.02 (t, J = 6.6 Hz, 2 H),
5.12 (m, J," = 61.6 Hz, 1 H), 5.66 (m, J3” = 137.4 Hz, 1 H). “’C NMR (75 MHz,
CDCIa) for E: 6 171.2, 147.7, 128.5, 64.0, 33.9, 29.2, 29.1, 27.2, 21.0, 13.7, 9.3
for lntemal: 6 171.2, 153.9, 125.5, 64.1, 37.2, 29.3, 29.1, 27.4, 20.9, 13.7, 9.5;
HRMS (El) m/z 361.1 192 [(M*-Bu); calcd. for C,5H29028n 361.1192].

(radical mediated, mbr1-65):

In a 25 mL flask 6 mL benzene, 12 mg (0.1 mmol) AIBN and 112 mg
(0.89 mmol) 5-aceto—1-pentyne was added. A preheated oil bath was used to
maintain the temperature of the reaction at 80 °C. Then 0.4 mL (1.5 mmol)

Buaan was added dropwise. The reaction was stopped after 3 hrs. A crude

39

NMR was taken to establish the ratio of the regioisomers formed, E/IntemaIlZ
182021. The mixture was passed through a silica column using 95:5 petroleum
ether/ethyl acetate, R, = 0.45. The isolated yield was 75 % (326 mg mixture of
the E and Z isomer). IR (neat) 2960, 2920, 2870, 2850, 1720, 1470, 1340,
1210, 1030 cm"; 1H NMR (300 MHz, CDCIs) for E: 6 0.85 (m, 15 H), 1.25 (m, 12
H), 1.44 (m, 12 H), 1.70 (m, 2 H), 2.01 (s, 3 H), 2.17 (m, 2 H), 4.03 (t, J: 6.6 Hz,
2 H), 5.90 (m, 2 H) for Z: 6 0.85 (m, 15 H), 1.25 (m, 12 H), 1.44 (m, 12 H), 1.70
(m, 2 H), 2.01 (s, 3 H), 2.17 (m, 2 H), 4.03 (t, J = 6.6 Hz, 2 H), 5.83 (dt, J = 12.4
Hz, 1.1 Hz, 1 H), (dt, J: 12.3 Hz, 6.9 Hz, 1 H); ”C NMR (75 MHz, CDCIa) for E: 6
171.1, 147.7, 128.5, 64.0, 33.9, 29.2, 29.1, 27.2, 20.9, 13.7, 9.3 for Z: 6 171.1,
147.4, 129.2, 64.0, 33.3, 29.2, 29.1, 27.2, 20.9, 13.7, 9.3; HRMS (El) m/z
361.1194 [(M"-Bu); calcd. for C,5H29028n 361.1192].

Hydrostannylation of 6-aceto-1-hexyne (Pd(0), mbr1-52)

MSW/YK ‘3ij Wk

In a 25 mL flask 5 mL THF, 5.6 mg (7.9 umol) (PhaP)2 PdCI2 and 140 mg
(1 mmol) 6-aceto—1-hexyne was added. An ice bath was used to maintain the
temperature of the reaction at 0 °C. Then 0.4 mL (1.5 mmol) Bu38nH was
added dropwise. The reaction was stopped after 50 min. A crude NMR was
taken to establish the ratio of the regioisomers formed, E/lntemaI/Z 1.2:1:0. The
mixture was passed through a silica column using 95:5 petroleum ether/ethyl

acetate, R, = 0.30. The isolated yield was 99% (412 mg mixture of the E and

40

internal isomer). IR (neat) 2950, 2910, 2870, 2820, 1770,1210; 1H NMR (300
MHz, CDCIa) for E: 6 0.86 (m, 15 H), 1.28 (m, 12 H), 1.44 (m, 12 H), 1.58 (m, 4
H).2.02 (s, 3 H), 2.12 (dt, J = 4.4 Hz, 7.4 Hz, 2H), 4.03 (t, J = 6.6 Hz, 2 H), 5.87
(m, 2 H) for Internal: 6 0.86 (m, 15 H), 1.28 (m, 12 H), 1.44 (m, 12 H), 1.58 (m, 4
H), 2.02 (s, 3 H), 2.24 (t, J: 7.5 Hz, 2 H), 4.03 (t, J = 6.6 Hz, 2 H), 5.09 (m, 1 H),
5.64 (m, 1 H); ‘30 NMR (75 MHz, CDCIa) for E: 6 171.1, 148.5, 127.7, 64.3, 37.2,
29.1, 28.0, 27.2, 25.1, 13.6, 9.3 for lntemal: 6 171.1, 154.4, 125.0, 65.7, 37.3,
29.2, 28.1, 27.3, 25.8, 13.6, 9.5; HRMS (El) m/z 375.1347 [(M*-Bu); calcd. for
C,6H3,OZSn 375.1349]. The spectroscopic data was consistent with those

previously reported in the literature: Sharma 8.; Oehlschlager A. J. Org. Chem.

1989, 54, 5064-5073.
(radical mediated, mbr1-36):

In a 25 mL flask 15 mL benzene, 18 mg (0.15 mmol) AIBN and 139 mg (1
mmol) 6-aceto-1-hexyne was added. A preheated oil bath was used to
maintain the temperature of the reaction at 80 °C. Then 0.27 mL 3113an was
added dropwise. The reaction was stopped after 2 hrs. A crude NMR was
taken to establish the ratio of the regioisomers formed, Ellntemal/Z 3.2:0:1. The
mixture was passed through a silica column using 99:1 petroleum ether/ethyl
acetate, R, = 0.50. The isolated yield was 61% (263 mg mixture of the E and Z
isomer). 1H NMR (300 MHz, CDCIa) for E: 6 0.86 (m, 15 H), 1.29 (m, 12 H), 1.46
(m, 12 H), 1.59 (m, 4 H), 2.01 (s, 3 H), 2.13 ((11, J: 4.4 Hz, 7.4 Hz, 2 H), 4.03 (t, J
= 6.6 Hz, 2 H), 5.88 (m, 2 H) for Z 6 0.86 (m, 15 H), 1.29 (m, 12 H), 1.46 (m, 12

H), 1.59 (m, 4 H), 2.01 (s, 3 H), 2.13 (dt, J = 4.4 Hz, 7.4 Hz, 2H), 4.03 (t, J = 6.6

41

Hz, 2H), 5.88 (dt, J: 12.4 Hz, 1.1 Hz, 1H), 6.46 (dt, J: 6.8 Hz, 12.4 Hz, 1H, Z);
13C NMR (75 MHz, 00013) for E: 6 171.1, 148.7, 127.8, 64.4, 37.3, 29.1, 28.0,
27.3, 25.2, 13.8, 9.4 for Z 6 171.1, 148.3, 128.2, 64.4, 37.3, 29.2, 28.0, 27.4,
21.1, 13.8, 9.4; HRMS (EI) m/z 375.1346 [(M*-Bu); calcd. for C,6H3,02$n
375.1349].
Hydrostannylation of 3,5-dimethyI-1-hexyn-3-ol (mbr1-75)
B S
.. W

In a 100 mL flask 50 mL THF, 23 mg (0.03 mmol) (PhaP)deCIz and 757
mg (6 mmol) 3,5-dimethyI-1-hexyn-3-ol was added. An ice bath was used to
maintain the temperature of the reaction at 0 °C. Then 1.84 mL (6.5 mmol)
Bu38nH was added dropwise. The reaction was stopped after 60 min. The
mixture was passed through a silica column using 9:1 hexanes/petroleum ether,
R, = 0.25. The isolated yield was 54% (1.94 g). 1H NMR (300 MHz, 00013) for
E; 6 0.86-0.95 (m, 21 H), 1.22-1.37 (m, 9 H), 1.42-1.55 (m, 8 H), 1.60-1.72 (m, 1
H), 6.01 (d, J: 19.3 Hz, 1 H), 6.08 (d, J = 19.3 Hz, 1 H). The spectroscopic data

was consistent with those previously reported in the literature: Maleczka, Jr. R.;

Terstiege, I J. Org. Chem. 1998, 63, 9622-9623.

Hydrostannylation of 3-amino-3-ethyI-1-pentyne (mbr1-76)

42

In a 100 mL flask 50 mL THF, 23 mg (.03 mmol) (Ph3P)2 PdCl2 and 667
mg (6 mmol) 3-amino-3-ethyl-1-pentyne was added. An ice bath was used to
maintain the temperature of the reaction at 0 °C. Then 1.84 mL (6.5 mmol)
Buaan was added dropwise. The reaction was stopped after 60 min. The
mixture was passed through a silica column using 9:1 hexanes/petroleum ether,
R, = 0.1. The isolated yield was 80% (1.90 g). 1H NMR (300 MHz, CD013) for E;
6 0.79 (t, J: 7.6 Hz, 6 H), 0.87 (m, 15 H), 1.29 (m, 6 H), 1.43 (q, J = 7.5 Hz, 4 H),
1.46 (m, 6 H), 5.96 (m, 2 H). “’0 NMR (75 Mhz, CDCIa) 6 3.4, 4.9, 9.1, 22.7, 24.5,
29.1.4 29.1, 53.8, 118.7, 150.9. The spectroscopic data was consistent with
those previously reported in the literature: Maleczka, Jr. R.; Terstiege, I J. Org.

Chem. 1998, 63, 9622-9623.

Hydrostannylation of 3,3-dimethyI-1-butyne (mbr1-83)

In a 50 mL flask 25 mL THF, 22 mg (PhaP)2PdCIz (0.03 mmol), 0.37 mL
PMHS, 1.89 g BuasnF (6.1 mmol), and 492 mg 6-aceto-1-hexyne (6 mmol) was
added. Then a catalytic amount of TBAF was added. The reaction was stopped
after 60 min. The mixture was passed through a silica column using pentane, R,
= 0.77. The isolated yield was 44% (0.97 g). 1H NMR (300 MHz, 600,) for E; 6
0.87 (m, 15 H), 0.98 (s, 9 H), 1.26-1.35 (m, 6 H), 1.43 - 1.53 (m, 6 H), 5.76 (d, J =
19.3 Hz, 1 H), 5.96 (d, J: 19.3 Hz, 1 H); ‘30 NMR (75 Mhz, CDCIa) 6 9.4, 13.7,

27.2, 29.1.4 29.2, 35.9, 119.7, 160.0. The spectroscopic data was consistent

43

with those previously reported in the literature: Maleczka. Jr. R.; Terstiege, I J.

Org. Chem. 1993, 63, 9622-9623.

Coupling of bromostyrene with:

3,5-dimethyI-1-(tributylstannyI)-1(E)-buten-3-ol (mbr1 -77)

OH
W

In a 50 mL flask 2 mL THF, 9 mg (Ph,,P)2PdCI2 (0.01 mmol), 0.62 g
bromostyrene (3.3 mmol) was added. Then 1.30 g 3,5-dimethyI-1-
(tributylstannyI)-1(E)-buten-3-ol (3 mmol) was added to the reaction. After a
few days of stirring at room temperature starting material was still present
according to TLC. At this point the reaction was brought to reflux and a small
amount of catalyst was added. After two days the reaction was stopped and the
mixture was passed through a silica column using 9:1 hexanes/ethyl acetate, R,
= 0.14. The isolated yield was 45% (306 mg). 1H NMR (300 MHz, CDCIa); 6
0.92 (d, J=4.7 Hz, 3 H), 0.94 (d, J = 4.4 Hz, 3 H), 1.33 (s, 3 H), 1.50 (d, J = 6.0
Hz, 2 H), 1.76 (m. 1 H), 5.88 (d, J: 15.4 Hz, 1 H), 6.39 (dd, J: 15.4 Hz, 10.4 Hz.
1 H), 6.53 (d, J = 15.7 Hz, 1 H), 6.76 (dd, J = 15.7 Hz, 10.4 Hz, 1 H), 7.22-7.39
(m. 5 H); 13C NMR (75 MHz, 00013) 6 24.4, 24.6, 29.1, 51.4, 73.6, 126.2, 127.2,
127.3, 128.5, 128.6, 131.8, 137.3, 141.6. The spectroscopic data was
consistent with those previously reported in the literature: Maleczka, Jr. R.;

Terstiege, I J. Org. Chem. 1998, 63, 9622-9623.

44

3-amino-3-ethyl-1-(tributylstannyI)-1(E)-pentene (mbr1-78)

NH:
W

In a 25 mL flask 2 mL THF, 9 mg (Ph,,P)2PdCl2 (0.01 mmol), 0.60 g
bromostyrene (3.3 mmol) was added. Then 1.30 g 3-amino-3-ethyl-1-
(tributylstannyl)-1(E)-pentene (3 mmol) was added to the reaction. After a few
days of stirring at room temperature starting material was still present according
to TLC. At this point the reaction was brought to reflux and a small amount of
catalyst was added. After four days the reaction was stopped, to separate the
product to the hexabutyl tin byproduct the mixture was added to a solution of KF
and stirred overnight. After extracting with diethyl ether (3x), dried over MgSO,,
and concentrated down via rotovap. The resulting oil was passed through a
silica column using 9:1 hexanes/ethyl acetate, R, = 0.15. The isolated yield was
47% (306 mg). ‘H NMR (300 MHz, CDCla); 6 0.84 (t. J: 7.4 Hz, 6 H). 1.33 (br, 2
H). 1.48 (q, J = 7.4 Hz. 4 H). 5.74 (d. J = 15.4 Hz. 1 H), 6.28 (dd, J = 15.4 Hz,
10.4 Hz. 1 H), 6.49 (d, J = 15.7 Hz, 1 H), 6.78 (dd, J: 15.7 Hz, 15.4 Hz. 10.4 Hz,
10.2 Hz, 1 H), 7.15-7.38 (m, 5 H); 13C NMR (75 MHz, CDCIa) 6 8.1, 34.0, 56.3,
126.1. 127.1. 128.1, 128.6. 129.1, 130.9, 137.5, 142.4. The spectroscopic data
was consistent with those previously reported in the literature: Maleczka, Jr. R.;

Terstiege, l J. Org. Chem. 1998. 63, 9622-9623.

45

3,3-dimethyl -1-(trlbutylstannyI)-1(E)-butene (mbr1-84)

W

In a 25 mL flask 5 mL THF, 7 mg (PhaP)2PdClz (0.01 mmol), 530 mg
bromostyrene (2.9 mmol) was added. Then 980 mg 3.3-dimethyI-1-
(tributylstannyI)-1(E)-butene (2.6 mmol) was added to the reaction. The
reaction was refluxed for 2.5 days. The mixture was passed through a silica
column using pentane, R, = 0.10. Trace amount of BuSSnBr were still present so
the resulting oil was stirred in a KF aq. The aqueous layer was extracted with
diethyl ether (3x) and then the organic layer was dried over M9304 and
concentrated. The isolated yield was 41% (197 mg). ‘H NMR (300 MHz,
CD013) 6 1.09 (s, 9 H), 5.87 (d, J: 15.4 Hz. 1 H), 6.16 (dd, J: 15.4 Hz. 10.2 Hz.
1 H), 6.48 (d, J = 15.7 Hz, 1 H). 6.76 (dd, J = 15.7 Hz. 10.2 Hz, 1 H), 7.20-7.42
(m. 5 H); 13C NMR (75 MHz. 00013) 6 29.6, 33.4, 125.4, 126.1, 127.0, 128.6,
129.9, 130.2. 137.7. 146.8. The spectroscopic data was consistent with those
previously reported in the literature: Maleczka, Jr. R.; Terstiege, l J. Org. Chem.

1998, 63, 9622-9623.

46

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122

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