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dissertation entitled

INTRAMOLECULAR REACTIONS: USE OF
ORGANOMETALLIC INTERMEDIATES IN THE
SYNTHESIS OF CARBOCYCLES

presented by

ARTHUR E. HARMS

has been accepted towards fulfillment
of the requirements for

Ph. D. Organic Chemistry

 

 

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Date /é WW ?_3

 

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INTRAMOLECULAR REACTIONS:
USE OF ORGAN OMETALLIC INTERMEDIATES
IN THE SYNTHESIS OF CARBOCYCLES

BY

ARTHUR E. HARMS

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1993

ABSTRACT

INTRAMOLECULAR REACTIONS:
USE OF ORGAN OMETALLIC INTERMEDIATES
IN THE SYNTHESIS OF CARBOCYCLES

By

Arthur Eugene Harms

Organometallic reagents have been employed in the synthesis of various
carbocycles. Ziegler-Nana conditions were the first studied that accomplished an
intramolecular addition to yield four-, five-, and six-membered rings. Cyclization
occurred through the treatment of an alkyltitanocene chloride with a Lewis acid (EtAlC12
or MezAlCl) to produce alkylidenecycloalkanes in good to excellent yields. The
methodology included synthesis of the acyclic precursors. Stereochemistry of carbon-
titanium insertion into a carbon-carbon triple bond was shown to result from a syn
addition, and as a result. the cyclization produced only one isomer from an asymmetric
substrate. Substitution on the alkync was varied to study the effect of a trimethylsilyl
group compared to the corresponding methyl substituted alkyne, and the results showed
the steric bulk of the trimethylsilyl group impeded cyclization.

Another organometallic methodology to accomplish ring formation employed
allylic ethers and an organometallic nucleophile. Organometallic nucleophile displaced
the allylic ether in an SN' fashion to produce vinyl substituted five- and six-membered
carbocycles. Substrates for the cyclization study were prepared that varied in tether
length between the halide and the allylic functionality. Both cis and trans olefinic

isomers were studied to investigate the effect of the olefin Stereochemistry on the SN'

Arthur Eugene Harms

cyclization. Metals that were successful for the promotion of SN' cyclization were
magnesium, lithium, and magnesium with a catalytic amount of various c0pper(I) salts.
The synthesis of cis-bicyclo[4.3.0]non-1-ene was accomplished through the exploitation
of the preferred nucleophilic SN' displacement from the side anti to the leaving group. In
a separate study, the competition of SN versus SN' cyclization showed that minor amounts
of SN' cyclization occurred in the four- versus six-membered ring formation; however, in
the five- versus seven-membered ring competition, significant amounts of SN cyclization

(five-membered ring formation) took place.

Dedicated to my Mom, Dad, Aunt Wilma, Uncle Dee

Alan, Claire, and most importantly My Wife

TABLE OF CONTENTS

LIST OF TABLES

LIST OF SCHEMES

LIST OF FIGURES

LIST OF ABBREVIATIONS

CHAPTER I. INTRAMOLECULAR REACTION WITH ALKYNES
VIA ZIEGLER-NATTA CONDITIONS

1. INTRODUCTION
A. Radical Cyclization
B. Anionic Cyclization
C. Transition Metal Mediated Cyclization

D. Ziegler-Nana Conditions for Intramolecular Addition With Alkenes

E. Ziegler-Nana Conditions for Intermolecular Reactions of Alkynes

F. Goals For Ziegler-Nana Methodology

II. RESULTS AND DISCUSSION
A. Preparation of Acetylenic Substrates
B. Preparation of Standards

C. Cyclization of Acetylenic Substrates
IH. CONCLUSIONS
IV. EXPERIMENTAL

V. REFERENCES

iii

vi
vii

viii

\lANN

10

10
10
13
14

19

20

34

 

ETHERS

I. INTRODUCTION
A. Intermolecular SNZ' Reaction
1. Organocuprate Nucleophiles
B. Intramolecular SN' Reaction
1. Anionic Cyclization
2. SN' Reactions with Organocuprate Reagents
3. SN' Reactions with Organolithium Reagents

4. Goals for SN' Methodology

II. RESULTS AND DISCUSSION
A. Preparation of Substrates for SN' Cyclizations
B. Preparation of Substrates for SN Versus SN' Investigation
C. Cyclization of Substrates
1. SN' Cyclization
a. Five-Membered Ring Formation
b. Six-Membered Ring Formation
c. Seven-Membered Ring Formation
d. Four-Membered Ring Formation
e. Bicyclo[4.3.0]nonene Formation
2. SN Versus SN' Cyclizations
a. Four- Versus Six-Membered Ring Formation
b. Five- Versus Seven Membered Ring Formation
III. CONCLUSIONS
IV. EXPERIMENTAL
V. REFERENCES

iv

CHAPTER II. ORGANOMETALLIC SN' CYCLIZATIONS WITH ALLYLIC

37
38
38
40
40
41
41
43

48
49
49
49
52
53
54
54
55
55
56
56
57
74

 

 

LIST OF TABLES

CHAPTER I. INTRAMOLECULAR REACTION WITH ALKYNES
VIA ZIEGLER-NATTA CONDITIONS

Table 1. Results of Alkyltitanocene Cyclization 17
Table 2. Study of The Effects of Methyl Versus Silyl Substitution on Cyclization 18

CHAPTER II. ORGANOMETALLIC SN' CYCLIZATIONS WITH ALLYLIC
ETHERS

Table 1. Results of Five-Membered Ring Formation Via Grignard SN' Cyclization 50
Table 2. Results of Five-Membered Ring Formation Via Copper(I) Catalyzed SN'
Cyclization With Trans Olefins 51
Table 3. Results of Five-Membered Ring Formation Via Copper(I) Catalyzed SN'
Cyclization With Cis Olefins 51
Table 4. Results of Five-Membered Ring Formation Via Organolithium SN'
Cyclization 52
Table 5. Results of Six-Membered Ring Formation Via Copper(I) Catalyzed SN'
Cyclization With Trans Olefins 52
Table 6. Results of Five-Membered Ring Formation Via Copper(I) Catalyzed SN'
Cyclization With Cis Olefins 53
Table 7. Results of Six-Membered Ring Formation Via Organolithium SN'
' Cyclization 53
Table 8. Results of Bicyclic Ring Formation 55

 

 

LIST OF SCHEMES

CHAPTER I. INTRAMOLECULAR REACTION WITH ALKYNES
VIA ZIEGLER-NATI‘A CONDITIONS

Scheme 1. Synthesis of Alkyl Substituted Acyclic Substrates 11
Scheme II. Synthesis of Trimethylsilyl Substituted Acyclic Substrates 12
Scheme 111. Synthesis of Precursor for Stereoselectivity Study 12
Scheme IV. Preparation of Standards of Cyclized Products 13
Scheme V. Synthesis of Acyclic Standards 13
Scheme VI. Synthesis of Alkyltitanocene Compounds 15

Scheme VII. Synthesis and Cyclization of Substrate for Stereoselectivity Study 19

CHAPTER II. ORGANOMETALLIC SN’ CYCLIZATIONS WITH ALLYLIC

ETHERS
Scheme 1. Nucleophilic Additions to Cyclic Allyl Ethers 39
Scheme II. SN' Cyclization in Dodecahedrane Intermediate ~ 42
Scheme III. Synthesis of Precursor to Cis and Trans Olefins 44
Scheme IV. Preparation of Trans Olefins for SN' Cyclization 45
Scheme V. Preparation of Cis Olefins for SN' Cyclization 45
Scheme VI. Potential Reaction Pathways for Cis and Trans Olefins 46
Scheme VII. Synthesis of Four-Membered Ring Precursor (Trans Olefin) 46
Scheme VIII. Synthesis of Precursor for Bicyclic System 47

Scheme IX. Synthesis of SN Versus SN' Substrate (Four- Versus Six-Membered Rings)
48
Scheme X. Synthesis of SN Versus SN' Substrate (Five- Versus Seven-Membered

Rings) 49

vi

LIST OF FIGURES

CHAPTER I. INTRAMOLECULAR REACTION WITH ALKYNES
VIA ZIEGLER-NATTA CONDITIONS

Figure 1. Proposed Transition State For Intramolecular Addition
Under Ziegler -Natta Polymerization Conditions

vii'

16

LIST OF ABBREVIATIONS

AIBN
Bu
BuLi

DHP

DMF

DMPU

DMSO

PMDTA

PPTs

RedAl®

TBDMS

viii

Azobisisobutyronitrile

Butyl

Butyllithium

Cyclopentadienyl
Dihydropyran
N,N-Dimethylformamide -
l,3-Dimethyl—3,4,5,6-tetrahydro-
2(1H)-pyrimidinone
Dimethylsulfoxide

Ethylene Diamine

Ethyl
Hexamethylphosphoramide
Lithum Aluminum Hydride
Methyl

N—Bromosuccinimide

Phenyl
N,N,N',N”,N"-Pentamethyl
diethylenetriamine

Pyridinium p-Toluenesulfonate
Sodium Bis(2-methoxyethoxy)-
aluminum Hydride
Tetrabutylammonium Fluoride

ten-Butyldimethylsilyl

TMS

ix

Tetrahydrofuran
Tetrahydropyranyl

N, N,N ',N T etramethylethylene
diarnine

Trimethylsilyl

 

CHAPTER I

IN TRAMOLECULAR REACTION WITH ALKYNES
VIA ZIEGLER-NA'ITA CONDITIONS

 

I. INTRODUCTION

Alternate methods for carbon-carbon bond formation are constantly explored by
organic chemists. When a new procedure can be applied in an intramolecular fashion
with regio- and stereoselectivity, the methodology becomes an exceedingly powerful tool
for synthesis. In the Stille labs, the Ziegler-Nana polymerization conditions were shown
to facilitate intramolecular cyclization with regio- and diastereoselectivity.l Specifically,
the exo insertion of an alkyne into a carbon-titanium bond proceeded to form five- and
six-membered rings when the alkyltitanocene complex was treated with a Lewis acid.2

In the literature, intramolecular additions have been accomplished by several
methods. This chapter reviews past methods of ring formation accomplished through
insertion of activated sp3 hybridized carbons into acetylenic bonds. In addition, the

results of the intramolecular Ziegler-Nana reaction with alkynes are presented.

A. Radical Cyclization

Radical cyclization was Shown to be a very versatile means for natural product
synthesis.3 Generation of an alkyl radical can be accomplished by several methods, and
successful techniques that are discussed utilize butyllithium,4 chromium (II) salts,5 zinc,6
zinc/copper,7 samarium (II) iodide,8 and azoisobutyronitrile (AIBN) initiated stannane
derivatives9’10 for intramolecular reactions. One of the first examples of an
intramolecular cyclization of a radical with an alkyne used n-butyllithium and bromide 1
(eq 1).3 The major products of the reaction were 3 (60% yield), 4 (20% yield), and 5 (3%
yield).

PI] _ l)n’BULI
——'\(— (\ I’ll—fl 1:461
n Br 2) H20 (fin ( )
1: n=2 3: n=2 60% 4: n=2, 20%
5: n=6, 3%

 

3
Another reagent that was used for radical cyclization was chromium (II)

perchlorate. Employment of a different radical generator, and use of the iodide increased
the cyclization of 2 to yield 3 in 96% yield (eq 2).5 In the model systems designed to
give five-membered rings, the distinction in yields between the butyl and phenyl
substituents was trivial, but in the case of the six-membered rings, substantial differences
were observed (eq 2). These results suggested that the phenyl group may have stabilized

the transient vinyl radical which in turn facilitated cyclization.5

R
1
raw/l W» (2)
“ 2) 1130* )n
2: n=0, R=Ph 3: n=0, R=Ph, 95%
6: n=0, R=(CH2)3CH3 7: n=0, R=(CH2)3CH3, 85%
8: n=1, R=Ph 9: n=1, R=Ph, 86%
10; n=l, R=(CH2)3CH3 11: n=l, R=(CH2)3CH3, 12%

Another metal used to generate the radical from the halide was zinc.6 Knochel
produced a radical intermediate by treatment of 2 with zinc in THF. As before, 3 was the
major product (75% yield). This study only probed the formation of five-membered
carbocycles. When this reaction was run in N,N—dimethylforrnamide (DMF), an atom
transfer reaction took place to convert 6 to 13.7 The use of zinc in DMF was not as
efficient for the promotion of cyclization as the conditions developed by Curran (vide
infra).10

Radical cyclization with samarium(II) iodide was quite successful in the
cyclization of 2 and 6.8 Conditions for the cyclization included DMPU (1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone, a less toxic alternative to HMPA) in THF at
reflux. Yields for the formation of 3 and 7 were 80% and 81%, respectively.

Standard radical methodology using AIBN with tributyltin hydride did not work

as well as the previously discussed radical methods.9 The use of the same substrate

(compound 2), resulted in only a 58:42 ratio of the cyclized product 3 to the reduced open
chain alkyne 4 in a combined yield of 65%. An alternate method used a catalytic amount
of bis(tributyltin) with 12 to produce 13 in 77% yield (eq 3).10 Under the same
conditions, 14 cyclized to produce 15 in 95% yield with 15:1 stereoselectivity (E:Z).

However, 16 only gave 17 in a 3.3:1 (E:Z) ratio for an 87% yield.

I
I R1
\NL BugSnSnBU3 (cat) (3)
R2 ’ 2
R1 R
12; R1=R2=H 13; R1=R2 =H, 77%
14; R1=R2=CH3 15: R1=R2=CH3, 15:1 (E:Z), 95%
16: R1=H, R2=CH3 17: R1=H, R2=CH3, 3.3:1 (E:Z), 87%

Although the conditions for radical cyclization were generally mild and were
tolerated by many functional groups, this process had several drawbacks. Unfortunately,
intermolecular processess (i.e. hydrogen abstraction from the radical terminator prior to
cyclization) forced the reaction to be run at high dilution (0.01-0.05M). Unlike alkenes,
alkynes cyclized to form five- and six-membered rings selectively with good to excellent
yields; however, most of the cyclizations required phenyl substitution on the alkyne.
Another serious drawback was the limitation for further transformation of the cyclized
product; but with use of a catalytic amount of the bis(tributyltin) radical initiator, a vinyl

iodide was generated that could be employed for further functionalization.10

B. Anionic Cyclization

1. Lithium Mediated Cyclization. Anionic lithium cyclizations form five-
membered rings quite easily. The anion was formed through lithium-iodide exchange.11
Treatment of 2 with t-butyllithium (-78 to -25 °C) provided 3 in 94% yield.11 Under
similar conditions, six-membered rings have been formed with 18, but the yield was only

50% (eq 4).12 Excellent stereoselectivity was observed in the cyclization of 20 (eq 5)12

5
and 22 (eq 6).11 Each cyclization produced only one olefinic isomer with 85% and 75%

yields, respectively.

I
I l l) t-BuLi
2) H20
50%
18
I
1) t-BuLi
: Bu 2) H20
Me Me 85%
20
I
|\ /\ : Bu 1) t-BuLi int-‘5
2) H20
5‘ 75%
2 2 2 3

Unlike radical cyclizations, lithium anionic cyclizations were not particularly
tolerant of additional functional groups due to the basicity of the lithium reagent.
However, five-membered ring formation was efficient and gave excellent
stereoselectivity, and the resultant vinyllithium reagent could be easily functionalized

with various electrophiles.11

2. Magnesium Mediated Cyclization. Alkyl Grignard reagents were easily
generated from the corresponding alkyl halides (except fluoride), and the subsequent
organomagnesium intermediate reacted with alkynes in an intramolecular fashion to
generate exocyclic alkenes. Grignard cyclizations formed cyclopentanes in excellent

yields. In 1968, Richey Showed that 7-chloro-2-heptyne cyclized in the exo manner to

 

6
form ethylidenecyclopentane in 90% yield, but the cyclization required a temperature of

100 °C for six days.13 This methodology was vastly improved through replacement of
the methyl and the chloride with a trimethylsilyl group and a bromide, respectively.
When 24 was treated with magnesium in diethyl ether at reflux, the organomagnesium
intermediate cyclized after one hour and, when quenched with allyl bromide, provided 25
in 97% yield (eq 6).14 Six-membered ring formation in dibutyl ether at reflux was
successful and produced a nearly quantitative yield of 27. Attempts to form the four-
membered ring produced only 9% of the cyclized product. When a methyl group was
placed at to the alkyne (compound 28), the resultant stereoselectivity was 91:9 ratio of Z
to E isomers (29:30) with an 87% yield (eq 7).14 The stereoselectivity was reversed

when compound 31 was subjected to similar conditions.

TMS /
Br : TMS 1) Mg, solvent (6)
" E" In 2) CHZCHCHgBr
n
24: n=1 25: n=1, 97%
26: n=2 27 : n=2, 99%
TMS TMS
R2
_ 1) Mg, EIZO Me Me
BIWT'TMS 2)—H20—> + (7)
1
R 29 30
28: R1=H, R2=CH3 91 9
87%
31: R1=CH3, R2=H 5 95
86%

Although the strongly basic conditions used in the aforementioned method
prohibited the use of most functional groups (especially acidic and carbonyl containing

functional groups), the efficiency of cyclization surpassed most methods. The high

 

7 .
temperatures required for generation of the six-membered ring can easily be disregarded

when one considered the yield of cyclization, and when the compound cyclized, the vinyl

Grignard can react with many electrophiles for further functionalization.

3) Copper Mediated Cyclization. Through the employment of lithium di(t-
butyl)cuprate, Crandall determined that 2 cyclized to give a 90% yield of 3.15 Under the
same conditions, 9 was formed in only 58% yield along with several other products (32,
33, eq 8). Attempts at seven-membered ring formation failed to give any cyclized
product. Treatment of 34 with lithium di(n-butyl)cuprate followed by reflux (40 °C) for
three hours successfully produced 35 in 79% yield (eq 9).15

I Pb _ Ph
/ I) (n-Bu)2CuLi . + PI] {W Me ( 8 )
2) H20 11

 

 

 

8 9 58% 32: n=3, 12%
33: n=7, 11%
Ph’\
Ph é—v 1) (n-Bu)2CuLi p j (9)
Br 2) H20 ~
79%
34 35

As was mentioned for the organomagnesium cyclization, the resultant vinyl
cuprate reagent can also be functionalized in a variety of ways.5b’15 Another advantage
of the lithium dialkylcuprates is their well known tolerance of many functional groups.
Although the success of Six-membered ring formation was marginal, the ability to make

four-membered rings was noteworthy.

C. Transition Metal Mediated Cyclization
Early transition metals have also been shown to affect intramolecular cyclization.

Studies conducted by Negishi proved that when 36 was treated with triisobutylaluminum

 

8
and a catalytic amount of zirconocene dichloride, 37 was formed in 85% yield (eq 10).16

Likewise, 38 was treated with the same reagents to provide 39 in 72% yield.

Unfortunately, attempts to produce four- and seven-membered rings were unsuccessful.

TMS
1) (i-Bu)3Al
// n\ gamma), (10)
TMS 2) H3o* )n
36: n=1 37: n=1, 85%
38: n=2 39: n=2, 72%

The stereoselectivity of the insertion was not affected when a methyl group was
positioned on the or carbon. Through the use of triisobutylaluminum and a catalytic
amount of zirconocene dichloride, compound 40 yielded 41 in a 50:50 mixture of E and Z

isomers (79% yield, eq 11), but with zirconocene diiodide, the ratio was increased to

 

80:20 (E:Z).16
TMS
M: 1) (i-Bu)3Al
// 2) 1130*
TMS
40 41

X=Cl, 50:50 (E:Z), 79%
X=I, 80:20 (E:Z), 80%

The methodology developed by Negishi was an effective way to make five- and
six-membered rings. The extremely mild conditions far exceed the relatively harsh
conditions of the magnesium cyclization, but yet, the yields and stereoselectivity with

zirconocene could not compare to those of the magnesium cyclization.

D. Ziegler-Nana Conditions for Intramolecular Addition of Alkenes
A study published by Grubbs gave an indication that intramolecular cyclization

through the use of Ziegler-Nana conditions should be successful.17 This study showed

 

9
that olefins inserted into titanium-alkyl bonds to generate a carbocycle under Ziegler-type

conditions gave excellent yields (eq 12). Our labs have now examined this reaction in
detail.1 Early investigations showed that e-alken-l-yltitanocene chlorides, upon
treatment with ethylaluminum dichloride, cyclized in the exo manner, and after
protonolysis gave good yields of substituted cyclopentanes.1a Further studies proved that
the cyclization proceeded with high diastereoselectivity (>96z4).lb.c Various 5-hexen—1-
yl ligands with a methyl group on the tether were cyclized to give high yields of
dimethylcyc10pentanes. The selectivity was due to the equatorial preference of the bulky
titanocene moiety, and the requirement that the alkene and the carbon-titanium bond must
be c0planar for insertion (see Figure l for representation of the transition state for alkyne
cyclization). Formation of six-membered rings has been very effective through the

Ziegler-Nana method. 1C

Me
i) EtAlCl
M Ti(Cl)Cp2 ——Tg> O ( 12)
u) H30

E. Ziegler-Nana Conditions for Intermolecular Reactions of Alkynes

An obvious extension of the Ziegler-Natta methodology was to investigate the
cyclization of alkynes under similar conditions. Several observations have been made
that encouraged the study of the intramolecular Ziegler-Nana chemistry with alkynes.
The observations were as follows: 1) acetylene, like propylene, polymerized under
Ziegler-Nana conditions,18 2) syn addition of the titanium-carbon bond into acetylene has
been observed through the use of titanocene dichloride/methylaluminum dichloride
polymerization catalyst (eq 13)19 and 3) conditions that were similar to the Ziegler-Natta
methodology accomplished four-membered ring formation via an organozinc
intermediate and titanocene dichloride (eq 14).6 When the organozinc intermediate was
treated with titanocene dichloride, cyclization occurred to provide 35 in reportedly good

yields.

10

 

+
_ szTiClz '
Ph—:TMS M ezAlCl [M16] >=<':Mic:2] AlCl4 (13)
Ph
Ph——___—\/\ 1) Z“ = (14)
1 2) szTiClz
3 5

F. Goals For Ziegler-Natta Methodology
From the literature review on intramolecular cyclizations of acetylenic

compounds, we realized that methods which had the ability to generate carbocycles with
stereocontrol under mild conditions without the activation of the alkyne were rare.
Improvements for the synthesis of alkylidenecycloalkanes would have to meet the
following objectives:

1) Ability to make small to medium sized rings under mild conditions.

2) Cyclizations without the aid of phenyl or silyl groups on the alkyne.

3) Stereocontrol over olefin product formation.

4) Further functionalization of the resultant vinyltitanocene complex.

11. RESULTS AND DISCUSSION
A. Preparation of Acetylenic Substrates

In order to test the feasability of Ziegler-Natta conditions for intramolecular
cyclizations with alkynes, substrates were synthesized that differed in tether length
between the bromide and the alkyne. The investigation began with the synthesis of the
five-membered ring precursor 43. First, commercially available 5-hexyn-l-ol (40) was
protected as the tetrahydropyranyl ether (41, Scheme I).20 Ethylation of the terminal
alkyne with subsequent deprotection afforded 5-octyn-1-ol (42) in 80% yield.
Conversion of the alcohol to the bromide using N-bromosuccinimide and

triphenylphosphine provided l-brorno-S-octyne (43) in 79% yield.

11
The synthesis of the six- and seven-membered ring precursors was approached

from a slightly different angle. Terminal alkynes 46, 52, and 57 were deprotonated with
butyllithium and quenched with paraforrnaldehyde to provide 2-alkyn-l-ols 47, 53, and
59 (Scheme I).21 Using Brown’s “acetylenic zipper”,22 the internal acetylene was
"walked out" to the end of the chain opposite the alcohol to yield alkynols 48, 54, and 59.
Compound 48 was subjected to the same reaction sequence as 5-hexyn-l-ol (42) to yield

bromide 51.

Scheme I. Synthesis of Alkyl Substituted Acyclic Substrates.

 

OH
i) n-Buti \ on
/ ii) (CH20)n ICH _
/ -—H—O-+—V // E? \
Me n 111) 3 Me n n
42: n=1 DHP,
46: n=2 47: n=2, 85% 48: n=2, 82% pst
52: n=3 53: n=3, 86% 54: n=3, 76%
57: n=4 58: n=4, 81% 59: n=4, 87%
V
RWNB SRWHRI 1) ”Hum
PM 2) PPTs, Wm?
MeOH
45: n=1, R=Et, 79% 44: n=1, R=Et, 76% 43: n=1, 95%
51: n=2, R=Me, 90% 50: n=2, R=Me, 80% 49: n=2
56: n=3, R=Me, 90% 55: n=3, R=Me

Synthesis of seven-membered ring precursor 56 utilized the increased
thermodynamic stability of internal over terminal alkynes. Treatment of 59 with a
catalytic amount of potassium t-butoXide in dimethylsulfoxide at 80 °C provided 55 (92%

yield, eq 15),21 which was easily converted to bromide 56 (Scheme I).

Me OH

59: n=4 55: n=3

 

12
The synthesis of compounds 26 and 62 started with alkynols 48 and 54 (Scheme

11). The method described previously was employed to convert the alcohol to the
bromide. The resulting alkyne was deprotonated using n-butyllithium and quenched with
trimethylsilyl chloride to give the desired products 26 and 62.21

Scheme II. Synthesis of Trimethylsilyl Substituted Acyclic Substrates.
NBS ‘ i) n-BuLi

 

H : —> B \ (fr—z ——> B Ve—r————TMS
“ Ph3P * r ‘1 ii) MegsiCl r n
48: n=4 60: n=4, 84% 26: n=4, 76%
54: n=5 61: n=5, 82% 62: n=5, 93%

Since Crandall's methodology formed cyclobutane,7 the same four-membered ring
precursor was synthesized. The synthesis was simply accomplished by alkylation of the

phenylacetylide anion with 1,3-dibromopropane to yield bromide 34 (eq. 16).

' / i) BuLi / Br
// ii) Br(CH2)3Br ' W (16)

Ph
66%
63 34

 

Scheme 111. Synthesis of Precursor for Stereoselectivity Study.

Me Me

/ N 3H C02Et Me
Et
BM + Et02CJ\ C OzEt -—’DMF 02%
MC 3
87%
64 65

LiCl, H20
DMSO
190 °C
80%

Br OH

Me Me CO Et Me
NBS LAH 2
V IPhi? V ' 86% //
Me 3 86% Me 3 Me 3

68 67 66

13
An asymmetric precursor was made through alkylation of the methylmalonate

ester anion with 64 (Scheme III). Deethoxycarboxylation was required to convert the
diester to ester 66.23 Using standard procedures, the ester was transformed to bromide 68
in two steps, with an overall yield of 74% from 66. The Stereochemistry of the carbon-

titanium insertion was investigated through cyclization of compound 68.

B. Preparation of Standards

In order to confirm the identity of the cyclized products from the intramolecular
Ziegler-Nana cyclization, possible products of the cyclizations were made by alternate
methods. Alkylidenecycloalkanes (69, 70, and 71) were synthesized using Corey’s
modification of the Wittig olefination (Scheme IV).24 Standards for the cyclized
vinylsilanes (Table 1, R=SiMe3) were not commercially available, and the synthesis was
not easily accessible, so the products of the cyclization were isolated by preparatory gas
chromatography and fully characterized. Dehalogenated acyclic alkynes were
synthesized either by protonolysis of the alkylmagnesium bromide or by methylation of
the corresponding terminal alkyne (Scheme V).

Scheme IV. Preparation of Standards of Cyclized Products.

 

R
0 l
. )n Pb3PCHR ’ . )u
n=0,1, or 2 69: n=0, R=Et, NY A%

70: n=1, R=Me, 70%
71: n=2, R=Me, 58%

Scheme V. Synthesis of Acyclic Standards.

Br __ R l)Mg,THF _ R l)n-BuLi
W‘— 2) HCl, Et2 Mafia—— I2)RI Mafia——

 

 

 

n: 2,3,4, or 5
R: Ph, Me, Et, or TMS

14
C. Cyclization of Acetylenic Substrates

With substrates in hand, our attention was turned toward synthesis of the
alkyltitanocene and the corresponding cyclization. Preparation of the alkyltitanocene
required the formation of the organomagnesium complex (Scheme VI). Since addition of
Grignard reagents to alkynes was known,13 care was taken to minimize cyclization
during Grignard formation from 45. , Grignard formation was accomplished through a
slow addition (3-6 hours) of bromide 45 to a stirred suspension of magnesium (4 equiv)
in tetrahydrofuran (THF) at 0 °C followed by 1 hour at ambient temperature. Cannula
transfer of the Grignard reagent to a solution of titanocene dichloride (1.2 equiv) in
dichloromethane (CH2C12) at -40 °C was kept at -40 °C for 30 minutes and, at room
temperature for 4 hours. After a series of extractions and filtrations (see Experimental),
the alkyltitanocene chloride 72 was isolated, and an aliquot was quenched with an
HCl/ether solution at -78 °C, and the volatiles were analyzed by capillary gas
chromatography. Results of the analysis showed 96% of 3-octyne and 69 (3%) in a
combined yield of 67%. Compound assignments were based on retention times of known
standards with confirmation of the compound through co-injection, and the yields were
calculated relative to an internal standard with corrections for detector response. Upon
treatment with ethylaluminum dichloride (0.5 equiv) at -78 °C for 20 minutes followed
by an HCl quench, 72 yielded 69 (89% yield) and 3-octyne (4% yield, Table 1). In
comparison, radical cyclization of 45 using AIBN and tributyltin hydride gave similar
results. Products from endo cyclization (l-ethylcyclohexene) were not seen in either the

radical or the titanocene cyclization.

 

 

15
Scheme VI. Synthesis of Alkyltitanocene Compounds.

 

 

Br “ _ R 12)) 1icilpzricrzl CpZ<CDTi \/6 in — R
45: n=3, R=Et 72: nfl, R=Et, 67%
51: n=4, R=Me 73: n=4, R=Me, 65%
26: n=4, R=SIM% 74: n=4, R=SiMe3, 55%
56: n=5, R=Me 75: n=5, R=Me, 62%
62: n=5, R=SiMe3 76: n=5, R=SiMe3, 79%
34: n=2, R=Ph ‘ 77: n=0, R=Ph, 50%

Results of Six-membered ring formation were encouraging albeit perplexing.
Formation of 73 occurred using the same conditions as before. Results of the
alkyltitanocene protonolysis prior to addition of Lewis acid showed 2-octyne (>99%) and
70 (<1%) for a 65% yield from the bromide 51 (Scheme VI). A solution of 73 (0.07-
0.10M in toluene) at -30 °C was treated with dimethylaluminum chloride (2 equiv). After
1.5 hrs, analysis of the quenched products showed the progression of cyclization, but the
recovery of the uncyclized and cyclized products decreased significantly. At the same
time, an Unidentified peak of a higher retention time became more prominent. When 70
was subjected to the same protonolysis conditions, analysis also showed the same peak.
Protonation of ethylidenecyclohexane resulted in a tertiary carbocation which was
quenched by the chloride (eq 18). The glacial acetic acid/water (1/1 by volume) quench
stopped the hydrochlorination of the alkene. The reaction was run again with the new
protonolysis conditions. Analysis showed a 96:4 ratio of 70 to 2-octyne for a 75% yield
(Table 1). The use of ethylaluminum dichloride (1 equiv) at -40 °C was also investigated,
but these conditions only gave an 88:12 ratio of 70 to 2-octyne in only 42% yield.
Comparison to standard radical cyclization conditions, 1-bromo-6-octyne yielded only a
78:22 ratio of 2-octyne to 70 for an 86% recovery. Again, no endo product (1-

methylcycloheptene) was observed.

Me

Cp2(Cl)Ti Me .
HCl, Et20 Cl

Another facet of the Ziegler-Nana methodology to be investigated was the effect
of a trimethylsilyl group on the cyclization. In all of the previous cyclization methods
discussed, the trimethylsilyl group significantly aided cyclization. Under the Lewis
acidic conditions generated in the Ziegler-Nana cyclization, one may envision a transition
state as shown in Figure 1. In the transition state (A), a partial positive charge develops
on the B carbon. Silyl groups, which stablized vinyl B-carbocations, have not been
observed to any great extent. However, Johnson and co-workers showed experimentally
that silyl groups stabilized vinylic cations in their polyene biomimetic cyclizations.25
This stabilization, we hoped, would facilitate our cyclization. On the other hand, the silyl
group may also hinder cyclization, since trimethylsilyl groups are quite bulky, which may
inhibit the approach of the titanocene. Expectations were that the stabilization effect

would far outweigh the steric effect.

 

 

AlCl2Et - IIUCI2EI "
+ F
@ lg “n8 5- Ti.‘ 5-
Me3$i _, 61
% —8+
M6331
A

Cp2(Cl)Ti
TMS

Figure 1. Proposed Transition State For Intramolecular Addition
Under Ziegler-Nana Polymerization Conditions.

17
The cyclization of compound 26 was then investigated (Scheme VI and Table 1).

Synthesis of 74 was accomplished using the standard conditions for a 62% yield from the
bromide 26. Initial cyclization utilized dimethylaluminum chloride (3.6 equiv) at -30 °C.
After 6.5 hours, the mixture was quenched with acetic acid/1120 to yield 75 (97 %) and 1-
trimethylsilyl-Z-heptyne (3%) in a 72% yield. This cyclization was repeated with
ethylaluminum dichloride (2 equiv) as the catalyst at -7 8 °C. After 30 minutes, analysis
of the quenched reaction products revealed 75 (84% conversion) and l-uimethylsilyl-Z-
heptyne for 44% mass recovery.

Unfortunately, the seven-membered ring formation could not overcome the
entropic energy needed for cyclization. The alkyltitanocenes of the methyl and silyl
substituted alkynes were generated in good yields, but compounds 75 and 76 failed to
cyclize (Scheme VI and Table 2). The use of dimethylaluminum chloride (2 to 4 equiv)
at ~30 and at 0 °C destroyed starting material with no evidence of cyclized product. The
cyclizations were run at both 0.08 and at 0.02M. At higher dilution, the starting
alkyltitanocene chloride lasted longer, but still no cyclization had taken place.

Table 1. Results of Alkyltitanocene Cyclization.

 

 

 

Cp2(Cl)TiW-)n'—_—-R Lewis acid )11 +Me R
Yield

Compound Lewis acid (equiv) Temp(°C) Time (hr) A: B (A + B) A

72 n=1, R=Et EtAlC12 (0.5) -78 0.3 96: 4 93 69

73 n=2, R=Me MeZAlCl (1.5) -30 4.0 96:4 75 70
EtAlC12 (1.0) -40 0.5 88:12 42

74 n=2, R=SiMe3 MezAlCl (3.6) -30 6.5 97:3 72 78
EtAlC12 (2.0) -78 0.5 84:16 44

75 n=3, R=Me Me2A1C1(2.0) 0 1.3 0:100 56 71

76 n=3, R=SiMe4 Me2A1C1(4.0) 0 4.5 0: 100 68 79

77 n=0, R=Ph EtAlC12 (6.0) -30—>- 10 8.0 96:4 84 80

 

18
Alkyltitanocene complex 79 underwent intramolecular cyclization to generate 35

(Table 1). Ethylaluminum dichloride (6 equiv) catalyzed the reaction to give 96%
cyclization. In an eXperiment similar to Crandall's,6 the cyclization of alkyltitanocene 77
was catalyzed by zinc chloride at 60 °C; however, only 76% cyclization occurred.

In order to determine the effect of a silyl group on the rate of cyclization, an
experiment was run in which equal amounts of the titanocene complexes 73 and 74 were
generated in the same reaction flask. The vessel was cooled to -30 °C, and
dimethylaluminum chloride (2 equiv) was added. After an allotted period of time, an
aliquot was removed and quenched with acetic acid/water. The results showed that the
methyl substituted alkyne cyclized more rapidly (Table 2). The experiment was repeated
with 1.5 equivalents of dimethylaluminum chloride in order to validate the results of the
previous competetive Study. The second cyclization confirmed that the steric bulk of the
silyl group inhibited the approach to the activated carbon which resulted in a slower rate
of cyclization.

Table 2. Study of The Effects of Methyl Versus Silyl Substitution on Cyclization.

R
Cp2(Cl)Tin-)-4——._——R & : W_E_R

 

 

73/74
Lewis acid
Substrates (equiv) Timealm =M_e =TMS)
73 R=Me] AlMeZCI (2.0) 0.5 90:10 (34:66)
74 R=TMS 1.5 90:10 (52:48)
3.5 88:12 (56:43)
73 R=Me/ A1Me2c1 (1,5 ) 0.5 80:20 (22:78)
74 R=TMS 1.0 86:14 (29:71)
3.0 87:13 (37:64)

Placement of a methyl group on the alkyl tether provided the means to investigate
stereoselectivity of the carbometallation of the alkyne. Standard preparation of the

alkyltitanocene chloride was followed by treatment with ethylaluminum dichloride

 

19
(Scheme VII). A reaction took place to yield compound 80 along with a trace of the

dehalogenated uncyclized substrate (81, 5%). The structure was confirmed by nuclear
Overhauser enhancement NMR experiments. These results prove that carbometallation
occurred through syn addition of the carbon and titanium across the alkyne, and no olefin
isomerism takes place on the ligand. When compound 68 was submitted to radical
conditions, only 28% cyclization took place with equal amounts of each olefin

stereoisomer in the product mixture.

Scheme VII. Synthesis and Cyclization of Substrate for Stereoselectivity Study.

B
Wm Mg’-‘——>)THF mm
Me / ii) szTiClz MCWMC
64%
68
i) EtAlCl2
ii) AcOH/H20
Me
I Me / Me
/
. + Me)\/\/
Me
82 (95:5) 83
83%
III. CONCLUSIONS

The results of these studies show that the alkyltitanocene chlorides can be
accessed through the corresponding organomagnesium intermediate in moderate yields
(SO-79%). Our Ziegler-Nana methodology does not require the use of stabilizing groups
(i. e. phenyl and silyl groups) for cyclization to take place. Exo cyclization to form four,
five, and six-membered rings occurred with the use of Lewis acids such as

dimethylaluminum chloride and ethylaluminum chloride which produced high conversion

20
in moderate to excellent yields of the alkylidenecycloalkanes. Unfortunately, attempts to

form seven-membered rings failed to provide any cyclized substrates. Competitive rate
studies between the trimethylsilyl and methyl substituted alkynes showed that the steric
bulk of the trimethylsilyl group dominated over the trimethylsilyl electronic effect which
resulted in inhibited cyclization. The intramolecular alkyne insertion was observed to be
stereospecific from syn addition of the organotitaniurn species to the alkyne, and no
olefin isomerization occurred at the metal. Overall, the Ziegler-Nana methodology
provided a reasonable alternative for the synthesis of alkylidenecycloalkanes which could
be functionalized,26 and further proved that alkyne insertion occurred through syn

addition.

IV. EXPERIMENTAL

General methods. All reactions were carried out under a positive pressure of dry
nitrogen or dry argon and employed freshly distilled solvents under anhydrous conditions
unless otherwise stated. Diethyl ether, hexane, toluene, and THF were distilled from
benzophenone-sodium ketyl; triethylamine and dichloromethane from calcium hydride;
and ethylene diamine from sodium metal. All glassware was oven-dried and, when
necessary, evacuated through theuse of a Schlenk line. Reagents and solvents were
handled with standard syringe and cannula techniques. Paraformaldehyde was dried
under vacuum over anhydrous phosphorus pentoxide. Other reagents were used as
received from the manufacturer. Distillation of compounds through Kugelrohr apparatus
was reported as the oven temperature at which the compound distilled.

Analytical TLC was carried out on 0.25 mm B. Merck precoated silica gel plates
(60F-254) with detection by 5% phosphomolybdic acid in ethanol and potassium
permanganate solutions. Mass spectra were recorded on a Finnigan 9610 instrument.
Infrared spectra were recorded on a Nicolet IR/42 Spectrometer. Gas chromatographs

were carried out on a Perkin—Elmer 8500 equipped with RSL200 column (methyl 5%

21
phenylsilicone equivalent to SE54 or DB -5) and Hewlett Packard 5880A series equipped

with RTX-l column (Restek Corp.). Preparatory gas chromatography was carried out on
a Varian Aerograph 90-P equipped with a 20% SE-30 column. 1H and 13C NMR were
recorded on Varian VXR-300. 13C spectra were completely decoupled. NMR chemical
shifts are reported in ppm downfield from TMS. The following abbreviations were used
to describe peak patterns when appropriate: 3 = singlet, bs = broad singlet, d = doublet, t

= triplet, q = quartet, quint = quintet, sext = sextet, and m = multiplet

Typical Procedure for Protection of Alcohol as the THP Ether. A solution of 5-
hexynol (42, 2.0 g, 20.4 mmol), dihydropyran (3.4 g, 40.8 mmol), pyridinium p-
toluenesulfonate (0.5 g, 2.0 mmol) and dichloromethane (20 mL) was stirred at ambient
temperature for 2 hours. The reaction was diluted with diethyl ether (16 mL) and washed
with half-saturated sodium chloride (3 x 8 mL). Organic layers were dried (MgSO4),
filtered, and concentrated (rotary evaporator). Bulb-to-bulb distillation produced 3.5 g
(95% yield) of the THP protected alcohol (43). bp 99-100 °C (7 mmHg); 1H NMR (300
MHz, CDC13) 5 1.43-1.87 (m, 10H), 1.87 (t, 1H), 2.16 (m, 2H), 3.30-3.50 (m, 2H), 3.67-
3.86 (m, 2H), 4.53 (t, 1H). 13C NMR (75 MHz, CDC13) 8 18.0, 19.5, 25.2, 25.4, 28.7,
30.9, 62.2, 66.8, 68.3, 84.5, 98.7. IR (film) 3298, 2943, 2870, 2180, 1033 cm'l.

Preparation of 5-Octyn-1-ol (44). 51ml. To tetrahydrofuran (72 mL) at -78 °C, n
-butyllithium (2.4 mL, 2.3 M in hexane, 5.5 mmol) was added. 5-Hexyn-l-yl THP ether
(9.0 g, 42.8 mmol) was added over a 10 minute period and stirred at -78 °C for 1.5 hours.
The cold bath was removed for 5 minutes and then returned. Ethyl iodide (26.7 g, 171.2
mmol) was added, and the reaction was allowed to warm to ambient temperature. The
was stirred for 24 hours and partitioned between half-saturated brine (120 mL) and
diethyl ether (120 mL). The aqueous layer was extracted with diethyl ether (2 x 30 mL).

The combined organic layers were washed with water (1 x 45 mL), dried (sodium

22
sulfate), filtered and concentrated (rotary evaporator). Distillation of the residue through

a short path equipped with an insulated vigreaux column resulted in 8.3 g. (81% yield) of
product (RF 0.53 in 30% diethyl ether in petroleum ether, stained with phosphomolybdic
acid and potassium permanganate). bp 87-92 °C (<3 mmHg); 1H NMR (300 MHz,
CDC13) 5 1.06 (t, J = 7.4 Hz, 3H), l.43-1.87 (m, 10H), 2.05-2.17 (m, 4H), 3.36 (m, 1H),
3.45 (m, 1H), 3.70 (m, 1H), 3.81 (m, ~1H), 4.53 (t, J = 3.4 Hz, 1H); 13C NMR (75 MHz,
CDC13) 6 12.5, 14.3, 18.8, 19.7, 25.6, 26.0, 29.0, 31.0, 62.2, 67.1, 79.0, 81.7, 98.8; IR
(film) 2943, 2870, 1035 cm'l. Step}. A solution of the above THP ether (8.0 g, 33.6
mmol), and PPTs (0.84 g., 3.4 mmol) in ethanol (264 mL) was heated at 55 °C for 10
hours. The reaction was cooled to room temperature, and the solvent was removed in
vacuo. Flash chromatography of the residual oil yielded 4.0 g (94% yield, 76% yield
from 42) of the desired product (Rf: 0.18 in 30% diethyl ether in petroleum ether, stained
with phosphomolybdic acid and potassium permanganate). 1H NMR (300 MHz, CDC13)
8 1.07 (t, J: 7.3 Hz, 3H), 1.45-1.67 (m, 4H), 1.77 (bs, 1H), 2.07-2.19 (m, 4H), 3.62 (t, J:
6.3 Hz, 2H); 13C NMR (75 MHz, CDC13) 8 12.2, 14.2, 18.4, 25.2, 31.6, 62.3, 78.9, 81.9.
IR (fihn) 3358, 2974, 2939, 2874, 1062 cm'l; HRMS calcd for C3H14O m/z 126.1045,
obsd m/z 126.1053.

Typical Procedure for Synthesis of Propargylic Alcohol from the Corresponding
Alkynes. To a stirred solution of n-butyllithium (10.8 mL, 27 mmol, 2.5M in hexanes) in
THF (54 mL) at -78 °C was introduced l-hexyne (2.4 g, 30 mmol) followed by 30
minutes at -78 °C. The cold bath was taken away for 5 minutes and replaced with an ice-
water bath. After the addition of paraforrnaldehyde (2.2 g), the reaction was stirred at rt
for 1 hr and at 45-50 °C for an additional 1.5 hr. The reaction was poured into a NH4Cl
solution (7 mL of sat. NH4C1 diluted to 70 mL with water) followed by extractions with
diethyl ether (5 x 20 mL). The organic layers were dried (MgSO4), filtered and

concentrated (rotary evaporator). Distillation of the residue provided 2-heptyn-l-ol (47).

23
Physical data of 2-heptyn-l-ol (47). 2.9 g, 85% yield, bp 67-68 °c (5 mmHg, lit. 94”);

1H NMR (300 MHz, CDC13) 6 0.87 (t, J=7.1 Hz, 3H), 1.31-1.52 (m, 4H), 1.82 (bs, 1H),
2.28 (it, J=7.0, 2.0 Hz, 2H), 4.21 (t, J=2.0 Hz, 2H); 13c NMR (75 MHz, CDC13) 8 12.4,
18.3, 21.9, 30.7, 51.3, 78.2, 86.5; IR (neat)3600-3100, 2960, 2950, 2870, 2270, 2200,
1000 cm’l.

Physical data of 2-octyn-1-ol (53). - 11.3 g, 86% yield, bp 79-80 °C (5 mmHg); 1H
NMR (300 MHz, CDC13) 5 0.86 (t, J=6.8 Hz, 3H), 1.30 (m, 2H), 1.49 (quint, J=7.0 Hz,
2H), 1.82 (s, 1H), 2.15 (tt, J=2.5, 6.0 Hz, 2H), 4.19 (t, 1:2.5 Hz, 2H); 13c NMR (75
MHz, CDC13) 8 13.9, 18.6, 22.0, 28.0, 31.0, 51.2, 78.2, 86.3; IR (neat) 3400-3200, 2960,
2930, 2850, 2270, 2200, 1020 cm".

Physical data of 2-nonyn-l-ol (58). 10.3 g, 81% yield, hp 73-74 °C (1 mmHg); 1H
NMR (300 MHz, CDC13) 5 0.85 (t, J=6.8 Hz, 3H), 1.19-1.40 (m, 6H), 1.46 (quint, 1:75
Hz, 2H), 1.86 (bs, 1H), 2.17 (tt, J=2.2, 7.0 Hz, 2H), 4.22 (t, J=2.2 Hz, 2H); 13C NMR
(75 MHz, CDC13) 5 14.1, 18.6, 22.5, 28.4, 28.5, 31.3, 51.3, 78.2, 86.4. IR (neat) 3400-
3100, 2960,2930, 2870, 2320,2260, 1000 cm'l.

Separation of Potassium Hydride From its Protective Oil. In a glove bag filled with
nitrogen, potassium hydride (6.9 g of a 35% oil dispersion, 60 mmol of KH) was weighed
out into a 100 mL round bottom flask equipped with a magnetic stir bar. The round
bottom flask was removed from the glove bag, and the solids were treated with light
petroleum ether (70 mL). The suspension was stirred briefly and allowed to settle with
occasional tapping. The solvent was removed by cannula transfer to an erlenmeyer flask
which contained t-butanol in order to quench any residual potassium hydride. This
procedure was repeated two more times. Nitrogen was gently blown through the flask to

remove the last traces of solvent.

24
Typical Procedure for Isomerization of PrOpargylic Alcohol to the Terminal

Alkynol . A solution of KAPA was prepared by slowly adding 1,3-diaminopr0pane (45
mL) to KH (2.4 g, 60 mmol) and stirred for 1 hr at rt. Hept-2-yn-1-ol (47, 2.2 g, 20
mmol) was introduced, and the mixture was stirred overnight The reaction was very
carefully poured into ice/water (150 mL). [Bewarel Potassium metal is present in KH].
The mixture was extracted with diethyl ether (6 x 100 mL). The organic layers were
washed with an acidic NaCl solution (100 mL, half sat'd brine/cone. HCl, 9:1), dried
(MgSO4), filtered and concentrated (rotary evaporator). Bulb-to-bulb distillation of the
yellow residue yielded 6-heptyn-l-ol (48).

Physical data for 6-heptyn-1-ol (48). 2.1 g, 82% yield, bp oven=80-90 °C (8 mmHg, lit.
10520); 1H NMR (300 MHz, CDC13) 5 1.40-1.60 (m, 6H), 1.72 (bs, 1H), 1.91 (t, J=2.6
Hz, 1H), 2.16 (td, J=6.7, 2.6 Hz, 2H), 3.61 (t, J=6.4 Hz, 2H); 13C NMR (75 MHz,
CDC13) 8 18.1, 24.7, 28.2, 32.1, 62.4, 69.1, 84.2; IR (neat) 3400-3100, 2940, 2870, 2190,
1050 cm’l.

Physical data for 7-octyn-1-ol (54). 6.8 g, 76% yield, bp 85-87 °c (5 mmHg); 1H
NMR (300 MHz, CDC13) 8 1.26-1.57 (m, 8H), 1.70 (bs, 1H), 1.90 (t, J=2.6 Hz, 1H), 2.27
(dt, J=2.6, 6.8 Hz, 2H), 3.60 (t, J=6.6 Hz, 2H); 13C NMR (75 MHz, CDC13) 5 19.0, 25.1,
28.4,. 28.5, 32.5, 62.6, 68.1, 84.5; IR (neat) 3400-3100, 2930, 2870, 2110, 1060 cm'l.
Physical data for 8-nonyn-1-ol (59). 5.3 g, 87% yield, bp 68-69 °C (1 mmHg); 1H
NMR (300 MHz, CDC13) 8 1.22-1.55 (m, 10H), 1.86 (t, J=2.6 Hz, 1H), 1.92 (bs, 1H),
2.14 (dt, J=2.6, 7.0 Hz, 2H), 3.56 (t, J=6.6 Hz, 2H); 13C NMR (75 MHz, CDC13) 8 18.3,
25.5, 28.3, 28.5, 28.7, 32.6, 62.7, 68.1, 84.6; IR (neat) 3400-3100, 2940, 2860, 2130,
1450, 1050 cm'l.

Preparation of 6-Octyn-1-ol (50). To tetrahydrofuran (65 mL) at -78 °C, n
-butyllithium (17.2 mL, 2.5 M in hexane, 42.8 mmol) was added. 6-Heptyn-l-yl THP

ether (49, 7 .0 g, 35.6 mmol) was added over a 10 minute period and stirred at -78 °C for

 

25
1.5 hours. The cold bath was removed for 5 minutes and then returned. Methyl iodide

(10.1 g, 71.3 mmol) was added, and the reaction was allowed to warm to ambient
temperature. The reaction was stirred for 24 hours and then partitioned between half-
saturated brine (40 mL) and diethyl ether (40 mL). The aqueous layer was extracted with
diethyl ether (3 x 15 mL). The combined organic layers were washed with brine (1 x 10
mL), dried (MgSO4), filtered and concentrated. The residue was taken up in methanol
(200 mL), treated with PPTs (1.0 g) and refluxed for three hours. Methanol was removed
by atmospheric pressure distillation until 15 mL of residue remained. The residue was
partitioned between half-saturated brine (40 mL) and diethyl ether (40 mL). The aqueous
layer was washed with diethyl ether (3 x 25 mL). The combined organic layers were
dried (MgSO4), filtered and concentrated (rotary evaporator). The yellow oil was
distilled to yield 3.5 g. (80% yield) of 6-octyn-1-ol (50). bp 55-57 °C (<1 mmHg); 1H
NMR (300 MHz, CDC13) 8 1.38-1.61 (m, 7H), 1.74 (t, J =2.6 Hz, 3H), 1.80 (bs, 1H),
2.11 (tq, J =6.7, 2.6 Hz, 2H), 3.61 (t, J =6.4 Hz, 2H); 13C NMR (75 MHz, CDC13) 5 3.4,
18.4, 24.9, 28.6, 32.1, 62.5, 75.5, 78.9; IR (neat) 3600-3200, 2940, 2860, 1420, 1050 cm'
1. HRMS calcd for C3H14O m/z 126.1045, obsd m/z 126.1074.

Isomerization of _a Terminal Alkynol to a Methyl Substituted Alkynol (55). To a
solution of potassium t-butoxide (0.08 g, 0.7 mmol) in DMSO (7 mL), 8-nonyn-1-ol (59,
0.5 g, 3.6 mmol) was introduced. The mixture was stirred at rt for 2 minutes, at which
point, the reaction was heated to 80 °C and kept there for 2 to 3 minutes. The reaction
was cooled to rt and diluted with water (80 mL). The mixture was extracted with a
diethyl ether/pentane mixture (6 x 90 mL, 1:1 by volume). The organic phases were
dried (MgSO4) and concentrated (rotary evaporator). Distillation yielded 0.5 g of 6-
octyn-l-ol (53.92% yield). hp oven=85-100 °c (5 mmHg); 1H NMR (300 MHz, CDC13)
8 1.21-1.52 (tn, 8H), 1.68 (t, 1:25 Hz, 3H), 2.02 (m, 2H), 3.53 (t, J=6.7 Hz, 2H); 13c
NMR (75 MHz, CDC13) 8 3.2, 18.3, 25.1, 28.6, 28.8, 32.7, 62.6, 75.4, 79.1; IR (neat)

26
3400-3200, 2940, 2860, 1055 cm'l; HRMS calcd for C9H16O m/z 140.1201, obsd m/z

140.1262.

Typical Procedure for Silylation of Terminal Alkynyl Bromides. A solution of 1-
bromo-6-heptyne (60, 1.8 g, 10.6 mmol) in THF (8 mL) was cooled to -78 °C. n-
Butyllithium (4.4 mL, 11.1 mmol, 2.5M in hexanes) was introduced over a 15 minute
period. Once the addition was complete, the reaction was stirred for two minutes, and
TMSCl (1.5 g, 13.8 mmol) was added. The reaction was warmed to -10 °C and stirred
for 20 minutes at this temperature. Ice water (20 mL) was added, and the mixture was
vigorously stirred. The aqueous phase was extracted with diethyl ether (3 x 15 mL). The
organic phase was dried (MgSO4), concentrated (rotary evaporator) and distilled to
provide 7-bromo-1-trimethylsilyl- l-heptyne (26).

Physical data for 7-bromo-1-trimethylsilyl-1-heptyne (26). 2.0 g, 76% yield, bp 71-73
°c (<1 mmHg); 1H NMR (300 MHz, CDC13) 8 0.12 (s, 9H), 1.52 (m, 4H), 1.85 (m, 2H),
2.21 (m, 2H), 3.39 (t, J=6.8 Hz, 2H); 13C NMR (75 MHz, CDC13) 8 0.2, 19.6, 27.2, 27.5,
32.2, 33.3, 84.6, 106.8; IR (neat) 2960, 2930, 2870, 2850, 2170, 1260 cm'l. 8

Physical data for 8-bromo-l-trimethylsilyl-l-octyne (62). 2.6 g, 93% yield, bp
oven=70-80 °C (<1 mmHg); 1H NMR (300 MHz, CDC13) 8 0.12 (s, 9H), 1.37-1.56 (m,
6H), 1.84 (quint, J=7.0 Hz, 2H), 2.20 (t, J=6.8 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H); 13C
NMR (75 MHz, CDC13) 8 0.3, 19.6, 27.5, 27.7, 28.1, 32.6, 33.5, 84.4, 107.1; IR (neat)
2950, 2910, 2850, 2170, 1240 cm'l; HRMS calcd for C3H13Br m/z 188.0200, obsd m/z
188.0195.

Preparation of 1-Bromo-S-phenyl-Z-pentyne (34). To a precooled solution of
phenylacetylene (2.0 g, 20.0 mmol) in tetrahydrofuran (40 mL) at -78 °C, n -butyllithium
(9.2 mL, 2.4 M in hexane, 22.2 mmol) was added. The reaction was stirred at -78°C for

30 minutes and without the dry ice-acetone bath for 5 minutes. 1,3-Dibromopropane

27
(12.1 g, 60.0 mmol) was added, and the reaction was allowed to warm to ambient

temperature. The reaction was stirred for 48 hours and quenched by the addition of water
(20 mL). The aqueous layer was extracted with light petroleum ether (3 x 20 mL). The
combined organic layers were dried (MgSO4), filtered and concentrated (rotary
evaporator). Distillation of the residue resulted in 2.9 g (66% yield) of product. bp 107-
110 °C (1 mmHg); 1H NMR (300 MHz, CDC13) 8 2.16 (quint, J: 6.6 Hz, 2H), 2.60 (t,
J=6.7 Hz, 2H) 3.56 (t, J=6.7 Hz, 2H), 7.23-7.42 (m, 5H); 13C NMR (75 MHz, CDC13) 8
18.1, 31.3, 32.4, 81.6, 87.9, 123.5, 127.7, 128.2, 131.7; IR (neat) 3220, 3200, 2950, 2800,
2250, 1610, 1490, 1250 cm'l; HRMS calcd for C11H11Br m/z 222.0044, obsd m/z
222.0037.

Synthesis of Diethyl 2-(5'-heptyn-l'-yl)-2-methy|-1,3-propanedioate (65). A 50 mL
round bottom flask equipped with a pressure equalizing dropping funnel was charged
with sodium hydride (0.7 g, 30.0 mmol) followed by the addition of dry N,N-
dirnethylforrnamide (28 mL). Diethyl methylrnalonate (4.8 g, 27.3 mmol) was added via
the addition funnel over a 15 minute period to the sodium hydride suspension. After 2
hours at ambient temperature, l-bromo-4-hexyne (64, 4.4 g, 27.3 mmol) was slowly
added. Upon completion of the addition, the reaction was stirred at rt for 30 minutes and
at 65 °C for several hours. The reaction was cooled to rt and diluted with diethyl ether
(45 mL). The mixture was washed with water (2 x 20 mL). The water layer was
extracted with diethyl ether (2 x 10 mL), and the combined organic layers were dried
(MgSO4). After concentration (rotary evaporation), the colorless residue was distilled
(124-127 °C, <1mmHg) to yield 6.0 g (87% yield) of the title compound. 1H NMR (300
MHz, CDC13) 8 1.20 (t, J=7.1 Hz, 6H), 1.71 (t, J=2.5 Hz, 3H), 1.90 (m, 2H), 1.92 (t,
J=2.5 Hz, 3H), 2.09 (qt. J=2.4, 7.1 Hz, 2H), 4.14 (q, J=7.1 Hz, 4H); 13C NMR (75 MHz,
CDC13) 8 3.2, 13.8, 18.8, 19.6, 23.8, 34.5, 53.2, 61.0, 75.7, 78.4, 172.2; IR (neat) 2970,
2850, 2810, 1690, 1720 cm‘l.

 

28
Deethoxy Carboxylation of Diethyl 2-(4'-Hexyn-l'-yl)-2-methyl-1,3-propanedioate

(63). A 100 mL round bottom flask was loaded with lithium chloride (1.8 g, 41.8 mmol),
water (0.8 g, 44.0 mmol), DMSO (45 mL) and the diester (67, 5.6 g, 22.0 mmol). The
mixture was heated at 200 °C until completion. The reaction was cooled to rt, and water
(50 mL) was added. The mixture was extracted with diethyl ether (6 x 60 mL). The
organic layers were washed with water (2 x 12 mL), dried (MgSO4), and concentrated
(rotary evaporator). Distillation of the yellow residue provided 3.2 g (80% yield) of ethyl
2-methyl-7-nonynoate (66). bp 82-85 °C (<1mmHg); 1H NMR (300 MHz, CDC13) 8
1.02 (d, J=7.0 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H), 1.40-1.70 (m, 4H), 1.73 (t, J=2.5 Hz, 3H),
2.08 (tq, 1:25, 6.7 Hz, 2H), 2.38 (sext, J=7.0 Hz, 1H), 4.08 (q, #70 Hz, 2H); 13c NMR
(75 MHz, CDC13) 8 3.3, 14.0, 16.9, 18.2, 26.7, 32.8, 39.0, 59.8, 75.4, 78.5, 176.2. IR
(neat) 2970, 2930, 2850, 1730, 1400 cm'l.

Reduction of Ethyl 2-Methyl-6-octynoate (66). Ethyl 2-methyl-6-octynoate (66, 2.8 g,
15.3 mmol) in diethyl ether (47 mL) was added dropwise to a solution of lithium
aluminum hydride (0.37 g, 9.9 mmol) in diethyl ether (30 mL) at 0 °C. The reaction was
allowed to warm to rt and then stirred for 3 hr. The reaction was cooled to 0 °C, and
water (0.4 mL) was carefully added. Addition of 15% aqueous sodium hydroxide (0.4
mL) and water (1.2 mL) completed the quench. The reaction was warmed to rt and
stirred for 30 minutes. Via cannula filtration, the solvent was transferred to another flask,
and the solvent was removed in vacuo. Distillation of the residue provided 1.8 g (86%
yield) of 2-methyl-6-octyn-l-ol (65). bp 85-87 °C (1 mmHg); 1H NMR (300 MHz,
CDC13) 8 0.86 (d, J=6.7 Hz, 3H), 1.39-1.67 (m, 6H), 2.08 (m, 2H), 3.33-3.51 (m, 2H);
13C NMR (75 MHz, CDC13) 8 3.4, 12.3, 19.0, 26.3, 32.4, 35.2, 68.0, 75.5, 79.0; IR
(neat) 3600-3100, 2910, 2870, 1050 cm'l; HRMS calcd for C9H16O m/z 140.1202, obsd
m/z 140.1176.

 

29
Typical Procedure for Conversion of an Alcohol to a Bromide. A solution of 6-

heptyn-l-ol (48, 2.7 g, 23.8 mmol) and triphenylphosphine (7.4 g, 28.5 mmol) in
dichloromethane (25 mL) was cooled to 0 °C. N-Bromosuccinimide (5.0 g, 28.5 mmol)
was added over a 15 minute period. The reaction was stirred at 0 °C for 1 hour and at
ambient temperature for 1 hr was followed by removal of dichloromethane in vacuo.
Dichloromethane (11 mL) was added to the dark orange sludge, and the mixture was
stirred for five minutes. Light petroleum ether (47 mL) was added, and the reaction was
stirred vigorously followed by solvent removal via cannula filtration. The remainder of
the solids were washed with light petroleum ether (2 x 25 mL). The filtration procedure
was repeated. The solvent was removed in vacuo until 3-4 mL remained, at which point,
the residue was filtered through 1" of basic alumina in a pipette and rinsed through with
petroleum ether (10 mL). The solvent again was removed with a rotary evaporator.
Distillation yielded l-bromo-6-heptyne (60).

Physical data for l-bromo-S-octyne (45). 1.0 g, 79% yield, bp oven=50-60 °C (1
mmHg); 1H NMR (300 MHz, CDC13) 8 1.06 (t, J=7.4 Hz, 3H), 1.56 (quint, J=7.3 Hz,
2H), 1.95 (quint, J=7.1 Hz, 2H), 2.09-2.20 (m, 4H), 3.41 (t, J=6.7 Hz, 2H); 13C NMR (75
MHz, CDC13) 8 12.6, 14.3, 18.0, 27.5, 31.8, 34.0, 78.5, 81.5; IR (film) 2974, 2937, 2876,
2845, 1452, 1435, 1251 cm". HRMS calcd for C3H13Br m/z 188.0200, obsd m/z
188.0201.

Physical data for l-bromo-6-octyne (51). 1.8 g, 90% yield, bp 40-45 °C (<1 mmHg);
1H NMR (300 MHz, CDC13) 8 1.42-1.56 (m, 4H), 1.75 (t, J=2.6 Hz, 3H), 1.83 (m, 2H),
2.12 (m, 2H), 3.39 (t, J=6.8 Hz, 2H); 13C NMR (75 MHz, CDC13) 8 3.5, 18.4, 27.3, 28.1,
32.3, 33.6, 75.7, 78.6; IR (neat) 2970, 2930, 2870, 1410 cm‘l; HRMS calcd for
C3H13Br m/z 188.0194, obsd m/z 188.0194.

Physical data for 1-bromo-7-nonyne (56). 2.7 g, 90% yield, bp oven=110-120 °C (8
mmHg); 1H NMR (300 MHz, CDC13) 8 1.32-1.50 (m, 6H), 1.74 (t, J=2.6 Hz, 3H), 1.82
(quint, J=7.0 Hz, 2H), 2.09 (tq, J=2.6, 7.0 Hz), 3.38 (t, J=6.8 Hz, 2H); 13c NMR (75

30
MHz, CDC13) 8 3.3, 18.4, 27.6, 27.8, 28.6, 32.6, 33.8, 75.2, 79.0; IR (neat) 2940, 2860,

1190 cm'l; HRMS calcd for C9H15Br m/z 202.0358, obsd m/z 202.0348.

Physical data for 1-bromo-6-heptyne (60). 3.3 g, 84% yield, bp 31-33 °C (<1 mmHg);
1H NMR (300 MHz, CDC13) 8 1.45-1.60 (m, 4H), 1.74 (t, J=2.6 Hz, 3H), 1.85 (m, 2H),
1.91 (t, J=2.6 Hz, 1H), 2.18 (m, 2H), 3.38 (t, J=6.7 Hz, 2H); 13c NMR (75 MHz,
CDC13) 8 18.2, 27.2, 27.5, 32.1, 335,685, 84.0; IR (neat) 3300, 2930,2860, 2090 cm";
HRMS calcd for C7H11Br m/z 174.0044, obsdd m/z 174.0051.

Physical data for l-bromo-7-octyne (61). 3.7 g, 82% yield, bp 79-80 °C (5 mmHg);
1H NMR (300 MHz, CDC13) 8 1.39-1.60 (m, 6H), 1.85 (m, 2H), 1.91 (t, J=2.6 Hz, 1H),
2.17 (dt, J=2.6, 7.0 Hz, 2H), 3.38 (t, J=6.7 Hz, 2H); 13c NMR (75 MHz, CDC13) 8 18.3,
27.5, 27.7, 28.1, 32.6, 33.5, 68.1, 84.3; IR (neat) 3300, 2930, 2870, 2120, 1470, 1410,
cm'l; HRMS calcd for C3H13Br m/z 188.0200, obsd m/z 188.0195.

Physical data for 1-bromo-2-methyl-6-octyne (68). 1.9 g, 86% yield, bp oven: 51-62
°C (1 mmHg); 1H NMR (300 MHz, coc13) 8 0.98 (d, J=6.7 Hz, 3H), 1.20-1.56 (m, 2H),
1.62-1.81 (m, 2H), 1.72 (t, J=2.6 Hz, 3H), 2.40 (m, 1H), 3.28 (dd, 1:59, 9.8 Hz, 1H),
3.36 (dd, 5.0, 9.8 Hz, 1H); 13C NMR (75 MHz, CDC13) 8 3.4, 18.5, 18.7, 26.0, 34.0,
34.7, 41.1, 75.6, 78.7; IR (neat) 2940, 2920, 2860, 1420, 1210 cm-1.

Synthesis of Propylidenecyclopentane (69). Sodium hydride (0.17 g., 7.1 mmol) was
weighed out into a 25 mL round bottom flask followed by addition of anhydrous
dimethyl sulfoxide (3.0 mL). The mixture was heated at 7 5-80 °C for 45 minutes or until
evolution of hydrogen ceased. The dark green solution was cooled in an ice-water bath.
A solution of n-propyltriphenylphosphonium bromide (2.75 g, 7.1 mmol) in warm
dimethyl sulfoxide (7.1 mL) was added. The resultant dark red solution was stirred at
ambient temperature for 10 minutes. At which time, cyclopentanone (0.5 g., 5.9 mmol)
was added and allowed to react at room temperature for 2 hours. Water (15 mL) was

used to quench the reaction. The reaction mixture was extracted with pentane (3 x 10

31
mL), and the combined organic layers were washed with water (2 x 10 mL), dried

(NaSO4) filtered, and concentrated. Preparatory gas chromatography was used to purify
the product. 1H NMR (300 MHz, CDC13) 8 0.92 (t, J=7.5 Hz, 3H), 1.50-1.68 (m, 4H),
1.95 (m, 2H), 2.10-2.23 (m, 4H), 5.21 (m, 1H); 13C NMR (75 MHz, CDC13) 8 14.0,
23.7, 26.2, 26.4, 28.3, 33.2, 123.0, 127.2; IR (neat) 3040,2960, 2890, 2870, 2840, 1450,
1430 cm'l; MS m/z (rel. intensity) 110 (31), 95 (26), 81 (32), 67 (100), 41 (28).

Physical data for ethylidenecyclohexane (70). 2.3 g, 70% yield, bp 128-130 °C (760
mmHg); 1H NMR (300 MHz, CDC13) 8 1.30-1.52 (m, 6H), 1.60 (d, J=6.7 Hz, 3H), 2.04
(t, J=4.4 Hz, 2H), 2.11 (t, J=5.4 Hz, 2H), 5.11 (qt, J=l.1, 6.7 Hz, 1H); 13c NMR (75
MHz, CDC13) 8 12.5, 26.9, 27.6, 28.2, 28.6, 37.1, 115.0, 140.1: IR (neat) 3050, 2920,
2860, 1440 cm'l.

Physical data for ethylidenecycloheptane (71). 1.9 g, 58% yield, bp 69-70 °C (30
mmHg); 1H NMR (300 MHz, CDC13) 8 1.30-1.52 (m, 11H), 2.04-2.13 (m, 4H), 5.09
(qt, J=l.1, 6.7 Hz, 1H); 13C NMR (75 MHz, CDC13) 8 12.9, 23.4, 24.5, 24.6, 24.8, 25.1,
29.9, 119.3, 142.0; IR (neat) 3010,2950, 1440 cm'l.

General Procedure for Grignard Formation. A Schlenk flask equipped with a
magnetic stirring bar and activated magnesium (4.0 mmol) was placed under vacuum and
heated with a flame for 10 minutes to drive off any advantageous water. The flask was
cooled, and the flask was purged with argon for .30 minutes after the glass stopper was
replaced with a rubber septum. At the desired temperature, two to three drops of the
bromide were used to initiate the Grignard formation. Tetrahydrofuran (1 mL) was added
followed by the remainder of the bromide (1.0 mmol, total) at a rate of 1 drop every 5
minutes. After addition, the reaction was followed by gas chromatography. The aliquots

were quenched at -78 °C with 1:1 methanol/HCl solution.

32
General Method for Transmetallation to Titanocene Dichloride. The Grignard

mixture from above was transferred via cannula into a previously evacuated Schlenk flask
charged with titanocene dichloride (1.2 mmol) in dichloromethane (4.0 mL) at -40 °C.
Additional tetrahydrofuran (0.5 mL) was used to transfer any residual organomagnesium
bromide. The dark red solution was stirred at -40 °C for 30 minutes and at room
temperature for 5—6 hours. After the solvent was removed in vacuo, the residue was taken
up in toluene (2.5 mL) and hexane (2.5 mL). Removal of the excess titanocene
dichloride and Grignard salts was accomplished by filtration at 0 °C via cannula filter
into another deoxygenated Schlenk flask. Additional toluene (2 mL) was used to wash
the solids, and the solids were dissolved in dichloromethane (2 mL). Toluene (2.5 mL)
and hexane (2.5 mL) was then introduced into the flask. The slurry was filtered and
washed as before. Evaporation of the solvents resulted in a dark red oil that was taken up
in toluene (10 mL), and n-octane (internal standard, 1.0 mmol) was added. With
methanol/HCI as the method of protonolysis, analysis of the 5-octyn-1-yltitanocene
chloride revealed 80% yield (72% of 5-octyne, 8% of propylidenecyclopentane) based on

the bromide.

Procedure for 5-Octynyltitanocene Cyclization. Ethylaluminum dichloride (0.01 mL,
0.02 mmol, 1.8M in toluene) was added to a 0.5M 5-octyn-1—yltitanocene chloride (72
2.0 mL, 0.1 mmol) in toluene at -78 °C. After 15 minutes, the reaction was quenched in
the usual manner. With n-octane as an internal standard, the go. analysis revealed 96%
cyclization with 4% of 3-octyne for a 93% combined yield. [Note: substrates that were

sensitive to the methanolic HCl were quenched with a water/acetic acid mixture (1:1)].

Cyclization of 74 and Isolation of Vinylsilane 78. Dimethylaluminum dichloride (2
mL, 3.6 mmol, 1.8M in toluene) was added to 7-trimethylsilyl-6-heptyn-1-yltitanocene
chloride (74, 2.0 mL, 0.1 mmol, 0.07M) in toluene at -30 °C. After 6.5h, the reaction was

33
quenched with a water/acetic acid mixture (1:1 by volume) at -50 °C. Analysis of the

volatiles by g.c. showed 97% cyclization (72% combined yield). The organic layer was
washed with sat. NaHC03 (2 x 10 mL), water (10 mL), and dried (MgSO4). Vinylsilane
(78) was isolated by preparatory gas chromatography. 1H NMR (300 MHz, CDC13) 8
0.05 (s, 9H), 1.51 (m, 6H), 2.10-2.21 (m, 4H), 5.17 (s, III); 13C NMR (75 MHz, CDC13)
8 0.03, 26.2, 28.5, 28.9, 34.5, 40.3, 120.1, 160.0; MS m/z (rel. intensity) 168 (16), 153
(100), 125 (32), 73 (44), 59 (40).

IV. REFERENCES

(1)

(2)
(3)

(4)
(5)
(6)

(7)
(8)
(9)
(10)
(11)

(12)
(13)

(14)
(15)

(a) Rigollier, P; Young, J.R.; Fowley, L.A.; Stille, J.R. J. Am. Chem Soc.

1990, 112, 9441. (b) Young, J.R.; Stille, J.R. Organometallics 1990, 9, 3022.
(c) Young, J.R.; Stille, J.R. J. Am. Chem. Soc. 1992, 112, 4936.

Harms, A.E.; Stille, J.R. Tetrahedron Lett. 1992, 33, 6565.

(a) Schwartz, C.E.; Curran, D.P. J. Am. Chem. Soc. 1990, 112, 9272. (b) Curran,
D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107, 1448.

Ward, H.R. J. Am. Chem. Soc. 1967, 89, 5517.

Crandall, J.K.; Michaely, WJ. J. Org. Chem. 1984, 49, 4244.

 

(a) Yeh, M.C.P.; Knochel, P. Tetrahedron Lett. 1989, 4799. (b) Rao, S.A.,
Knochel, P. J. Am. Chem. Soc. 1991, 113, 5735. For Cu with Mg see: Stemberg,
E.D.; Vollhardt, K.P.C. J. Org. Chem. 1984, 49, 1574.

Crandall, J.K.; Ayers, T.A. Organometallics 1992, 11, 473.

Bennett, S.M.; Larouche, D. Synlett 1991, 805.

Crandall, J.K.; Keyton, D.J. Tetrahedron Lett. 1969, 1653.

Curran, D.P.; Chem, M.-H.; Kim, D. J. Am. Chem. Soc. 1986, 108, 2489.

(a) Bailey, W.F.; Ovaska, T.V. J. Am. Chem. Soc. 1993, 115, 3080, (b) Bailey,
W.F.; Ovaska, T.V. Tetrahedron Lett. 1990, 627. (c) Bailey, W.F.; Ovaska,
T.V.; Leipert, T.K. Tetrahedron Lett. 1989, 3901. (d) Bailey, W.F.; Ovaska,
T.V. Organometallics 1990, 9, 1694.

Wu, G.; Cederbaum, F.E.; Negishi, E. Tetrahedron Lett. 1990, 493.

(a) Richey, H.G., Jr.; Rothman, A. M. Tetrahedron Lett. 1968, 1457. (b) Kossa,
W.C.; Rees, T.C.; Richey, H.G. Jr. Tetrahedron Lett. 1971, 3455.

Fujikara, S.; Inoue, M.; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984, 1999.
Crandall, J.K.; Baittioni, P.; Wehlacz, J.T.; Bindra, R. J. Am. Chem. Soc. 1975,
97, 7171.

34

(16)

(17)

(18)

(19)

(20)
(21)

(22)
(23)

(24)
(25)
(26)

35
(a) Miller, J .A.; Negishi, E. Isr. Jour. Chem 1984, 24, 76. (b) For a related

cyclization with Ni(CO)4 see: Crandall, J .K.; Michaely, W.J. J. Organomet.
Chem. 1973 51, 375.

Clawson, L.; Soto, J .; Buchwald, S.L.; Steigerwald, M.L.; Grubbs, R.H. J. Am.
Chem. Soc. 1985, 107, 3377.

Watson, W.H.; McMordie, W.C., Jr.; Lands, L.G. J. Polym Sci. 1961, 55,
137.

Eisch, J J.; Piotrowski, A.M.; Brownstein, S.K.; Gabe, E.J.; Lee, F.L. J. Am
Chem. Soc. 1985, 107, 7219.

Miyashita, N.; Yoshikoshi, A.; Grieco, P.A. J. Org. Chem 1977, 42, 3772.
Brandsma, L. Preparative Acetylenic Chemistry, Elsevier, New York, 1988 (2nd
ed.).

Brown, C.A.; Yamashita, A. J. Chem. Soc, Chem. Commun. 1976, 959.
Beckwith, A.L.J.; Easton, L.J.; Lawrence, T.; Serelis, A.K Aust. J . Chem
1983, 36, 545.

Greenwald, R.; Chaykovsky, M.; Corey, E.J. J. Org. Chem 1963, 28, 1128.
Johnson, W.S. Bioorganic Chem. 1976, 5, 51.

Reetz, M.T. Organotitanium Reagents in Organic Synthesis, Springer Verlag,

New York, 1986.

CHAPTER 11

ORGANOMETALLIC SN' CYCLIZATIONS WITH ALLYLIC ETHERS

36

37
I. INTRODUCTION

Many natural products contain a variety of elaborate as well as relatively simple
ring skeletons. The synthesis of such compounds depends heavily on the
functionalization and Stereochemistry desired in the molecule. Complex natural products
could not have been synthesized without methods of cyclization which generated
stereocontrolled ring systems in the presence of various functional groups. One simple
method of cyclization utilized an attack of a nucleophilic carbon on a carbon bearing a
leaving group (SN reaction). Unfortunately, this method was unable to maintain
functionality for further transformations. A variation of this cyclization involved a
nucleophilic attack upon an allylic system bearing a leaving group which resulted in an
olefin in the final product (SN' reaction). Intramolecular SN' reactions have occurred one

of three ways (eqs 2-4).1

   

Nu " LG 7 Nu ( 1)
A
LG
- LG
‘ (2)
- LG
Nu 7 fl (3)
\) \ak A Nu /
a LG
- LG
‘ N (4)
Nu 7 LG u

38
In the discussion that follows, past methods for SN' reaction that employed

various organometallic nucleophiles to diSplace an allylic alkoxy group will be presented.
In addition, advancements with our proposed methodology will be discussed. This
methodology has addressed the synthesis of various carbocycles, and the olefin

Stereochemistry was varied to further investigate the SN' reaction}:2

A. Intermolecular SN2' Reactions

1. Organocuprate Nucleophiles.”3 Although stable toward lower order
cuprates (R2CuLi), allylic ethers reacted with Grignard reagents in the presence of Cu(I)
halides (eq 5).4 In cases where the 8 carbon was more substituted than the or carbon, the
nucleophiles added in an 8N2 fashion (eq 6).5 The opposite regiochemistry was observed
when the or carbon was more substituted than the 8 carbon (eq 7).5 As demonstrated in
the previous examples (eq 6 and 7), intermolecular SN2' additions were sensitive to the

steric bulk of the electrophilic carbon.

OCH3 i) MeMgBr \ OH

Me ii) H30

1) C7H15MgCl

Me 7 CuBr (5%) Me (6)
__ _, _
>—\/ 051 ii) 1130+ h C7H15

 

Me or 83% Me
7 1) C711, 5MgCl M
a OMe CuBr (5%) r C71115 _ e (7)
ii) H30+ <
Me Me 70% Me

The Stereochemistry of the nucleophilic addition was probed through 1 and 2 (eq
8).6 As seen in both examples, the nucleophile preferred the addition anti to the leaving
group. An important observation was that both 1 and 2 resulted in the same SN2 product
(4). The intermediate copper complex must have some bond rotation, since the 8N2

product has exclusively the E Stereochemistry regardless of the starting olefin.

39

Et Me , M M 1
I) ctil gBr Me “R M 8

\\
Me‘ H R2 3 4
1 R1=CH20H, R2=H 1 : 2
2 R1=H, R2=CH20H 4 : 1

Intermolecular addition onto a cyclic allyl ether also exhibited poor
regioselectivity. When 5 was treated with butylrnagnesium chloride in the presence of
5% CuBr, both regioisomers were, generated in nearly equal amounts (Scheme I).7 The
1,4-isomer (6) also gave the same products in the same ratios, while the corresponding
trans isomers (7 and 8) only yielded one regio- and stereochemical isomer under similar
conditions (Scheme 1).7 The reason for this selectivity was based on the anti-preference
of the incoming nucleophile. In both cases, the isopropyl group impeded one
nucleophilic pathway. In 6, the isopropyl group blocked the olefin from SN2' attack, and
in 7, the isopropyl group blocked the top face from 8N2 attack.

Scheme I. Nucleophilic Additions of Cyclic Allyl Ethers.

 

OMe n- Ba
i'Pri)nBuM " i-Pri)n-BuMgC
CuBr§ CuBr (5%)
ii) H30 “6 191130
77%.1‘ 60% M
5
QMe
' 1"“ i) n-BuM Cl i-Pr i) n-BuMgCl i-Pr
CuBr (3%) CuBr (5%)
ii) Hgo+ ii) 1130+ ,.
60% ".13., 50% Med‘
7 8

Another family of compounds that SN2' additions have occurred in are

vinyloxiranes. Vinyloxiranes behave in the same manner as the methoxy groups, but due

40
to the increased reactivity as a result of the ring strain, the vinyloxir 31163 Will not be

discussed here.8

B. Intramolecular SN' Reaction

1. Anionic Cyclization. In order to appreciate the SN' cyclizations, ring
formatiOn through the intramolecular insertion of an unactivated alkene into a carbon-
1ithium bond will be discussed. Litllium'mediated cyclization is a powerful tool for the
formation of five-membered carbocycles with reasonably good diastereoselectivity (eq
9).9 However, compounds with an alkyl group on the terminal olefinic carbon failed to
cyclize under anionic conditions (eq 10).9 In the case of six-membered ring formation,
only a moderate conversion to the cyclized product was detected (eq 11).921

Me
Me PMDTA
-78 °C—> rt ' Me (9)

I 81%
34:1 (transzcis)

Me Me

‘78 °C—> It, (10)
ii) H30+ Me

I / i)t-BuLi Me /
-78 C—ig . + (11)

ii) H30+
68% 31%

Lithium anionic cyclization has taken place in the presence of an allylic methoxy
group (eq 12),10 and with this substrate, the trajectory for the nucleophile to initiate an
SN' attack cannot be accommodated due to geometrical constraints. The trajectory
needed for an SN' attack follows the same pathway as if the nucleophile attacked a

carbonyl carbon. As a result, the typical anionic exo cyclization was observed.

41
Me

11) H30

40%

Although lithium mediated cyclizations were efficient for the formation of five-
membered rings, the methodology for six-membered ring formation suffered from low
conversion. While limited to the cyclization of monosubstituted alkenes, the
methodology was strengthened by the ability to functionalize the molecule once

cyclization was complete.

—2. SN' Reactions with Organocuprate Reagents. A rare SN' cyclization with a
cuprate reagent was seen when attempts were made to methylate 9. The cyclization was
observed when 9 was treated with lithium dimethylcuprate to yield not only the
methylated product but also the SN' cyclized product 11 (eq 13).11 The formation of 11
was quite remarkable since tetrahydropyranyl ethers (TI-1P), which were commonly used
for protection in organometallic reactions, functioned as the leaving group. The reason

for this unexpected reactivity can be partially attributed to the allylic nature of the THP

ether.
Me Me
I
\ 0THP \ OTHP Me CH OH
1) MC2CuLi 2
——-> + (13)
ii) 1130+
I CHZOH M CHZOH
9 10 30% 11 30%

3. SN' Reactions with Organolithium Reagents. SN' reactions have been used
to generate tetrahydrofuran derivatives. The or-alkoxylithium reagent that has succeeded
in tetrahyrofuran formation was produced by the treatment of 12 with t-butyllithium (eq

14).12 After transmetallation, the anion underwent cyclization to produce 13 in poor

42
yields, and when a disubstituted olefin was used, no cyclization occurred (eq 15).12 The

efficiency of cyclization was greatly improved with the employment of an allylic
methoxy substituent as in 14 (eq 16). Such cyclizations provided higher yields and
higher cis to trans ratios, and the resultant vinyl group was easily handled and was

suitable for further transformations.

Me

i) n-BuLi'o
432% (14)
/\ ii) H30
c-CcH 13 o SnBU3 49% «2,1113 0
12 13 11:1 (cis:trans)
C3“? i) n-BuLi C3H7
[f ——»-7::g:c (if (15)
.. 6
0A SIIBU3 ll) 3 0’
i) n BuLio \
-78—)0 c (16)
H 0
SB“ “3 u) 78% M” O

15 >15:l (cisztrans)

A similar cyclization was seen in the formation of an intermediate for the
synthesis of dodecahedrane.13 The intermediate was to be generated by a bis [2,3]
sigmatropic rearrangement (Scheme 11), but instead of rearrangement, the compound
underwent an SN' cyclization to yield 18.

Scheme 11. SN' Cyclization in Dodecahedrane Intermediate.

 

CH20LI CHon
c *- 86
ii) 1130*
70% : g .
0 LiCHZO CHZOH

18 16 17

43
Vinyllithium intermediates have also undergone SN'cyclization.14 Preparation of

the vinyllithium was accomplished by the treatment of [(triisopropylphenyl)sulfonyl]-
hydrazone (NNHTris) with t—butyllithium (eq 20). The resultant vinyllithium displaced
the allylic methoxy group in an SN' fashion to yield the cyclic compound 21 in 60% yield.

Unfortunately, the formation of six-membered rings was not investigated in this study.

\ Li
Me X Mira: (Jim—sh (17)
O 60%

Me

19 X=NNHTris 20 21

 

4. Goals for SN' Methodology. In past methods for SN' cyclization, success in
six-membered ring formation was rare. In the methodology proposed, these six points
were addressed:

1) Efficient synthesis of SN' precursors.

2) High conversions and yields for the formation of small to medium size

carbocycles.

3) Use of stable methoxy and t-butyldimethylsilyloxy substituents as leaving

groups.

4) Investigation into the effect of the olefin Stereochemistry on the cyclization.

5) Exploitation of the anti-addition preference to generate stereoselective

products.

6) Investigation of competition between SN' and SN modes of cyclization (eq 18).

Nu (£9- Nu i1£> Q (18)
/ . \ LG Nu /

44
These points are invaluable to establish a methodology that could be incorporated into a

natural product synthetic scheme and would surpass the previously discussed SN'

cyclizations.

H. RESULTS AND DISCUSSION
A. Preparation of Substrates For SN' Cyclizations

The study of SN' cyclization required substrates that varied in tether length
between the activated sp3 carbon and the olefinic carbon of the allylic methoxy group (eq
2). After careful consideration, a substrate was designed that would be used for the
synthesis of both cis and trans olefinic isomers. Synthesis of these key substrates was
similar to the preparation of the alkyne substrates in the Ziegler-Natta study with
alkynes.15 Compounds 22a-c were protected as the THP ether 23, and with subsequent
deprotonation and paraforrnaldehyde quench quickly provided the key intermediate 24
(Scheme 11]).16

Scheme 111. Synthesis of Precursor to Cis and Trans Olefins.

H
0“ OTHP 0THP
I I DHP i i i. n-BuLi I I
n n 11
22a n=0 23 24
b n=1
c n=2

The synthetic pathway to the trans isomer employed a procedure developed by
Denmark.17 RedAl® [NaAlH2(OCH2CH20CH3)2] efficiently reduced the alkynol 24
stereoselectively to give only one isomer (Scheme IV). The resultant alcohol was
methylated, and the THP ether was removed to provide 26, 27, and 28, respectively.18
The sequence of reactions to synthesize 26, 27, and 28 was performed without
purification of the intermediate products. The resultant alcohols were then converted to

the corresponding bromides with triphenylphosphine and N-bromosuccinimide and to the

45
iodides by conversion of the alcohol to the mesylate which was displaced by the iodide of

sodium iodide.

Scheme IV. Preparation of Trans Olefins for SN' Cyclization.

 

  

24 RedAl 1111 0 I“ 1) MR. Mel )a
—’ / ii) PPTs, MeOH
H0 25 . _ i M . _
a. n—l 26. n—l, 56% from 22a
b: n=2 27: n=2, 58% from 22b
c: n=3 28: n=3, 57% from 22c
i) MsCl, TEA NBS
ii) Nal PPh3
I )n Bf )n
MeO MeO
32: n=1, 75% 29: n=1, 82%
33: n=2, 78% 30: n=2, 92%

31: n=3, 86%

Scheme V. Preparation of Cis Olefins for SN' Cyclization.

H2 THPO i) NaH, Mel H
4 P2N'k1 / ii)PPTsMeOH /
- 1C 6 9
HO MeO

 

 

34 a: n=1 35: n=1, 60% from 22a
b: n=2 36: n=2, 71% from 22b
c: n=3 37 : n=3, 56% from 22c
lNBS
PPh3
MeO / M60 /
41: n=1, 93% 38: n=1, 88%
42: n=2, 75% 39: n=2, 86%

43: n=3, 71% 40: n=3, 86%

 

46
In order to examine the stereochemical effects of the cis olefin on the SN'

cyclization, the cis olefin substrates were prepared in the same fashion as the trans isomer
with the exception of the establishment of the cis Stereochemistry with a hydrogen/nickel
boride reduction (Scheme V).19

In order to address the feasability of four-membered ring formation, the trans
isomer (44) was synthesized. .The decision to pursue the trans isomer was based on the
assumption that the cis isomer would most likely undergo SN cyclization to generate the
more stable six-membered carbocycle (Scheme VI). The trans olefin cannot undergo an

SN cyclization because the nucleophile cannot reach the distal allylic carbon.

Scheme VI. Potential Reaction Pathways For Cis And Trans Olef'ms.

Nuc OMe
”If

. ‘0
8353’ U % Nuc
,

. 0 I /
w (Nu/CV fi‘k’

/ 0M6

Scheme VII. Synthesis of Four-Membered Ring Precursor (Trans Olefin).

H n-Pr
H n-Pr

. . ®

BuL
ii) CHO THPO 36% THPO
Me/V

80%

45

44 46
l 1) NaH
Mel

 

2) PPI‘S
MeOH
50%

Me n-Pr Me -Pr
Br NBS, Ph3P HO
' I 87%

48 47

47
Synthesis of the four-membered ring precursor began with the deprotonation of

THP protected alcohol 44 followed by the addition of butanal to produce 45 (Scheme
VH). The use of butanal instead of paraforrnaldehyde was required to increase the
molecular weight, so go. analysis could be easily performed on the cyclization products.
RedAl® reduction yielded the trans isomer which was methylated and deprotected to
provide 47 in poor yields. Under the normal bromination conditions, 47 was converted to
48 in 87% yield.

. Scheme VIII. Synthesis of Precursor For Bicyclic System.

0
CHZCHCHzLi NaH, Mel
CuCN 88%

50/ 51/

 

  
 
    
 

i) CpZZrHCl i) CerHCl
ii) NBS ii) I;
529’ 56%
OMe OMe

<9

Br

Ul II
mg"

52

For the previous substrates, the exact nucleophilic approach was arbitrary since
the anti or syn displacement resulted in the same cyclic product. One method to
investigate the anti or syn approach was through a cyclization onto a preexisting ring.
Through the examination of molecular models, the cis 1,4 isomer had the best orbital
overlap for nucleophilic SN' displacement of the alkoxy group. Establishment of the cis

Stereochemistry was accomplished through the allylation of 3,4-epoxycyclohexene with

 

48

an allyl cuprate reagent (Scheme VIII).20 Alcohol 50 was protected as a methyl ether

followed by hydrozirconation21 and with subsequent treatment of NBS gave 52 or with

treatment with iodine yielded 53.

A. Preparation of Substrates For SN Versus SN' Investigation

For the study of SN versus SN' cyclizations, substrates were prepared that

positioned the methoxy group on the internal allylic carbon. Preparation of the substrates

for the competitive study between SN and SN' was accomplished with the three or four
carbon unit generated from trimethylene oxetane (54) or tetrahydrofuran (60),
respectively (Schemes IX and X).22 Lithium-iodide exchange with t-butyllithium

followed by addition of acrolein yielded the properly substituted carbon chains 56 and 62.

 

Further transformations of methylation and deprotection with tetrabutylammonium

fluoride23 provided alcohols 58 and 63, which were routinely converted to 59 and 64,

respectively.

Scheme IX. Synthesis of SN Versus SN' Substrate

1:1

54

Br HO
NBS, Pb P TB AF
CK We / «a /
OMe OMe
59 58

(Four- Versus Six-Membered Rings).

 

OTBDMS
TBDMSCI TBDMSO I i) t-BuLi ’ /
Nal, CH3CN ’ ii) CH2CHCHO
99% 33% on
55 56
NaH, Mel
88%

OTBDMS

OMe
57

49
Scheme X. Synthesis of SN Versus SN' Substrate

 

(Five- Versus Seven-Membered Rings). OTBDMS
O I OTBDMS \
TBDMSCI U i) t-BuLi ,
———'
Nal, CHgCN ii) CH2CHCHO H0
709’
60 97% 61 ° 62 g
l) NaH, MeI
2) TBAF
62%
Br OH
\ NBS, Ph3P \
87 %
MeO M30
64 63

Standards of cyclized products 66 and 67 were commercially available from
Aldrich or Wiley Organics. The uncyclized standards were obtained through

protonolysis of the corresponding organomagnesium intermediate prior to cyclization.

B. Cyclization of Substrates
1. SN' Cyclization.

a. Five-Membered Ring Formation. Anionic cyclization was first observed
when the Grignard intermediate of 38 was stirred at rt for 5 hrs (Table 1). The amount of
cyclization was increased dramatically when the Grignard intermediate was generated in
THF at reflux. Vinylcyclopentane (65) was formed in 94% conversion. Cyclization of
the transs isomer 29 was not as successful and only gave 87% conversion to 65. Some
cyclization for both the five- and six-membered ring studies occurred through a radical
intermediate, which resulted in 1-methoxy-2-cyclopentylethane or 1-methoxy-2-
cyclohexylethane, respectively. These compounds accounted for the balance of

recovered material for the five and six-membered ring cyclizations.

 

 

50
OMe

)1:

n=1 or 2

Table 1. Results of Five-Membered Ring FormationVia Grignard SN' Cyclization.

 

R1 R1

Br 2

1) Mg THF Me R

ii) H30+
29/38 66
Tem):5T1me Ratio % Yield
u tr (°C (hr) (65%) (65+66 )

29 R1=CH20Me, R2=H 66 15 87: 12 85
38 R1=H, R2=CH20Me 0—>25 5 13:85 68
66 15 94:6 87

In order to make this methodology more synthetically useful, alternate conditions
were investigated for the promotion of cyclization at lower temperatures. The above
cyclizations were repeated with the following changes: (1) Grignard formation
maintained at 0 0C to minimize cyclization, and (2) addition of copper(I) salt to reaction
mixture at -78 °C. Compounds 29 and 38 were subjected to these new conditions (T ables
2 and 3). The effects of the copper(I) salt were that the cyclizations occurred at lower
temperatures with slightly better conversions and yields. The addition of more copper(I)

salt (0.5 equiv) did not improve the efficiency of the cyclization (Table 2). All copper(I)

salts catalyzed the cyclization of 38 admirably.

 

51

Table 2. Results of Five-Membered Ring FormationVia Copper(I) Catalyzed
SN' Cyclization With Trans Olefins.

i) Mg,THF
ii) CuX

 

iii) H30
“:18“ 138’ 8:: 822.138.1811
CuI (0.05) -78-)rt 0.5 68:30 74
CuI (0.50) -78—>rt 0.5 66:33 68
CuBr (0.05) -78—>rt 0.5 69:30 64
CuBr-SMe2 (0.05) -78—)rt e 0.5 67:31 67

Table 3. Results of Five-Membered Ring FormationVia Copper(I) Catalyzed
SN' Cyclization With Cis Olefms.

Br
LrCHZOMCfi i) Mg, THF CHzoMe
ii) CuX

 

iii) H30
38
Copper(I) salt Tern Time Ratio % Yield
(equiv) ( °C (hr) (65:66b) (65+66b)
CuI (0.05) -78——>rt 0.5 92:8 76
CuBr (0.05) -78——>rt 0.5 93:7 81
CuBr-SMez (0.05) -78—>rt 0.5 91:9 74

Since the vinyllithium underwent an SN' displacement of the methoxy group in
Chamberlin's studies (eq 20), the decision was made to see if (the alkyllithium from
iodides 32 and 41 would undergo SN' cyclization. Lithium-halogen exchange with t-
butyllithium at -78 °C for 20 minutes generated the alkyllithium which, when warmed,
cyclized to provide 65 in high yields (Table 4). This procedure was as successful as the
copper catalyzed cyclizations. The lithium cyclization was repeated with a catalytic

amount CuI, but this resulted in decreased conversions to and yields of 65.

52

Table 4. Results of Five-Membered Ring FormationVia Organolithium
SN' Cyclization

R1
I R2
i) t-BuLi
ll) H30+

 

32/41
Temp Time Ratio % Yield
Substrate ( 1 ) (65: 66) t65+66i

 

41 R1=H, R2=CH20Me -78->rt 90:10 76

(hr
32 R1=CH20Me, R2 =H -78—)rt 2 94:6 88
2
41 + CuI (0. 05 equiv) -78—>rt 2 87:13 73

Table 5. Results of Six-Membered Ring FormationVia Copper(I) Catalyzed
SN' Cyclization With Trans Olef'ms.

i) Mg, THF
ii) CuX I
iii) 1130+
67

 

30
COPPCFU) salt T681) Time Rati tlo % Yield
(equiv) (° (hr) (67 :68§) (67+684)_
Cul (0.05) -78—>rt 1.0 83:17 66
CuBr (0.05) -78-—>rt 1.0 88:12 66
CuBr-3M62 (0.05) -78—>rt 1.0 85:15 68
-78-—>rt 1.0 84: 16 63

b. Six-Membered Ring Formation. Six-membered ring formation was the
major goal for the SN' methodology. When the organomagnesium intermediates of 30
and 39 were generated in THF at reflux, no cyclization occurred. However, when the
organomagnesium intermediate was treated with a catalytic amount of c0pper(I) salt at
lower temperatures, cyclization proceeded to provide vinylcyclohexane (67) in relatively

good yields (Tables 5 and 6).

 

53

Table 6. Results of Six-Membered Ring FormationVia C0pper(I) Catalyzed
SN' Cyclization With Cis Olefins.

 

Br /
M ,
CHZOMC i) Mg, THF 6 CHZOMe
ii) CuX ' ‘1'
ill) H30+
39 67 68b
Copper(I) salt Tern Time Ratio ‘7 Yield
(equin (°C)p (hr) 167:68b) (607+68b)
CuI (0.05) -78—->rt 1.0 84:12 74
CuBr (0.05) -78—)rt 1.0 67:30 66
CuBrSMe2 (0.05) -78—>rt 1.0 70:30 67

The lithium cyclizations to form six-membered carbocycles performed slightly
better than the copper catalyzed cyclizations, and vinylcyclohexane (67) was the observed
cyclized product. N,N,N',N'-Tetramethylethylenediamine (T MEDA) was added to
chelate the lithium cation to increase the reactivity of the carbanion, but unfortunately, no
Si gnificant improvement in either conversion or recovery was observed.

Table 7. Results of Six- Membered Ring FormationVia Organolithium
SN' Cyclization.

I R1
if ”m 0+6?
ii) I"13()+

 

33/42
Temp Time Ratio % Yield
_Sllhsuaie (°C) (hr) (67:68) (67+68)
33R =CHZOMe, R2=H , -78-—>rt 2 85:9 82
42 R1=H, R2=CH20Me -78—->rt 2 78:6 76

c. Seven-Membered Ring Formation. With the unprecedented results of six-
membered ring formation, attempts were made to synthesize vinylcycloheptane.

Conditions that were successful in earlier cyclizations could not cyclize bromides 31 or

40 or iodide 43 (eq 23).

54

X CH20Me

+ (23)
2
31, 40 or 43

d. Four-Membered Ring Formation. Under the same conditions as the copper
catalyzed cyclizations of the previous bromides, 48 cyclized to yield cyclobutane 69 with
only 26% conversion (eq 24). This result was not unexpected since intramolecular

cyclizations to yield four-membered rings were rare.

OMe OMe
Br -Pf
n-Pr . n Me n-Pr
——>.‘.) Mg’ THF + Kr (24)
n) CuI +
iii) H30
48 66% 69 70

26 : 74

e. Bicyclo[4.3.0]nonene Formation. Based on previous studies, the cyclization
of 52 and 53 was expected to generate the cis ring fusion from the nucleophilic attack
from the face opposite to that occupied by the methyl ether. When the organomagnesium
intermediate was generated in THF at reflux, 73% cyclization was observed.
Cyclizations with the copper catalyst had comparable conversions (Table 8). When the
methyl group was replaced by thet~butyldimethylsi1yl group, only 11% conversion to
cyclized product was obtained. After workup, the reaction mixture was reduced with
PtO4 and H2. The ratios were determined by coinjection with known standards of cis

and trans bicyclo[4.3.0]nonane.

55
Table 8. Results of Bicyclo[4.3.0]nonene Formation.

i) Reagents
ii) H30

 

M
V\X :\/ C
‘ A B C
Substrate Reagents Temp Time Ratio % Yield
(°C) (b) (A:B:C)
53 X=I t-BuLi -78—>rt 3 75:<3:22 77
54 X=Br Mg, THF 66 10 73:<3:24 59
54 X=Br i) Mg -78—)rt 10 77:<3:20 52
ii) CuBrSMe
(0.05 equiv)
54 X=Br i) Mg -78—-)rt 10 72:<3:25 58
ii) CuI
(0.05 equiv)

2. SN Versus SN' Cyclizations.

a. Four-Versus Six-Membered Ring Formation. As was mentioned briefly in
the introduction, the SN' reaction depicted in eq 3 has rarely been observed. Lithium
cyclizations do not undergo this type of SN' cyclization (eq 14), but the possibility
remained that softer copper nucleophiles would have a better propensity for ring
formation. In substrate 59, SN' cyclization occurred to a greater extent than the SN

cyclization. Unfortunately, only 5% conversion to the cyclohexene (72) was detected (eq

25).

Br / i) Mg F Me /
—”——» I: + + (25)
OMe 11) CM, 18 h OMe
72 73

 

59 iii) 1130+ 71
— 5 95

56
b. Five- Versus Seven-Membered Ring Formation. Cyclizations in the five-

versus seven-membered ring formation met with greater success than the four versus. six
competitive cyclization. The SN cyclization proceeded to yield 65 with only a trace of
the SN' product (74). The Grignard intermediate heated at 66 °C only had 11%
conversion to 65 with only a 40% combined yield. In comparison to the copper catalyzed

SN' cyclization (T ables 2 and 3), the SN' cyclization was the favored process to synthesize

Br I OM
ei) Mg (26)
ii) CuI
-178 °C- rt

 

iii) H3450
860 l l
k < 795
Y
86% yield

III. CONCLUSIONS

At the onset of the SN' cyclization study, several goals were established.
Synthesis of the precursors for four, five, and six-membered carbocycles was easily
accomplished with employment of the common alkyne intermediate. The cyclization to
form Vinylcyclopentane from both the cis and trans isomers went well for the Grignard
intermediate at 66 °C, copper(I) catalyzed Grignard cyclization, and for the lithium
mediated cyclization. Although the yields of the six-membered rings cyclization were
moderate, the high conversion to cyclized product in an area where six-membered ring
formation was rare made this a powerful method for intramolecular cyclization. The cis
isomer gave slightly better cyclization results than the corresponding trans isomer for six—
membered ring generation. Formation of vinylcycloheptane was not accomplished by the
SN methodology for either the bromide or the iodide. Generation of the cis
bicyclo[4.3.0]non—1—ene was moderately successful. Even with the aid of copper(I)

catalysts, the cyclization only proceeded 78% conversion. The competition between the

 

57
SN and SN' modes of cyclization in the copper(I) catalyzed case proved that four-

membered ring formation (SN) was not as efficient as six-membered formation (SN')
although the amount of cyclization for the SN' was trivial. In the competition between
five- and seven-membered rings, Vinylcyclopentane which was formed by SN cyclization
had formed with trace evidence of the cycloheptene. In comparison to the SN'
cyclization, the SN mode of cyclization was not as effective. Overall, a new method for
generation of vinylcyclopentanes and vinylcyclohexanes was developed which surpassed

the methods currently available.

IV. EXPERIMENTAL
General methods. See Chapter I for General Methods.

Typical Procedure for Protection of Alkynols as the THP ether (23). A solution of 6-
hexynol (22a, 2.0 g, 20.4 mmol), dihydropyran (3.4 g, 40.8 mmol), pyridinium p-
toluenesulfonate (0.5 g, 2.0 mmol) and dichloromethane (20 mL) was stirred at rt for 2
hours. The reaction was concentrated, and the oil partitioned between half-saturated
sodium chloride (24 mL) and diethyl ether (24 mL). The aqueous layer was extracted
with diethyl ether (3 x 24 mL), and the combined organic layers were dried (MgSO4),
filtered, and concentrated (rotary evaporator). The crude product was carried on without

purification. The yield was assumed to be quantitative.

Typical Procedure for Conversion of Compound 23 to Compound 24- Preparation
of 24b. To a solution of n-butyllithium (32.7 mL, 65.4 mmol, 2.0M in hexanes) in THF
(100 mL) at -78 °C was introduced 6-heptyn-1-yl THP ether (23b, 11.6 g, 59.4 mmol)
and the reaction was stirred for 30 minutes at -78 °C. The cold bath was removed for 5
minutes and replaced with an ice-water bath. Paraformaldehyde (4.0 g) was added, and

the reaction was stirred at rt for 1 hr and at 45-50 °C for an additional 1.5 hr. The

 

58
reaction was poured into a 10% NH4C1 solution (140 mL). The aqueous layer was

extracted with diethyl ether (4 x 75 mL), and the organic layers were dried (MgSO4),
filtered, and concentrated (rotary evaporator). The crude product was carried on without

purification. The yield was assumed to be quantitative.

Typical Procedure for Trans Reduction of Propargylic Alcohol 24- Preparation of
25b A solution of RedA1® (27 mL, 95.1 mmol, 3.4M in toluene) and diethyl ether (24
mL) was cooled to 0 °C and a solution of 1-hydroxy-2-octyn-l-yl THP ether (24b, 13.4 g,
59.4 mmol) in diethyl ether (24 mL) was added dropwise. Ten minutes after the addition
of the alkynol, the cold bath was removed, and the reaction was stirred at rt until reaction
was complete (approx. 1-2 hrs). Diethyl ether (50 mL) and 2N H2SO4 (43 mL) were
carefully added to the reaction flask, and the solids were subsequently filtered off.
Diethyl ether (2 x 20 mL) was used to wash the solids. The aqueous phase was washed
with diethyl ether (2 x 25 mL). The organic phase was washed with water (25 mL) and
brine (25 mL). Organic layers were dried (MgSO4), concentrated (rotary evaporator) and

carried on to the procedure for methylation and deprotection.

Typical Procedure for Cis Reduction of Propargylic Alcohol 24 - Preparation of 34b.
The reaction flask was charged with nickel acetate tetrahydrate (1.4 g, 6.0 mmol) and
denatured ethanol (80 mL). Sodium borohydride (0.68 g, 17.6 mmol) was slog/11 added
(H2 evolution), and the reaction was stirred at rt for 1 hr. After the addition of ethylene
diamine (0.75 mL, 12 mmol) and l-hydroxy-Z-octyn-8-yl THP ether (24b, 9.0 g, 39.8
mmol), the flask was placed under an atmosphere of hydrogen, and the hydrogen uptake
was monitored by a gas buret. Once the reaction was complete, the ethanol was removed
in vacuo, and the greyish-blue slush was diluted with diethyl ether (50 mL). The solution
was filtered through a pad of silica gel, and the silica pad was washed with diethyl ether

(3 x 50 mL). The organic layers were dried (MgSO4) and concentrated (rotary

59
evaporator). The crude product was carried on to the procedure for methylation and

deprotection without further purification.

Typical Procedure for Methylation and Deprotection of Compounds 25 and 34-
Preparation of 27. A suspension of sodium hydride (1.6 g, 65.3 mmol) in diethyl ether
(50 mL) at 0 °C was treated with E—l-hydroxy-Z—octen-8-yl THP ether (25b, 13.6 g, 59.4
mmol) in diethyl ether (10 mL). The reaction was stirred at It for 1 hr with subsequent
addition of methyl iodide (16.8 g, 118.8 mmol). The reaction was stirred at rt overnight.
A minimal amount of water was used to dissolve the inorganic salts, and the aqueous
layer was extracted with diethyl ether (2 x 10 mL). The organic layers were dried
(MgSO4) and concentrated (rotary evaporator). The residue was taken up in methanol
(90 mL) and treated with PPTs (1.7 g, 6.7 mmol). The reaction was heated at reflux for 2
hrs. Upon completion of the reaction, methanol was removed in vacuo, and the residue
was partitioned between half-saturated brine (50 mL) and diethyl ether (50 mL). The
aqueous layer was extracted with diethyl ether (2 x 50 mL), and the organic layers were
dried (MgSO4) and concentrated (rotary evaporator). Distillation of the residue provided
E-l-methoxy-Z-octen—8—ol (27).

Physical data for E-l-methoxy-Z-hepten-7-ol (26). 1.2 g, 56% yield from 5-hexyn-l-ol
22a, bp 85-90 °C (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.35-1.55 (m, 4H), 2.01 (q,
J=6.7 Hz, 2H), 2.30 (bs, 1H), 3.24 (s, 3H), 3.55 (t, J=6.4 Hz, 2H), 3.80 (dd, J=0.8, 6.1
Hz, 2H), 5.42-5.70 (m, 2H); 13c NMR (75 MHz, CDC13) 5 25.0, 32.0, 32.1, 57.3, 62.2,
73.0, 126.0, 134.2; IR (neat) 3600-3100, 2940, 2870, 1660 cm'l; HRMS calcd for
CgH1602 m/e 144.1150, obsd(M-1)m/e 143.1011.

Physical data of E-l-methoxy-Z-octen-S-ol (27). 5.5 g, 58% yield from 6-heptyn—l-ol
24b, bp 105-109 °C (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.25—1.40 (m, 4H), 1.49
(quint, J=6.8 Hz, 2H), 2.00 (q, J=6.6 Hz, 2H), 2.24 (bs, 1H), 3.23 (s, 3H), 3.54 (t, J=6.6
Hz, 2H), 3.79 (d, J=6.1 Hz, 2H), 5.50 (m, 1H), 5.61 (m, 1H); 13C NMR (75 MHz,

60
CDC13) 5 25.0, 28.7, 31.9, 32.3, 57.3, 62.2, 73.0, 125.9, 134.2; IR (neat) 3600-3100,

3010, 2920, 2870, 1670, 1080 cm'l. HRMS calcd for C9H1302 m/e 158.1307, obsd (M-
1) m/e 158.1311.

Physical data for E-l-methoxy-Z-nonen-9-ol (28). 1.9 g, 57% yield from 7-octyn-1-ol
22c, bp 113-115 °C (<1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.23-1.40 (m, 6H), 1.44
(quint, J=6.6 Hz, 2H), 1.99 (q, J=6.7 Hz,- 2H), 2.22 (bs, 1H), 3.25 (S, 3H), 3.55(t, J=6.6
Hz, 2H), 3.80 (d, J=6.1 Hz, 2H), 5.49 (m, 1H), 5.63 (m, 1H); 13C NMR (75 MHz,
CDC13) 8 25.3, 28.7, 28.8, 32.0, 32.3, 57.3, 62.2, 73.2, 126.0, 134.6; IR (neat) 3600-3100,
3010, 2920, 2870, 1610 cm'l.

Physical data for Z-l-metlioxy-Zéhepten-7-ol (35). 1.2 g, 60% yield from 5-hexyn-1-
01, 22a, bp 75-80 °c (1 mmHg); 1H NMR (300 MHz, CDC13) 5 1.37-1.47 (m, 2H), 1.50
(m, 1H), 1.53-1.67 (m, 2H), 2.08 (q, =6.7 Hz, 2H), 3.29 (s, 3H), 3.61 (t, J=6.4 Hz, 2H),
3.95 (d, J=5.0 Hz, 2H), 5.47-5.61 (m, 2H); 13c NMR (75 MHz, CDC13) 5 25.6, 27.2,
32.2, 57.9, 62.6, 68.0, 126.2, 133.3; IR (neat) 3600-3200, 3020, 2940, 2860, 2820, 1620,
1200 cm'l; HRMS calcd for C3H1602 m/e 144.1150, obsd m/e 144.1183.

Physical data for Z -1-methoxy-2-octen-8-ol (36). 4.4 g, 71% yield from 6-heptyn-l-ol
22b, bp 100-103 °C (1 mmHg); 1H NMR (300 MHz, CDC13) 5 1.32 (m, 4H), 1.49
(quint, J=6.7 Hz, 2H), 2.02 (q, J=6.7 Hz, 2H), 2.28 (bs, 1H), 3.25 (s, 3H), 3.54 (t, J=6.6
Hz, 2H), 3.91 (d, J=5.8 Hz, 2H), 5.40-5.56 (m, 2H); 13C NIVIR (75 MHz, CDC13) 5 25.0,
27.1, 29.0, 32.2, 57.7, 62.2, 68.0, 125.8, 133.3; IR (neat) 3020, 2920, 2860, 2810, 1650,
1110 cm'l. HRMS calcd for C9H1302 m/e 158.1307, obsd m/e 158.1324.

Physical data for Z-l-methoxy-Z-nonen-9-ol (37). 2.9 g, 56% yield from 7-octyn-1-ol
22c, bp 110-115 °C (<1 mmHg); 1H NMR (300 MHz, CDC13) 5 1.20-1.40 (m, 6H), 1.50
(quint, J=6.6 Hz, 2H), 2.06 (q, J=6.7Hz, 2H), 2.20 (bs, 1H), 3.26 (s, 3H), 3.55 (t, J=6.6
Hz, 2H), 3.91 (d, J=5.6 Hz, 2H), 5.40-5.59 (m, 2H); 13C NMR (75 MHz, CDC13) 6 25.3,
27.1, 28.7, 29.0, 32.3, 57.6, 62.4, 68.0, 125.7, 131.8; IR (neat) 3600-3200, 3070, 2930,
2870, 1610, 1200 cm’l.

 

61
Physical data for E-6-methoxy-4-nonen-l-ol (47). 0.9 g, 50% yield, bp 77-79 °C (<1

mmHg); 1H NMR 8 0.82 (t, J=7.2 Hz, 3H), 1.19-1.42 (m, 4H), 1.50 (m, 1H), 1.60 (quint,
J=7.0 Hz, 2H), 2.01 (bs, 1H), 2.09 (q, J=7.2 Hz, 2H), 3.18 (s, 3H), 3.42 (q, J=7.4 Hz,
1H), 3.58 (t, J=6.5 Hz, 2H), 5.24 (dd, J=15.3, 8.0 Hz, 1H), 5.55 (dt J=15.3, 6.7 Hz, 1H);
13C NMR 8 13.9, 18.5, 28.4, 32.1, 37.6, 55.6., 62.1, 82.2, 131.1, 133.1; IR 3100-3600,

2960, 2940, 2870, 2820, 1670, 1097, 970 cm'l.

Typical Procedure for Conversion of an Alcohol to the Corresponding Bromide-
Preparation of 29. A solution of E—l-methoxy-2-nonen-9-ol (28, 1.1 g, 6.3 mmol) and
triphenylphosphine (1.8 g, 7 .0 mmol) in dichloromethane (6 mL) was cooled to 0 °C. N
-Bromosuccinimide (1.2 g, 7.0 mmol) was added over a 15 minute period. The reaction
was stirred at 0 °C for 1 hour and at ambient temperature for 2 hours and concentrated in
vacuo. Dichloromethane (2 mL) was added to the dark orange sludge, and the mixture
was stirred for 5 minutes. Light petroleum ether (12 mL) was added, and the reaction
was stirred vigorously followed by solvent removal via cannula filtration. The solids
were washed with light petroleum ether (2 x 7 mL). The filtration procedure was
repeated, and the solvent was removed in vacuo until 3—4 mL remained, at which point,
the residue was filtered through 1" of basic alumina in a pipette and rinsed through with
petroleum ether (10 mL). The solvent again was removed with a rotary evaporator.
Bulb-to—bulb distillation yielded E—1-methoxy-9-bromo-2-nonene (31).

Physical data for E -1-methoxy-7-bromo-2-heptene (29). 1.0 g, 82% yield, bp
oven=80-90 °C (1 mmHg); 1H NMR (300 MHz, CDC13) 6 1.51 (quint, J=7.5 Hz, 2H),
1.82 (quint, J=7.2 Hz, 2H), 2.03 (q, J=7.1 Hz, 2H), 3.24 (s, 3H), 3.38 (t, J=6.8 Hz, 2H),
3.81 (dd, J=1.1, 5.8 Hz, 2H), 5.47 (m, 2H); 13c NMR (75 MHz, CDC13) 8 27.5, 31.3,
32.0, 33.6, 57.7, 126.7, 133.7; IR (neat) 2920, 2850, 1720, 1680, 1110 cm'l; HRMS
calcd for C3H15Br0 m/e 206.0306, obsd m/e 206.0267.

 

 

62
Physical data for E-l-methoxy-8-bromo-2-octene (30). 1.3 g, 92% yield, bp oven=84-

95 °C (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.40 (m, 4H), 1.80 (quint, J=6.8 Hz, 2
H), 2.03 (q, J=6.5 HZ, 2H), 3.27 (s, 3H), 3.36 (t, J=6.8 Hz, 2H), 3.82 (dd, J=1.0, 6.0 Hz,
2H), 5.53 (m, 1H), 5.62 (m, 1H); 130 NMR (75 MHz, CDC13) 8 27.6, 28.1, 31.9, 32.6,
33.6, 57.6, 73.1, 126.5, 134.1; IR (neat) 3010, 2930, 2860, 1620, 1110 cm'l; HRMS
calcd for C9H17BrO m/z 220.0463, obsd m/z 220.0451.

Physical data for E-1-methoxy-9-bromo—2-nonene (31). 1.2 g, 86% yield, bp oven=72-
80 °C (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.25-1.45 (m, 6H), 2.10 (q, J=6.6 Hz,
2H), 3.28 (s, 3H), 3.36 (t, J=6.7 Hz, 2H), 3.81 (dd, J=1.0, 5.0 Hz, 2H), 5.45—5.55 (m, 1H),
5.60-5.71 (m, 1H); 13C NMR (75 MHz, CDC13) 8 28.0, 28.2, 28.8, 32.1, 32.6, 33.9, 57.6,
73.2, 126.2, 134.5; IR (neat) 3020, 2934, 2856, 1670, 1116, 972 cm'l; HRMS calcd for
C10H19BrO m/e 234.0620, obsd m/e 234.0621.

Physical data for Z-1-methoxy-7-bromo-2-heptene (38). 2.3 g, 88% yield, bp 50-53
°C (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.50 (quint, J=7.2 Hz, 2H), 1.83 (quint,
J=7.2, 2H), 2.08 (q, J=6.7 Hz, 2H), 3.32 (s, 3H), 3.40 (t, J=6.7 Hz, 2H), 3.94 (d, J=4.5
Hz, 2H), 5.53 (m, 2H); 130 NMR (75 MHz, CDC13) 8 26.6, 27.9, 32.1, 33.4, 57.9, 68.0,
126.6, 132.6; IR (neat) 3020, 2930, 2890, 2860, 2820, 1110, 1450 cm'1;HRMS calcd for
C3H15BrO m/e 208.0286, obsd m/e 208.0198. ,

Physical data for Z-1-methoxy-8-bromo-2-octene (39). 1.2 g, 86% yield, bp 75-90 °C
(1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.32-1.60 (m, 4H), 1.83 (quint, J=7.0 Hz,
2H), 2.00 (q, J=6.3 Hz, 2H), 3.30 (s, 3H), 3.37 (t, J=6.8 Hz, 2H), 3.94 (d, J=5.3 Hz, 2H),
5.53 (m, 2H); 13c NMR (75 MHz, c1303) 8 27.2, 27.6, 28.6, 32.5, 33.6, 57.8, 68.0,
126.2, 133.1; IR (neat) 3020, 2920, 2860, 2810, 1650, 1095 731 cm’l; HRMS calcd for
C9H17Br0 m/z 220.0463, obsd ni/z 220.0307.

Physical data for Z-1-methoxy-9-bromo-2-nonene (40). 1.2 g, 86% yield, bp oven=75-
90 °c (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.22-1.47 (m, 6H), 1.82 (quint, J=7.0,
12H), 2.05 (q, J=6.4 Hz, 2H), 3.31 (s, 3H), 3.38 (t, J=6.8 Hz, 2H), 3.94 (d, J=5.0 Hz, 2H),

63
5.46-5.60 (m, 2H); 13C NMR (75 MHz, CDC13) 8 27.4, 27.9, 28.2, 29.2, 32.7, 33.9, 58.0.
68.0, 126.1, 143.4; IR (neat) 3010, 2930, 2850, 1650, 1100 727 cm'l; HRMS calcd for
C10H19B10 m/z 234.0620, obsd m/z 234.0631.
Physical data for E-l-brcmc 5 ‘L . 4 (48). 0.9 g, 87% yield, bp oven=60-

75 °C (1 mmHg); 1H NMR 0.87 8 (t, J=7.1 Hz, 3H), 1.20—1.80 (m, 4H), 1.92 (quint,

 

J=7.0, 2H), 2.20 (q, J=7.1 Hz, 2H), 3.21- (s, 3H), 3.38 (t, J=6.8 Hz, 3H), 3.41 (m, 1H);
13C NMR 8 12.1, 18.8, 30.7, 32.0, 33.0, 37.5, 56.0, 82.1, 131.7, 132.3; IR (neat) 2960,
2930, 1650, 1500, 1190.990 cm'l.

Typical Procedure for Conversion of an Alcohol to the Corresponding Iodide-
Preparation of 29. At -10 °C, a solution of E-l-methoxy—Z—hepten-7-ol (26, 0.7 g, 4.8
mmol), triethylamine (1 mL, 7.2 mmol) in CH2C12 (20 mL) was treated dropwise with
methanesulfonyl chloride (0.6 g, 5.3 mmol). After 15 minutes at -10 °C, the reaction
was diluted with CH2C12 (18 mL), and the mixture was washed with 10% aqueous HCl
(1 mL), saturated NaHCO3 (9 mL) and brine (1 mL). The organic layer was dried
(MgSO4) and concentrated (rotary evaporator). The residue was added to a solution of
sodium iodide (1.4 g, 9.7 mmol) in THF (12 mL) at 0 °C. The reaction was warmed to rt
and stirred until complete. The reaction was diluted with diethyl ether (35 mL) and
washed with saturated NaHC03 (2 x 65 mL) and brine (6 mL). The organic layer was
dried (MgSO4) and concentrated (rotary evaporator). Bulb-to-bulb distillation provided
E-7-iodo-l-methoxy—2—heptene (32).

Physical data for E-7-iodo-1-methoxy-2-heptene (32). 0.9 g, 75% yield, bp oven=54-
70 °C (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.46 (quint, J=7.5 Hz, 2H), 1.80 (quint,
J=7.2 Hz, 2H), 2.05 (q, J=6.8 Hz, 2H), 3.16 (t, J=7.0 Hz, 2H), 3.29 (s, 3H), 3.83 (dd,
J=0.8, 5.8 Hz, 2H), 5.43-5.71 (m, 2H); 13c NMR (75 MHz, CDC13) 8 6.6, 29.7, 31.0,
33.0, 57.8, 73.0, 126.8, 133.8; IR (neat) 3010, 2930,2850, 1670, 1110 cm'l.

Physical data for E-8-iodo-1-methoxy-2-octene (33). 2.2 g, 78% yield, bp oven=70-90
°C (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.34—1.47 (m, 4H), 1.76-1.87 (m, 2H),

 

64
2.30 (dq, J=0.84, 6.1 Hz, 2H), 3.17 (t, J=7.0 Hz, 2H), 3.30 (s, 3H), 3.83 (dd,J=0.84, 5.8

Hz, 2H), 5.57 (m, 1H), 5.65 (m, 1H); 13C NMR (75 MHz, CDC13) 8 6.6, 28.0, 30.0,
32.0, 33.4, 57.8, 72.6, 126.3, 134.2; IR (neat) 3010, 2920, 2860, 1600, 1110 cm'l.
Physical data for Z-7-iodo-1-methoxy-2-heptene (41). 1.8 g, 93% yield, bp oven=64-
70 °c (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.45 (quint, J=7.4 Hz, 2H), 1.80 (quint,
J=7.3 Hz, 2H), 2.07 (q, J=6.7 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 3.29 (s, 3H), 3.93 (d,J=4.5
Hz, 2H), 5.50—5.56 (m, 2H); 13c NMR (75 MHz, CDC13) 8 6.4, 26.4, 30.2, 32.9, 57.9,
68.0, 126.7, 132.6 cm'l; HRMS calcd for C3H15IO m/z 254.0168, obsd m/z 254.0170.
Physical data for Z-8-iodo-1-methoxy-2-octene(42). 0.9 g, 75% yield, bp oven=70-85
°c (1 mmHg); 1H NMR (300 MHz, CDC13)8 1.32-1.40 (m, 2H), 1.72-1.84 (m, 2H),
2.00-2.10 (m, 2H), 3.15 (1, J=7.0 Hz, 2H), 3.29 (s, 3H), 3.93 (d,J=5.3 Hz, 2H), 5.44-5.56
(m, 2H); 13c NMR (75 MHz, CDC13) 8 6.8, 27.2, 28.3, 30.0, 33.3, 57.8, 68.0, 126.2,
133.1; IR (neat) 2990, 2930, 2850, 1650, 1480, 1200 cm‘l; HRMS calcd for C9H17IO
m/z 268.0325, obsd m/z 268.0377.

Physical data for Z-9-iodo-l-methoxy-Z-nonene (43). 1.5 g, 71% yield, bp oven=80-95
°c (1 mmHg); 1H NMR (300 MHz, CDC13) 8 1.22-1.41 (m, 6H), 1.79 (quint, 1:73 Hz,
2H), 2.02 (q, J=6.4 Hz, 2H), 3.28 (s, 3H), 3.57 (t, J=7.0 Hz, 2H), 3.82 (dd,J=0.98, 6.1 Hz,
2H), 5.43-5.60 (m, 2H); 13c NMR (75 MHz, CDC13) 8 7.0, 27.3, 27.9, 29.2, 30.2, 33.3,
57.8, 68.0, 126.0, 133.3; IR (neat) 3010, 2930, 2850, 1670, 1500, 1100 cm'l.

Preparation of 45. A solution of 44 in THF (60 mL) was, cooled to -78 °C, and n-
butyllithium (5.3 mL, 13.2 mmol, 2.5M in hexanes) was added. The mixture was stirred
at -78 °C for 30 minutes, at which point, the cold bath was removed for 5 minutes, and
the cold bath was returned. Butyraldehyde (0.9 g, 13.2 mmol) was introduced into the
reaction dropwise. Upon completion of the addition, the reaction Was stirred at -78 °C for
10 minutes and slowly warmed to rt. The mixture was stirred at rt overnight. The

reaction was quenched with 10% NH4C1 (40 mL). The layers were separated, and the

 

65
aqueous layer was extracted with diethyl ether (3 x 40 mL). The organic layers were

dried (MgSO4), filered, and concentrated. Flash chromatography yielded 2.2 g (82%
yield) of the desired product. Rt=0.4 (50% diethyl ether/petroleum ether, stained with
phosphomolybdic acid); 1H NMR (300 MHz) 8 0.92 (t, J=7 .1 Hz, 3H), 1.36-1.82 (m,
12H), 1.97 (bs, 1H), 2.30 (dt, J=1.7, 6.8 Hz, 2H), 3.40-3.53 (m, 2H), 3.74-3.87 (m, 2H),
4.31 (m, 1H), 4.57 (t, J=7.1 Hz, 1H); 13C NMR (75 MHz) 8 13.7, 15.6, 18.4, 19.5, 25.4,
28.8, 30.6, 40.2, 62.2, 62.4, 65.8, 81.8, 84.6, 98.7; IR 3600-3100, 2955, 2872, 2212 cm‘l.

Preparation of 3,4-epoxycyclohex-1-ene (49).23 A mixture of glacial acetic acid (24 g),
90% hydrogen peroxide (22 g) and H2SO4 (0.3 mL) was stirred for 3h at rt. This solution
with sodium acetate (0.3 g) was added dropwise to a solution of sodium carbonate (60 g),
1,3—cyclohexadiene (18 g, 224.6 mmol) in dichloromethane (150 mL), and the mixture
was stirred overnight. The solids were filtered off, and the dichloromethane was removed
by distillation at atmospheric pressure. Vacuum distillation yielded 14.1 g (65% yield) of
desired product. bp 64-65 °C (65 mmHg), 1H NMR (300 MHz) 8 1.53 (m, 1H), 1.81-
2.05 (m, 2H), 3.13 (dt, J=2.0, 4.0 Hz, 1H), 3.40 (ddd, J=1.4, 2.6, 5.4 Hz, 1H), 5.75-5.90
(m, 2H); 13C NMR (75 MHz) 8 20.5, 20.8, 47.0, 55.1, 123.0, 133.0; IR 3040, 3017, 2934,
2847, 1639, 1024

cm'l.

Preparation of 50. To a 500 mL round bottom flask equipped with a pressure equalizing
addition funnel were added Li (4.2 g, 0.6 mol) anf THF (50 mL). The flask was cooled to
-15 °C, and allyl phenyl ether (6.7 g, 50.0 mmol) in diethyl ether (25 mL) was added
dropwise. The reaction was stirred at ~15 °C for 45 minutes and at rt for 20 minutes. The
dark red solution was cannula transferred to copper(I) cyanide in diethyl ether (10 mL) at
-40 °C and stirred at this temperature for 30 minutes. 3,4-Epoxycyclohex-1-ene (2.4 g,

25.0 mmol) was introduced, and the reaction was allowed to warm to rt. Water (75 mL)

66
and diethyl ether (75 mL) were added, and the aqueous layer was extracted with diethyl

ether (3 x 75 mL). The combined organic layers were washed with 10% N aOH (50 mL),
brine (75 mL), dried (MgSO4) and concentrated (rotary evaporator) to yield an oil that
was distilled to yield 2.3 g of crude product. bp 75-80 °C (1 mmHg), RF0.6 (40% ethyl
acetate/petroleum ether, stained with phosphomolybdic acid); 1H NMR (300 MHz) 8
1.23 (m,'1H), 1.45 (m, 1H), 1.80 (m, 1H), 1.90-2.28 (m, 1H), 2.30 (bs, 1H), 4.18 (m, 1H),
4.95—5.05 (m, 2H), 5.60-5.57 (m, 2H); 13C NMR (75 MHz) 8 26.6, 31.7, 35.0, 40.0, 66.8,
116.2, 130.6, 133.5, 136.4; IR 3100-3600, 3076, 3020, 2932, 2858, 1641, 1448, 1060,
736 cm'l.

Preparation of TBDMS Protected 50. The crude 50 (2.6 g) in DMF (18 mL) at 0 °C
was treated with TBDMSCl (3.1 g, 20.7 mmol) and imidazole (2.8 g, 41.4 mmol). The
reaction was stirred at rt for 4h. Water (30 ml) was added, and the mixture was extracted
with diethyl ether (3 x 30 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated (rotary evaporator). Flash chromatography yielded 3.0 g (48%
yield from 49) of pure desired product. Rf=0.10 (100% light petroleum ether, stained
with phosphomolybdic acid); 1H NMR (300 MHz) 8 0.059 (s, 3H), 0.060 (s, 3H), 0.89 (s,
9H), 1..18 (m, 1H), 1.50 (m, 1H), 1.81 (m, 1H), 1.87-2.08 (m, 4H), 2.16 (m, 1H), 4.22
(m, 1H), 4.99 (dd, J=15.3, 1.8 Hz, 1H), 5.00 (dd, J=11.7, 1.8 Hz, 1 H), 5.57 (m, 1H), 5.58
(s, 1H); 13C NMR (75 MHz) 8 -4.6, -4.5, 18.2, 25.9, 27.2, 32.4, 35.2, 40.4, 67.9, 116.0,
131.5, 132.4, 136.5; IR (neat) 3078, 3024, 2932, 2858, 1641, 1471, 1093 cm'l.

Preparation of 3-Methoxy-6-allylcyclohex-l-ene (51). At 0 °C, a suspension of NaH
(0.3 g, 12.5 mmol) in THF (9 mL) was treated with 50 ( 1.6 g, 11.4 mmol) in THF (1 mL).
The mixture was stirred for 2h at rt. The reaction was cooled to 0 °C, and methyl iodide
(3.2 g, 22.8 mmol) was added dropwise. The reaction was allowed to warm to rt and

stirred ovemight. Upon completion of reaction, a minimal amount of water was added to

 

 

67
dissolve the inorganic salts. The layers were separated, and the aqueous layer was

extracted with diethyl ether (1 x 5 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated (rotary evaporator). The residue was distilled to
yield 1.5 g (88% yield) of the methyl ether. hp 33-35 °C (1 mmHg); 1H NMR 8 1.18 (m,
1H), 1.44 (m, 1H), 1.82 (m, 1H), 1.93-2.10 (m, 3H), 2.16 (m, 1H), 3.33 (s, 3H), 3.75 (m,
1H), 4.98 (d, J=11.7 Hz, ll-I), 4.99 (dd, J=_17.0, 5.3 Hz, 1H) 5.64-5.82 (m, 3H); 13C NMR
8 26.6, 27.7, 35.3, 40.2, 55.6, 75.4, 116.1, 128.0, 134.0, 136.5; IR (neat) 3076, 3024,
2978, 2930, 2862, 2818, 1641, 1103 cm'l.

Preparation of 52. Diene 51 (3.2 g, 12.9 mmol) was added to a slurry of Cp2ZrHCl (3.6
g, 13.8 mmol) in 1,2-dichloroethane (20 mL) at 0 °C. The reaction was stirred at 0 °C for
2h and at rt until the reaction was complete. The reaction was cooled to 0 °C, NBS (2.4
g, 13.8 mmol) was introduced, and the reaction was stirred at rt 5h. Light petroleum
ether (60 mL) was added, and the suspension was filtered through silica gel. The silica
gel was eluted with petroleum ether. The organic layers were concentrated and
chromatographed to yield 1.2 g (56% yield) of the desired product. RF0.3 (10% diethyl
ether/petroleum ether, stained with phosphomolybdic acid); 1H NMR (300 MHz) 8 1.16
(m, 1H), 1.26-1.50 (m, 4H), 1.85 (quint, J=7.4 Hz, 2H), 1.98-2.16 (m, 2H), 3.32 (s, 3H),
3.36 (t, J=6.8 Hz, 2H), 3.74 (m, 1H), 5.60-5.75 (m, 211); 13C NMR 8 (75 MHz) 26.6,
27.6, 30.0, 33.8, 34.3, 34.8, 55.5, 75.3, 128.2, 133.9; IR (neat) 3022, 2932, 2858, 2818,
1651, 1450, 1103 cm].

TBDMS Protected 52. Diene 51 (3.2 g, 12.9 mmol) was added to a slurry of Cp2ZrHCl
(3.3 g, 12.9 mmol) in 1,2-dichloroethane (25 mL) at 0 °C. The reaction was stirred at 0
°C for 2h and at rt until the reaction was complete. Addition of 10% HCl (20 mL) was
followed by extraction with pentane (3 x 30 mL). The organic layers were dried

(MgSO4), filtered, and concentrated (rotary evaporator). The residue was distilled to

68
yield 3.0 g (70% yield) of desired product. bp 92-95 °C (1 mmHg), 1H NMR (300 MHz)

8 0.05 (s, 3H), 0.06 (8, 3H), 0.87 (s, 9H), 1.08-1.53 (m, 4H), 1.76-1.98 (m, 4H), 2.09 (m,
1H), 3.38 (t, J-=6.8, 2H), 4.21 (m, 1H), 5.56 (S, 2H); 13C NMR (75 MHZ) 5 -4.6, -4.4,
18.3, 25.9, 27.3, 30.1, 32.3, 33.8, 34.7, 34.8, 67.9, 132.1, 132.5; IR 3022, 2932, 2857.
1647, 1252, 1089 cm'l.

Preparation of 53. Diene 51 (1.0 g, 6.5 mmol) was added to a slurry of Cp22rHCl (2.4
g, 9.2 mmol) in benzene (20 mL) at 0 °C. The reaction was stirred at 0 °C for 2h and at rt
until the reaction was complete. The reaction was cooled to 0 °C, iodine (2.3 g, 9.2
mmol) was introduced, and the reaction was stirred for 3h. The reaction was filtered
through silica gel and concentrated. The residue was chromatographed chromatographed
to yield 1.0 g (56% yield) of the desired product. RFO.3 (10% diethyl ether/petroleum
ether, stained with phosphomolybdic acid); 1H NMR (300 MHz) 8 1.10-1.50 (m, 6H),
1.85 (quint, J=7.4 Hz, 2H), 2.05 (m, 1H), 3.13 (t, J=6.8 Hz, 2H), 3.32 (s, 3H), 3.74 (m,
1H), 5.60—5.75 (m

, 2H); 13C NMR 8 (75 MHz) 6.8, 26.6, 27.6, 30.8, 33.8, 34.3, 34.8, 55.5, 75.3, 128.2,

133.9; IR (neat) 3022, 2932, 2858, 2818, 1649, 1450, 1103 cm'l.

Preparation of TBDMS Protected 53. Corresponding bromide 52 (0.26 g, 0.8 mmol),
potassium iodide (1.3 g, 8.0 mmol) in DMF (4 mL) was heated to 55 °C for 18h. The
reaction was diluted with water (10 mL) with subsequent extractions with pentane (3 x 10
mL). The combined organic layers were washed with water (10 mL), dried (MgSO4),
and concentrated (rotary evaporator). The residual oil was filtered through basic alumina.
Rr:0.3 (10% diethyl ether in petroleum ether, stains with phosphomolybdic acid); 1H
NMR (300 MHz) 8 0.48 (s, 3H), 0.55 (s, 3H), 0.87 (s, 9H), 1.07-1.56 (m, 4H), 1.82 (q,
J=7.4 Hz, 3H), 1.92 (m, 1H), 2.08 (m, 1H), 3.15 (t, J=7.1 Hz, 2H), 4.2 (m, 1H), 5.56 (s,

69
2H); 13C NMR (75 MHz) 8 -4.7, -4.5, 7.0, 18.2, 25.9, 27.3, 30.8, 32.3, 34..6, 36.9, 67.8,

132.0, 132.5; IR (neat) 3022, 2932, 2858, 1643, 1471, 1253, 1091 cm'l.

Preparation of 1-t-butyldimethylsilyloxy-4-iodopropane (55). Trimethylene oxetane
(54, 2.6 g, 44.2 mmol), t-butyldimethylchlorosilane (4.4 g, 29.4 mmol) and sodium
iodide (8.8 g, 58.8 mmol) in acetonitrile (25 mL) were stirred for 3h at ambient
temperature. Water (75 mL) was added followed by extractions with petroleum
ether/diethyl ether (3 x 28 mL, 9:1 by volume). The organic layers were washed with
saturated sodium bicarbonate (12 mL) and dried (MgSO4). Solvent was removed in
vacuo, and the colorless oil (7.9 g, 99% yield) was used without further purification. 1H
NMR (300 MHz) 8 0.06 (s, 6H), 0.87 (s, 9H), 2.16 (quint, J: 6.2 Hz, 2H), 3.25 (t, J: 6.6
Hz, 2H), 3.64 (t, J: 5.6 Hz, 2H). 13C NMR (75.5 MHz, CDC13) 8 -5.3, 3.6, 18.2, 25.9,
30.0, 62.3. IR (neat) 2957, 2860, 1471, 1099 cm*1.

Synthesis of 6-t-butyldimethylsilyloxy-1-hexen-3—ol (S6). A solution l-t-
butyldimethylsilyloxy-4-iodopropane (7 .9 g, 26.3 mmol) in hexane/diethyl ether (132
mL/ 88 mL) at -78 °C was treated with t-butyllithium (34 mL, 1.7 M in pentane). The
reaction was stirred at -78 °C for 20 minutes and allowed to warm to -10 °C. The
reaction was cooled again to -78 °C, and acrolein (1.6 g, 28.9 mmol) was added. The
reaction was stirred for 2h at -78 °C and allowed to warm to room temperature. Work up
of the reaction was accomplished by the addition of half-saturated ammonium chloride
(200 mL). The layers were separated, and the aqueous layer was extracted with diethyl
ether (3 x 100 mL). Distillation provided the desired product (2.0 g, 33% yield). bp 72-
74 °C, (<1 mmHg); 1H NMR (300 MHz) 8 0.06 (s, 6H), 0.86 (s, 9H), 1.50-1.71 (m, 4H),
2.87 (bs, 1H), 3.63 (m, 2H), 4.11 (m, 1H), 5.23-5.27 (m, 2H), 5.77-5.92 (m, 1H). 13C
NMR (75.5 MHz, CDC13) 8 -5.4, 18.4, 25.9, 28.7, 34.3, 63.3, 72.6, 114.2, 141.2. IR
(neat) 3600-3200, 3080, 2859, 1645, 1105, 835 cm'l.

70

Methylation of 6 -t-butyldimethylsilyloxy-1-hexen-3-ol (57). A solution of 6-t—
butyldimethylsilyloxy-1-hexen-3-ol (1.7 g, 7.4 mmol) in THF (0.6 mL) was added
dropwise to sodium hydride (0.2 g, 8.8 mmol) in THF (5 mL). The reaction was stirred
for 1 h and cooled to 0 °C. At this time, iodomethane (2.1 g, 14.8 mmol) was introduced,
and the reaction was stirred for another 3 h. Standard workup provided the methylated

product in 88% yield.

Deprotection of 6-t-butyldimethylsilyloxy-3-methoxy-l-hexene (58). A solution of
tetrabutylammonium fluoride (TBAF) in THF (9.8 mL, 1.0M) was cooled to 0 °C, and 6-
t-butyldimethylsilyloxy-3-methoxy-1-hexene (56, 1.6 g, 6.5 mmol) was introduced. The
mixture was stirred at room temperature for 3 h. The reaction was worked up by addition
of half-saturated brine (20 mL) and subsequent extractions with diethyl ether (5 x 20
mL). The concentrated sample was chromatographed to yield 6-hydroxy-3-methoxy-l-
hexene (53, 0.6 g, 75% yield). Rg=0J7 (30% diethyl ether/petroleum ether), stained with
phosphomolybdic acid; 1H NMR (300 MHZ) 8 1.58-1.65 (m, 2H), 2.35 (bs, 1H), 3.26 (s,
3H), 3.47-3.62 (m, 3H), 5.12-5.20 (m, 2H), 5.63 (m, 1H); 13C NMR (75.5 MHz, CDC13)
8 28.7, 32.1, 56.1, 62.7, 82.8. 117.2, 138.3; IR (neat) 3600-3300, 3078, 2936, 1643,
1068, 927 cm'l.

Synthesis of 7-butyldimethylsilyloxy-1-hepten-3-ol (62). A solution 1-t-butyldimethyl-
silyloxy-4-iodobutane (9.2 g, 29.0 mmol, preparation similar to 55 except reaction was
heated to 55 °C overnight) in hexane/diethyl ether (130 mL/ 87 mL) at -78 °C was treated
with t-butyllithium (37.5 mL, 1.7 M in pentane). The reaction was stirred at -78 0C for
20 minutes and allowed to warm to -10 °C. The reaction was cooled again to -78 °C, and
acrolein (1.8 g, 32.0 mmol) was added. The reaction was stirred for 2h at -78 °C and

allowed to warm to room temperature. Work up of the reaction was accomplished by the

71
addition of half-saturated ammonium chloride (200 mL). The layers were separated, and

the aqueous layer was extracted with diethyl ether (3 x 100 mL). Chromatography
provided the desired product (5.0 g, 70% yield), or the crude product was carried on
without purification. Rf=0.5 (40% diethyl ether/petroleum ether), stained with
phosphomolybdic acid; 1H NMR (300 MHz) 8 0.02 (s, 6H), 0.84 (s, 9H), 1.30-1.53 (m,
6H), 1.83 (bs, 1H), 3.57 (t, J=6.4 Hz, 2H), 4.06 (bq, J=6.2 Hz, 1H), 5.05 (dt, J=10.6,
1.26, Hz, 2H), 5.17 (dt, J=17.3, 1.4 Hz, 1H), 5.82 (ddd, J=17.6, 10.5, 6.3 Hz, 1H). 13C
NMR (75.5 MHz, CDC13) 8 -5.3, 18.3, 21.6, 25.9, 32.6, 36.7, 63.0, 73.1, 114.5, 141.2.
IR (neat) 3600-3200, 3080, 2934, 2860, 1645, 920 cm'l.

Synthesis of 7-hydroxy-3-methoxy-l-heptene (63). A solution of 7-
butyldimethylsilyloxy-l-hepten-3-ol (1.7 g, 32.5 mmol, crude) in THF (4.0 mL) was
added dropwise to sodium hydride (0.8 g, 35.8 mmol) in THF (32 mL). The reaction was
stirred for 1 h and cooled to 0 °C. At this time, iodomethane (9.2 g, 65.0 mmol) was
introduced, and the reaction was stirred for another 3h. After workup, the residue was
added to a solution of TBAF (23 mL, 1.0M in THF) at 0 °C. The reaction was worked up
by addition of half-saturated brine (20 mL) and subsequent extractions with diethyl ether
(5 x 20 mL). The concentrated sample was chromatographed to yield 0.8 g (62% yield)
of 6-hydroxy-3-methoxy-l-hexene. Riv-0.17 (30% diethyl ether/petroleum ether), stained
with phosphomolybdic acid; 1H NMR (300 MHz) 8 1.30-1.62 (m, 6H), 2.00 (bs, 1H),
3.20 (s, 3H), 3.46 (m, 1H), 3.57 (t, J=6.4 Hz, 2H), 5.15 (ddd,J=0.84, 1.9', 18.4 Hz, 1H),
5.17 (dd, J-=1.0, 10.8 Hz, 1H), 5.60 (ddd,J=7.8, 10.9, 16.6 Hz, 1H); 13C NMR (75.5
MHz, CDC13) 8 21.4, 32.5, 34.9, 56.1, 62.6, 83.0, 117.1, 138.6; IR (neat) 3600-3100,
3080, 2934, 2858, 1643, 1080, 925 cm'l.

Synthesis of 7-bromo-3-methoxy-l-heptene (64). The preparation of 64 was

accomplished through use of the NBS/triphenylphosphine method. 0.7 g, 87% yield, bp

72
32-35 °C (4 mmHg); 1H NMR (300 MHz) 8 1.40-1.62 (m, 4H), 1.75-1.90 (m,, 2H), 3.22

(s, 3H), 3.36 (t, J=6.8 Hz, 2H), 3.46 (m, 1H), 5.15 (ddd, J=0.84, 1.6, 18.2 Hz, 1H), 5.17
(dd, J=0.86, 10.6 Hz, 1H), 5.60 (ddd, J=7.8, 10.6, 16.6 Hz, 1H); 13C NMR (75.5 MHz,
CDC13) 8 24.0, 32.7, 33.6, 34.4, 56.1, 82.6, 117.3, 138.5; IR (neat) 3078, 2980, 2938,
2820, 1643, 1101, 927 cm'l.

General Procedure for Grignard Formation. A Schlenk flask equipped with a
magnetic stirring bar and activated magnesium (10.0 mmol) was placed under vacuum,
and flame-dried for 5 minutes to drive off advantageous water. The flask was purged
with argon for 10 minutes after the glass stopper was replaced with a rubber septum. At
the desired temperature, two drops of the bromide were used to initiate the Grignard
formation. Tetrahydrofuran (10 mL) was added followed by the slow addition of the
bromide (1.0 mmol). The reaction was stirred at the desired temperature until Grignard

formation was complete as shown by g.c. analysis.

Typical Procedure for Copper Mediated Cyclization. A solution of the
organomagnesium bromide prepared as stated above was treated with a copper (I) salt
(0.05 equivalent) at the appropriate temperature by direct addition of the copper salt to
the Grignard solution. The cold bath was removed, and the mixture was stirred at room
temperature until reaction was complete. An aliquot was quenched by addition to a
cooled saturated NH4C1 solution and analyzed by gas chromatography. Yields were
determined with the use of an internal standard (n-heptane for five-membered ring study,
and n-octane for the six-membered ring study), and confirmation of peaks was

accomplished by co-injection with a known standard.

Typical Procedure for Lithium Mediated Cyclization. A solution of the iodide (1.05

mmol) in diethyl ether/hexane (10 mL, 2:3 by volume) was cooled to -78 °C. Addition of

73
t—butyllithium (1.3 mL of 1.7M in pentane, 2.2 mmol) was dropwise. After addition, the

reaction was stirred at -78 °C for 15 minutes. The dry ice-acetone bath was removed, and
the reaction was stirred until completion. An aliquot was quenched by addition to a
cooled saturated NH4C1 solution and analyzed by gas chromatography. Yields were

determined with the use of an internal standard (see copper mediated cyclization).

Bicyclization Hydrogenation. The cyclization was run on a 1 mmol scale. Upon
completion of cyclization, the reaction mixture was cannula transferred to an erlenmeyer
which contained sat NH4C1 (5 mL). The mixture was extracted with diethyl ether (3 x
SmL). the organic layers were dried and concentrated by distillation at atmospheric
pressure. Once all the solvent was removed, the residue was taken up in methanol (5
mL), and PtO4 was added. The reaction was placed under 1 atm of H2, and the reaction
was stirred for 3h. Identification of the cyclized products was determined through a
coinjection with standards of c and tbicyclo[4.3.0]nonane which were available from

Wiley Organics.

V. REFERENCES

(1) Paquette, L.A.; Stirling, C.J.M. Tetrahedron 1992, 48, 7383.

(2) For a review in SN' and SN2' chemistry see (a) Magid, R.M. Tetrahedron
1980, 36, 1901. (b) Erdik, E. Tetrahedron 1984, 40, 641. (c) ref. 1. (d)
Normant, J.F. Pure & Appl. Chem 1978, 50, 709.

(3) For a molecular description ofcuprate additions see: Corey, E.J., Boaz, N .W.
Tetrahedron Lett. 1984, 3063, and Hamon, L.; Levisalles, J. Tetrahedron
1989, 45, 489.

(4) Claesson, A.; Tamnefors,_T.; Olsson, L.I. Tetrahedron Lett. 1975, 1521.

(5) (a) Commercon, A.; Bourgain, M.; Delaumeny; Normant, J .F., Villieras. J.
Tetrahedron Lett. 1975, 3837. (b) Commercon, A.; Bourgain, M.;
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(6) Claesson, A.; Olsson, L.I. J. Chem. Soc., Chem. Commun. 1978, 621.

(7) (a) Gendreau, Y.; Normant, J .F. Tetrahedron 1979, 35, 1517. (b) Ghiribi, A.;
Alexakis, A.; Normant, J.F. Tetrahedron Lett. 1984, 3079.

(8) For a review of SN2‘ additions to Vinyloxiranes see Marshall, J.A. Chem. Rev.
1989, 89, 1503.

(9) (a) Bailey, W.F.; Nurmi, T.T.; Patricia, M.; Wang, W. J. Am. Chem Soc.
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(10) Smith, M.J.; Wilson, S.E. Tetrahedron Lett. 1981, 4615.

(11) Katzenellenbogen, J.A., Corey, E]. J. Org. Chem. 1972, 37, 1441.
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(b) Broka, C.A.; Shen, T. J. Am. Chem. Soc. 1989, III, 2981. (c) For three-
membered ring formation in steroids, see Fischer, P.M.; Howden, M.E.H. J.
Chem. Soc., Perkin Trans. 1 1987, 475.

(13) Farnum, D.G.; Monego, T. Tetrahedron Lett. 1983, 1361.

74

75
(14) Charnberlin, A.R.; Bloom, S.H.; Cervini, L.A.; Fotsch, C.H. J. Am. Chem.

Soc. 1988, 110, 4788.
(15) Harms, A.E.; Stille, J .R. Tetrahedron Lett. 1992, 6565.
(16) Brandsma, L. Preparative Acetylenic Chemistry, Elsevier, NY, NY (2“(1 ed.).
(17) Denmark, S.E.; Jones, T.K. J. Org. Chem. 1982, 47, 4595.
(18) Miyashita, N.; Yoshikoshi, A.; Grieco, P.A. J. Org. Chem. 1977, 42, 3772.
(19) Brown, C.A.; Ahula, V.K. J. Chem. Soc., Chem. Commun. 1973, 553.
(20) (a) Marino, J .P.; Floyd, D.M. Tetrahedron Lett. 1979, 675. (b) Eisch, J .J .;
Jacobs, A.M. J. Org. Chem. 1963, 28, 2145.
(21) Corey, E.J.; Venkateswarlu, A. J. Am. Chem. S06. 1972, 94, 6190.
(22) Miller, J .A.; Negishi, E. Isr. J. Chem. 1984, 24, 76. _
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