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93

This is to certify that the

dissertation entitled

Regioselective Carbocyclic Ring Formation
Mediated by Titanocene Chloride

presented by

Pascal Rigollier

has been accepted towards fulfillment
of the requirements for

Ph. D . degree in Chemistry

 

 

@614 /J%/

Major professor

Date /‘/ F54 7/

 

M5 U is an Affirmative Action/Eq ual Opportunity Institution 0-12771

 

 

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REGIOSELECTIVE CARBOCYCLIC RING FORMATION MEDIATED BY

TITAN OCENE CHLORIDE

By

Pascal Rigollier

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1991

éfi7~4905

ABSTRACT

REGIOSELECTIVE CARBOCYCLIC RING FORMATION MEDIATED BY
TITAN OCENE CHLORIDE

By

Pascal Rigollier

A new method for selective carbocyclic ring formation is
described. Soluble Ziegler-Natta type catalysts bearing an alkene
tether were designed and shown to undergo intramolecular
cyclization by olefin insertion into the carbon-titanium bond.
Typically, the cyclization process is a syn addition of the carbon-
metal bond on to alkene functionality, and proceeds very selectively
in an exo manner.

A variety of alkene bromide substrates were synthesized and
the corresponding Grignard reagents underwent transmetalation
when treated with titanocene dichloride. Upon addition of a Lewis
acid cocatalyst, the alkenyltitanocene chloride species were activated
and intramolecular olefin insertion occurred. The 5-hexen-l-yl type
ligands closed regioselectively to form cyclopentylmethyl units.
Bicyclic systems, such as bicyclo[3.3.0]octane, cis-l-methyl
bicyclo[3.3.0]octane and cis-1-methylbicyclo[4.3.0]nonane were

obtained in good yield by intramolecular carbon-titanium addition on

a cyclopentene, methylenecyclopentane, or methylenecyclohexane
preexisting ring.

Six-membered ring formation by cyclization of the 6-hepten-1-
yl ligand was also studied. The reaction was regioselective, but
somewhat sluggish compared to the counterpart five-membered ring
formation. Activation of the double bond by a suitably positioned
trimethylsilyl substituent was shown to cause rate enhancement for
the olefin insertion reaction. Influence of the solvent and the Lewis

acidic cocatalyst was also analyzed.

A mes Parents, Christine, et Violaine.

iv

ACKNOWLEDGEMENTS

I would like to express my gratitude to Prof. John Stille for his
assistance in this organometallic chemistry project. Likewise,
members of my guidance committee: Profs. Kim Dunbar, William
Reusch, Mike Karabatsos and Dan Nocera are greatly acknowledged
for their help and advice during my stay at Michigan State
University. Help from Dr. Evy Jackson, Kermit Johnson and Dr. Long
Le in running NMR experiments was very valuable. A special thank
also to Prof. Popov for his friendship and moral support, often
rendered in French. Generous financial support from the Department
of Chemistry at MSU made my completion of the program possible.

The 1987 crew at the Chem’ House: Jim Dailey, Steve Steffke,
Gary Schultz and Elizabeth Smith will be remembered. Living in that
place has been a real adventure! The French community and friends
in Lansing and MSU, all made my life in deep-Michigan much more
enjoyable and my “wild parties” well attended.

For thesis preparation and writing, thanks to Kim Dunbar for
choosing me when she needed a house-, cat-, and plant- sitter,
during the Christmas Holiday, Betty for providing me with a Mac.,
and friends for moral support. Finally, thanks to Anne Quillevéré for

making coffee for the defense.

TABLE OF CONTENTS

LIST OF TABLES ............................................................................................................ x
LIST OF SCHEMES ........................................................................................................ xi
LIST OF ABBREVIATIONS ..................................................................................... xiv
INTRODUCTION .............................................................................................................. 1
Carbocationic Cyclizations .................................................................................. 3
Free Radical Cyclizations ..................................................................................... 4
Anionic Cyclizations .............................................................................................. 6
Metal Promoted Cyclizations ............................................................................. 7
RESULTS AND DISCUSSION .................................................................................... 12

Selective Formation of Five-Membered Carbocycles
Mediated by Titanocene Chloride

1. Introduction ................................................................................................. 12

2. Synthesis of cis- and trans-l-Bromo-S-heptene and 1-
Bromo-S-hexene ......................................................................................... 13

3. Synthesis and Cyclization of cis- and trans-S-Hepten-l-
yltitanocene Chlorides .............................................................................. 17

4. Synthesis and Cyclization of S-Methyl-S-hexen-l-yl
titanocene Chloride .................................................................................... 23

vi

5.

6.

Compared Selectivities with the Free Radical nBu3SnH-
Initiated Ring Closure ............................................................................... 24

Conclusron ............................ 25

Selective Formation of Bicyclic Compounds Mediated

by

1.
2.

6.

Titanocene Chloride
Introduction ................................................................................................. 26

Synthesis and Cyclization of 3-(3-Bromopropyl)
cyclopentene ................................................................................................ 28

.Synthesis and Cyclization of 2-(3-Bromopropyl)-1-

methylenecyclopentane .......................................................................... 30

.Synthesis and Cyclization of 2- (3- HBromopropyl) 1-

methylenecyclohexane ............................................................................ 32

. Comparison of the Selectivities with the Free Radical

Ring Closure .................................................................................................. 34

Conclusion ...................................................................................................... 35

Six-Membered Ring and Attempted Seven-
Membered Ring Formation Mediated by Titanocene
Chloride

1.
2.

Introduction ................................................................................................. 36

Synthesis and Cyclization of 6-Hepten-1-yltitanocene
Chloride Catalyzed by Various Lewis Acids ................................... 37

.Synthesis and Cyclization of 6-Methyl-6-hepten-l-yl

titanocene Chloride Catalyzed by Various Lewis Acids ............. 40

.Synthesis and Cyclization of 4-(2-Cyclopentenyl)but-1-
yltitanocene Chloride Catalyzed by EtAlC12 43

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

.Synthesis and Attempted Cyclization of 7-Octen-1-yl

titanocene Chloride .................................................................................... 45

.Trimethylsilyl-Charge Accelerated Olefin Insertion for

Six- and Seven Membered Ring Closure .......................................... 47

vii

7. Synthesis and Cyclization of 7-Bromo-3-(trimethylsilyl)-

1-heptene ...................................................................................................... 49

8. Synthesis and Attempted Cyclization of 8-Bromo-3-
(trimethylsilyD-l-octene........................................................................52
9. Conclusion ...................................................................................................... 53
CONCLUSION ................................................................................................................ 55
EXPERIMENTAL .......................................................................................................... 56
REFERENCES ............................................................................................................... 103
APPENDIX .................................................................................................................. 110

viii

Table

Table

Table
Table
Table

Table

LIST OF TABLES

Product Distribution from Quench of cis-2-Hepten-1-
ylmetal Species and Isomers. ......................................................... 17

Product Distribution from Quench of trans-Z-Hepten-

l-ylmetal Species and Isomers ...................................................... 20
Product Distribution from Quench of Crude 30.... .................. 22
Compared Selectivities with Free Radical Cyclization. ......... 34
Cyclization of 60: Experimental Conditions and

Results ....................................................................................................... 42
Reaction Conditions for Attempted Cyclization of 74. ......... 47

ix

Scheme

Scheme
Scheme
Scheme
Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme
Scheme
Scheme

Scheme

Scheme

Scheme

9‘1"???)

>1

10.

11.
12.
13.
14.

15.
16.

LIST OF SCHEMES

Synthetic Routes to cis- and trans-l-Bromo-S-

heptene ............................................................................................... 15
Synthetic Route to 1-Bromo-5-methyl-5-hexene ............ 16
Potential Reaction Pathways of 27 with EtAlClz. ............. 19
Potential Reaction Pathways of 31 with EtAlClz. ............. 23
Synthetic Route to 39. ................................................................. 29
Most Probable Reaction Pathways of 32 with

EtAlClz. ................................................................................................ 29
Synthetic Route to 42. ................................................................. 31
Most Probable Reaction Pathways of 33 with

EtAlClz. ................................................................................................ 32
Synthetic Route to 46. ................................................................. 33
Most Probable Reaction Pathways of 34 with

EtAlClz. ................................................................................................ 33
Synthetic Route to l-Bromo-7-octene. ................................. 37
Potential Reaction Pathways of 2 with EtAlClz. ................ 38
Synthetic Route to 59. ................................................................. 41
Potential Reaction Pathways of 60 with Lewis

Acids. ................................................................................................... 42
Synthetic Route to 66. ................................................................. 44
Most Probable Reaction Pathways of 67. ............................ 44

Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme

Scheme

17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.

Synthetic Route to 70. ................................................................. 45

Exo and endo Cyclization Products of 74 ............................. 46
TMS-accelerated Olefin Insertion into C-Ti Bond ............. 48
Synthetic Route to 78. ................................................................ 50
Compared Rate of Cyclization of 88 and 2 .......................... 51
Synthetic Route to 79. ................................................................ 52
1H NMR Spectrum of 20. .......................................................... 110
13C NMR Spectrum of 20 .......................................................... 111
1H NMR Spectrum of 21. .......................................................... 112
13C NMR Spectrum of 21 .......................................................... 113
1H NMR Spectrum of 26. .......................................................... 114
13C NMR Spectrum of 26 .......................................................... 115
1H NMR Spectrum of 39. .......................................................... 116
13C NMR Spectrum of 39 .......................................................... 117
1H NMR Spectrum of 42. .......................................................... 118
13C NMR Spectrum of 42 .......................................................... 119
1H NMR Spectrum of 46. .......................................................... 120
13C NMR Spectrum of 46 .......................................................... 121
1H NMR Spectrum of 50 .............. 122
13C NMR Spectrum of 50 .......................................................... 123
1H NMR Spectrum of 59. .......................................................... 124
13C NMR Spectrum of 59 .......................................................... 125
1H NMR Spectrum of 66. .......................................................... 126
13C NMR Spectrum of 66 .......................................................... 127

xi

Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme
Scheme

Scheme

41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.

1H NMR Spectrum of 70. .......................................................... 128

13C NMR Spectrum of 70 .......................................................... 129
1H NMR Spectrum of 78. .......................................................... 130
13C NMR Spectrum of 78 .......................................................... 131
1H NMR Spectrum of 79. .......................................................... 132
13C NMR Spectrum of 79 .......................................................... 133
1H NMR Spectrum of 82. .......................................................... 134
13C NMR Spectrum of 82 .......................................................... 135
1H NMR Spectrum of 83. .......................................................... 136
13C NMR Spectrum of 83 .......................................................... 137
1H NMR Spectrum of 84. .......................................................... 138
13C NMR Spectrum of 84 .......................................................... 139
1H NMR Spectrum of 85. .......................................................... 140
13C NMR Spectrum of 85 .......................................................... 141
1H NMR Spectrum of 86. .......................................................... 142
13C NMR Spectrum of 86 .......................................................... 143
1H NMR Spectrum of 87. .......................................................... 144
13C NMR Spectrum of 87 .......................................................... 145
1H NMR Spectrum of 90. .......................................................... 146
13C NMR Spectrum of 90 .......................................................... 147
1H NMR Spectrum of 91. .......................................................... 148
13C NMR Spectrum of 91 .......................................................... 149
1H NMR Spectrum of cis-l-methylbicyclo[3.30]

octane. .............................................................................................. 150

xii

Scheme 64.

Scheme 65.

Scheme 66.

13C NMR Spectrum of cis-l-methylbicyclo[3.30]
octane. .............................................................................................. 151

1H NMR Spectrum of cis-l—methylbicyclo[4.30]
nonane .............................................................................................. 152

13C NMR Spectrum of cis-l-methylbicyclo[4.30]
nonane .............................................................................................. 153

xiii

LIST OF ABBREVIATIONS

Cp cyclopentadienyl
DHP dihydropyran
DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

NBS N-bromosuccinimide
PPTS p-toluenesulfonic acid
PTSA pyridinium p-toluenesulfonate

Red-A1 sodium bis(2-methoxyethoxy)aluminum hydride

TEA triethylamine
THF tetrahydrofuran
THP tetrahydropyranyl
TMS trimethylsilyl

xiv

INTRODUCTION

Carbon-carbon bond formation, along with functional groups
manipulation is certainly one of the most fundamental processes in
synthetic organic chemistry. In the last decades, organometallic
compounds have played an increasing role in performing such a task.
By careful design of "wonder" reagents, selective and very efficient
organic reactions were invented.1 Indeed, cyclopentyl- and
cyclohexyl—units have been ideal targets for these transformations as
they occur ' in many natural products of high architectural
complexity.2

An efficient method for five- and six-membered carbocycle
formation is presented. The principle behind this transformation is to
use established reactivity of metal-carbon bonds for the insertion of
alkene functionality.

Olefin insertion into a carbon-titanium bond is the fundamental
step in Ziegler-Natta polymerization.3 During the past 30 years,
literature reports have emerged to establish the course of the event.
Two major mechanisms, both supported by experimental evidence,
were advanced. The Cossee mechanism4 proposes direct alkene
insertion by olefin coordination prior to chain elongation by B-alkyl

migratory insertion. The Green and Rooney mechanism5 involves a

2

metathesis step followed by olefin addition onto the metal—carbene.
A process involving a-hydrogen "agostic" interaction has also been
proposed.6

Soluble catalysts for Ziegler-Natta polymerization of ethylene
were originally obtained by action of titanocene dichloride on
alkylaluminum chloride co-catalysts.7 Reaction of equimolar amounts
of titanocene dichloride with diethylaluminum chloride in toluene,
was proposed to generate an ethyltitanocene chloride/ethyl
aluminum dichloride system, responsible for the polymerization
process.8 Coordination of the Lewis acidic aluminum center to the
chloride ligand reduces. the electron density on the transition metal,
thus permitting olefin complexation and insertion. Direct preparation
of szTi(Cl)Et was accompliShed by action of ethylmagnesium
bromide on titanocene dichloride.9 Addition of EtAlC12 as a co-
catalyst produced the Ziegler-Natta conditions for ethylene
polymerization.1o The experiment shown in Equation lpwas designed
to probe for an isotope effect on the stereochemistry of the olefin
insertion, by employing alkenyltitanocene chlorides l and 2 with a
pendant olefin.loa They underwent single olefin insertion by
intramolecular reaction upon treatment with ethylaluminum
dichoride at -100 0C, to produce cyclopentyl- and
cyclohexylmethyltitanocene chlorides (3) and (4) after quenching the

co-catalyst with bipyridine.

 

 

_ H H _
.@ H
. 11 H
Cp2n\/(CH2)n\/ M 11th _. (31’2“?00121"(11
CI @ H H
1(n=4)2(n=5) _ forn=4 - 3(n=4)4(n=5)

From the organic ligand viewpoint, this reaction offers a new
approach to five- and six-membered ring formation. Protonolysis
(HCI) of complex 3, for example, would free the organic ligand of

interest (Equation 2).

 

szTI M 1. EINCIz 0, CH3 (2)
Cl 1 2. HCI

According to Baldwin's rules,“ the 5-hexen-1-yl ligand
undergoes a 5-exo-trig closure, whereas the 6-hepten-1-yl ligand
cyclizes in a 6-exo-trig manner.

Intramolecular addition of a reactive carbon to an unactivated
olefin via 5- or 6-exo-trig modes is a fundamental process for
cyclopentane or cyclohexane ring formation. Traditionally, the
reactive center has been in the form of a carbocation, a free radical
or a carbanion species. Other methods involve metal promoted
reactions. An overview is presented below. Examples were chosen to
illustrate major concepts behind five- or six-membered carbocycle
formation. They do not constitute an extensive and updated review

on the subject.12

Carbocationic Cyclizations

Although carbocationic cyclizations do not usually proceed in
an exo manner, they represent a powerful method for generating six-
membered rings.13 The regioselectivity is governed by the stability
of the cation product. The endo cyclization process for the simple 5-
hexen-l-yl cations is favored since a stable secondary carbocation is
generated. However five-membered ring formation can be controlled
by stabilizing the exo-carbocation product. Formolysis of sulfonate
ester 5 under the conditions shown in Equation 3 gave cyclopentane
products, all derived from 6.14 Evidently, the high stability of this
tertiary cation precluded the formation of the less stable secondary

carbocation endo-product.

osozc,,I+,No2 HCOzH. HCOzNa (3 )
75 °C, 6 mn

 

Other examples of 5-membered ring closure involve
the use of a styryl internal trap, where a benzylic cation is produced
upon exo-cyclization.13 Even if such requirements cause structural
restrictions on cyclopentane formation, the access to complex
systems such as steroids by polyannulation reactions to cyclohexane

units, makes the carbocationic cyclization a' very valuable process.

Free Radical Cyclizations

Free radical ring closure of 5-hexen-l-yl systems has been a
subject of interest for physical organic chemists as early as the
1960's.15 Reduction of 6-bromo-l-hexene with nBu3SnH, initiated by
AIBN, was elegantly used by Walling for cyclopentylmethyl radical
formation by free radical addition on the tethered olefin.16 Since
then, the tin hydride method has become the most common way of
generating and cyclizing 5-hexen-l-yl radicals. A better
understanding of the reaction process was made possible by the
stability and kinetic studies carried on the involved species.17 More
recently, a great amount of work has been invested in developing
this reaction for synthetically useful purposes.18 Access to
structurally complex natural products was achieved by tandem
cyclizations performed on carefully designed bromo or iodo
polyalkenes.19 However a fine control of the competitive reaction
rates was crucial and limitations still remain.

Because both cyclized and uncyclized radicals are present in
solution, quenching of these reactive species by hydrogen atom
transfer can cause premature reaction termination, prior to
cyclization.2o Functionality is lost when hydrogen abstraction, by the
carbon-centered radical 7 from Bu38nH, takes place during the
transfer step shown below (Equation 4). To overcome the problem,

functionalized traps have been designed.”

CH - .
O’ 2 + H-SnBua ———- m“ + SnBua (4)

7

6

Five-exo cyclization is kinetically preferred over the 6-endo
closure. However, highly stabilized cyanoester radicals, which
undergo equilibration with the endo- and exo-products, favor the
more stable 6-endo radical product.22 The S-methyl-S—hexen-l-yl
system closes predominantly in a 6-endo-trig manner by producing

the very stable tertiary cyclohexylmethyl radical (Equation 5).23

(if v élnfseoé (5)

Formation of cyclohexylmethyl radical from 6-exo closure of 6-

 

hepten—l-yl radical is an order of magnitude slower than the
analogous reaction cf the 5-hexen-l-yl radical.13° Tin hydride-
mediated cyclization produced a 85:15 ratio of exo and endo products

(Equation 6).24
C O + ‘6’
85 : 15

Free radicals have also been involved in carbocyclic ring

 

 

forming reactions that are initiated or mediated by a transition metal
species. Cobalt has received the most attention,18b but the use of
vanadium,” chromium,25 manganese”, or titanium28 has also been

reported.

Anionic cyclizations

Anionic cyclizations at sp3 centers remained, until very
recently, unprecedented. Bailey pioneered the area in 1985 by
reporting the preparation and cyclization of 5-hexen-l-yllithium.29
Metal-halogen exchange took place when 6-iodo-1-hexene in a
pentane/ether solution was treated with tBuLi at -78 OC. Ring closure

followed as the temperature was raised to 23 0C (Equation 7).

Li
d/ I tBuLi, -78 °C dlr Li -78 °C to RT & (7)
pentane/ether

A reaction performed on the analogous 6-bromo-1-hexene

 

 

gave a complex product mixture and was shown to proceed through
radical intermediates.3o Regiospecific ring closure of various
iodoalkenes led to cyclopentylmethyl-containing products.31AtranS-
bicyclo[3.3.0]octane, hardly accessible by other methods,32 was
obtained in 87% yield by tandem cyclization of 4-ethenyl-6-hepten-
l-yllithium.33 Based on reported results, this method is the most
efficient for five-membered ring formation. 6-Exo-trig closure of 6-
hepten-l-yllithium in presence of 2‘ equivalents of TMEDA did not go
to completion and produced a 68:32 ratio of methylcyclohexane and

1-heptene.313

8
Metal Promoted Cyclizations

Reactive species in which the activated carbon center is not
truly a free radical or a carbanion are included under this category.
They include most organometallic compounds with a covalent metal-
carbon bond. Halo alkenes and dienes are common starting materials.
Only the cases where a S-hexen-l-ylmetal intermediate, for 5-
membered ring formation, is generated prior to cyclization are
considered. The process by which the pendant olefin closes onto the
activated carbon center is referred to as an insertion into the carbon-
metal bond. Exo- or endo-ring closure determines the regioselectivity
of the reaction.

Early work on the subject centered around aluminum
complexes. Reactions involved the addition of a dialkylaluminum
hydride to a diene, intramolecular insertion of the pendant olefin
into the newly formed carbon-aluminum bond and hydrolysis
(Equation 8). Thus, treatment of 1,5-hexadicne with 2.1 equivalents
of diisobutylaluminum hydride at 70 0C for 16 hours produced n-
hexane and methylcyclopentane in 2.4% and 97.6% respectively.

However 1,6-heptadienc and longer chain dienes failed to cyclize.34

C/ “2“” Q/ —— OAA'F” “0/ (8)

AIR2

 

2-Methyl-l,5-hexadiene was submitted to similar reaction
conditions by Stefani in a study of the regiochemical outcome of the

aluminum cyclization reaction.35 Addition of one equivalent of EtgAlH

9

to 2-methy1-1,5-hexadiene for 24 hours at 23 oC generated after
hydrolysis 1,3-dimethylcyclopentane and 1,1-dimethylcyclopentane
in 32% and 65% yields respectively. The former requires alumination
of the most substituted olefin followed by cyclization, whereas the
later results from ring closure of 5-methyl-5-hexen-1-ylalane

species.

First reports mentioning five-membered ring formation
mediated by magnesium appeared in 1966.36 Upon hydrolysis,
methylcyclopentane was obtained as a sideproduct (5%) while
preparing the Grignard reagent of 6-bromo-1-hexene. Synthetic
applications employed a trimethylsilyl activating group on the
olefin.37 Treatment of 8 with magnesium produced the Grignard
reagent which cyclized in a very regio- and stereoselective manner
to 9 (Equation 9). The methyl substituent controlled. the relative
stereochemistry at the two tertiary carbon centers and the syn
addition of the carbon-magnesium bond onto the trans olefin

established the configuration of the third stereocenter.

 

TMS
H
_ Mg, THF 020 ms H:
o ‘ 81°/o
67 C, 6 h

8 Me9

The most successful examples of late transition metal-mediated
cyclization involve palladium. A variety of ways by which the initial
carbon-palladium bond is formed exist. Usually, Heck reaction

conditions are applied to an aryl, or vinyl iodide or bromide. A

10

limitation resides in the absence of B-hydrogens for the success of
the reaction, as B-hydride elimination competes with the cyclization
reaction. However, alkylpalladium species containing B-hydrogens
can occur as intermediates which cyclize and undergo B-hydride
elimination in the final step.38 More recently, an intramolecular
benzyl-palladation of alkene was reported.39 Sequential
carbopalladation conducted on 10 with a catalytic amount of
palladium (0) generated the spiroalkene 11 in 57% yield (Equation
10).

C1 CanPd

/ Pd(PPh3)4 W “
(ECU ——-O” 00>
1 l

l 0 reflux, 5 h

 

In a study of the preparation of organoaluminums by
hydrozirconation-transmetalation, Schwartz reported the ring closure
of 5-hexen-1-ylzirconocene chloride (12) to 14, when treated with
A1C13 (Equation 11)."'0 Coordination of the Lewis acidic AlC13 to the
chloride ligand of 12 and olefin insertion into the carbon-zirconium
bond was proposed. Transmetalation between 13 and AlCl3 freed
zirconocene dichloride and 14. 1

5‘
5+ cmmg

”if —— %z\:OW A1613 MAO (”1

14

11

The zirconium/aluminum system, which resembled well known
Ziegler-Natta catalysts, prompted our choice of the similar
homogeneous titanocene catalyst to perform intramolecular olefin
insertions. In chapters one and two, systems analogous to l were
investigated. The regioselectivity of the intramolecular addition of a
carbon-titanium bond to disubstituted olefins was studied. Once
optimum reaction conditions were obtained for these Simple
substrates, the Study was extended to bicyclic system formation.
Single ring closure onto a preexisting cyclopentene,
methylenecyclopentane or methylenecyclohexane tether generated
fused [3.3.0] or [4.3.0] bicyclic skeletons.

By increasing the tether length by one or two carbons,
cyclohexylmethyl- or cycloheptylmethyl-units are potential exo-
cyclized products. In chapter three, such unit formation by the
titanium based methodology with unactivated olefin terminators is
presented. In an effort to improve our results, activation of the olefin

with a trimethylsilyl substituent was investigated.

RESULTS AND DISCUSSION

Selective Formation of Five-Membered Carbocycles

Mediated by Titanocene Chloride

1.111111411911211

Our initial studies involved the simplest system, S-hexen-l-
yltitanocene chloride (1).“ The preparation of 1 followed established
procedures for the general two step formation of alkyltitanocene
chlorides from alkylhalides.9’10‘=l The S-hexen-l-ylmagnesium
bromide in THF was added to a suspension of szTiClz in CH2C12 at -
40 °C, and after 30 minutes the resulting homogeneous red solution
was warmed to room temperature and stirred for 2 hours.
Protonolysis of the mixture (HCI/MeOH, -78 oC) produced l-hexene
and methylcyclopentane in 98% yield from S-hexen-l-ylmagnesium
bromide in a 96:4 ratio. Quenching a sample of the Grignard reagent
(HCI/H20, -78 0C to 23 oC) generated the same products, also in a 96:4
ratio;42 thus, the transmetalation process did not result in further
Hgand cychzafion.

Intramolecular cyclization of 1 to the cyclopentylmethyl

titanocene chloride (3) was induced by the addition of

12

13

0.5 equivalent of EtAlClz to a 0.1 M toluene solution of l at -78 °C.43
After 30 minutes at ~78 0C, the solution was quenched with
HCl/MeOH, and a 1:99 mixture of l-hexene to methylcyclopentane
was produced in 88% yield from 1.

In the present chapter, we investigate the effects of
disubstituted olefin tethers on the insertion process. All three
possible disubstituted alkenes, analogous to 6-bromo-l-hexene and
bearing a methyl substituent, were synthesized. cis- and trans-1-
Bromo-S-heptenes (20) and (21) were probes to establish the
regioselectivity of carbon-titanium bond addition onto an internal
olefin. AS the geometry of the double bond was believed to influence
the insertion process, pure geometric isomers 20 and 21 were tested
individually. The third alkene substrate, l-bromo-S-methyl-S-
hexene (26) probed for. the ease of insertion of terminal and
disubstituted olefins into carbon-titanium bonds. Syn addition of the
carbon-titanium bond in an anti-Markovnikov manner was expected
to occur predominantly, by keeping away the bulky metal center

from the newly formed cyclopentyl unit.

2. 11710 '- a... u - -- 0110- -1‘1 2.10 ---3,0110 -

Alkene bromides 20,21, and 26, were chosen as substrates.
They were prepared from commercially available starting materials,
as outlined in Figure l and Figure 2. S-Hexyn-l-ol was converted to

its tetrahydropyranyl (THP) ether derivative 15 by reaction with

14

tetrahydropyran in CH2C12 containing a catalytic amount of
pyridinium para-toluenesulfonate (PPTS).44 Methylation conducted
by sequential treatment of 15 with n-BuLi and then iodomethane,
according to a reported procedure,45 afforded the THP ether 16 in
high yield. Deprotection catalyzed by PPTS44 was run in anhydrous
methanol and gave 17 in quantitative yield.

Alcohol 17 proved to be an ideal intermediate for
diastereoselective reduction to alkenols l8 and 19. Catalytic semi-
hydrogenation utilized a procedure developed by Brown et 01.45 The
"P-2 Nickel" catalyst, generated in situ and poisoned with
ethylenediamine, selectively converted 17 to 18 under atmospheric
pressure of H2.

Reduction to the trans alkenol 19 caused more problem. Our
initial attempt centered around the LiAlH4-induced reduction in
glyme solvents.47 Reflux of 17 with LiAlH4 in anhydrous diglyme for
12 hours generated 19 quantitatively but removal of the solvent
proved to be difficult. Replacement of diglyme by the lower boiling
monoglyme or the higher boiling tetraglyme did not promote
reduction. Finally, when 16 was submitted to the same reaction
conditions (diglyme under reflux) reduction occurred, but with the
appearance of side products. Reduction with sodium in liquid
ammonia, using reported procedures,48 circumvented the problem
and gave pure 19. For the bromination of 18 and 19 to 20 and 21,
N-bromosuccinimide was added in small portions to a solution of the
alcohol and triphenylphosphine in CHzClz at00C, using a modified

procedure from those reported."'9

15

HOM—fi

DHP, PPTS
CHzclz

THPOM—E

15

1. nBuLi, THF
2. CH3I

 

 

THPOM—E—
l 6

PPTS, MeOH

 

H2, P-2 Nickel 1 7

Na/NH |° .
EIOH/ \ 3 'q
Hem pro/WV

 

 

1 8 1 9
NBS, Ppha NBS, PPh3
0112012 creole
81% Br/VW
2 O 2 1

Scheme 1. Synthetic Routes to cis— and trans-l-Bromo-S-heptene.

16

S-Methyl-S-hexen-l-ol (25) was prepared in 90% yield (based
on GLC analysis) from 2-methyl-l,5-hexadiene by Sato et al.50
Regioselective hydroalumination of the least substituted double bond
of the diene with LiA1H4, catalyzed by TiCl4, followed by treatment
with BF3:OEt2 gave the tri(5-methyl-5-hexenyl)borane, which was
oxidized by alkaline hydrogen peroxide to the alcohol 25. In our
hands, 0.1 mole of 5-methy1-1,5-hexadiene produced 25 in 46%
yield and in 95% purity. Thus, the two-carbon homologation of 3-

methyl-B-buten-l—ol to 25 as shown in Scheme 2, was preferred.

,\/1\ NBS.PPha /\/1\ CH coca .NaH
HO \ __ Br \ 21 )2 M00051

CHZCIZ 2 2 DMF 2 3 COOEI

LiCI, H20, DMSO M LiAlH4, E120 /1\/\/\
/ coca __ / OH
2 4 2 5
NBS, PPh3 JV“
—— / Br

CH2012 2 6

 

 

Scheme 2. Synthetic Route to 1-Bromo-5-methyl-5-hexene.

Treatment of 3-methyl-3-buten-l-ol with NBS/PPh3 in CH2C12
at 0 0C produced 22, without double bond isomerization.
Monoalkylation of diethylmalonate by 22, carried in DMF, yielded
23. The diester was deethoxycarboxylated by reaction with LiCl and

water in DMSO heated to reflux. Reduction of the monoester 24 with

17

LiAlH4 in EtzO, produced alcohol 25 which was brominated to 26,

according to the general procedure.

1i ri

Treatment of cis-l-bromo-S-heptene (20) with activated
magnesium turnings in THF (1 M) at 65 0C for 5 hours produced cis-
S-hepten-l-ylmagncsium bromide in quantitative yield. GLC analysis
of a sample quenched with 10% aqueous HCI at 0 0C showed the

presence of cyclized material in the extent of 4% (Table 1, entry 1).

Table l.Product Distribution from Quench of cis-2-Hepten-1-ylmetal
Species and Isomers.

 

| “23:52:“ W5 1 or CT 1 or
1 Grignard R. 96 3 - 1
2 27 94 4 - 2
3 27 99 1 - -
4 28 1 98 1 -

 

 

 

 

 

 

 

 

Transmetalation of the Grignard reagent to szTiC12 was
achieved as described in the Experimental section. Prior to
concentration, extraction and dilution in toluene (work up). GLC

analysis of the crude solution provided the same composition of the

18

mixture (Table 1, entry 2). Thus, the transmetalation process did not
modify the nature of the organic ligand, as expected. Concentration of
the solution in vacuo, followed by addition of n-hexane, caused the
precipitation of all magnesium salts. Filtration of the mixture, and
subsequent washing of the salts with toluene, produced a solution of
cis-S-hepten-l-yltitanocene chloride (27). Removal of solvents in
vacuo produced a red brick paste, which was diluted to obtain a 0.1
M solution of 27 in toluene. This solution was somewhat different in 1
composition, according to the species generated by HCl/MeOH quench
(Table 1, entry 3). Obviously, the concentration in vacuo removed the
volatile vinylcyclopentane. Production of ethylcyclopentane, to an
extent of 4% from crude 27 (Table 1, entry 2), might have taken
place during the quenching procedure (HCl/MeOH, -78 0C to 23 0C)
since the solution of 27 was not free of the Lewis acidic magnesium
dihalide salts. Species 27 was obtained in 78% yield from cis-S-
hepten-l-ylmagnesium bromide by GLC analysis.

Addition of EtAlClz to promote intramolecular olefin insertion
could potentially result in a mixture of six products. Scheme 3 shows

the paths to formation of each of these products from compound 27.

19

(for W Odor

 

 

 

 

 

 

 

 

11 B-H elim. 11 13 'H 911m 11 BFH em
2 9 28
l HCI 1 HC' 1 HCI

U M GA
Scheme 3. Potential Reaction Pathways of 27 with EtAlClz.

Intramolecular olefin insertion into the carbon-titanium bond
through the exo mode would provide 28, while endo cyclization
would result in the less favorable species 29. Decomposition of 27,
28 or 29 by B-hydride elimination would produce cis-1,5—
heptadiene, ethylidenecyclopentane, vinylcyclopentane, l-methyl
cyclohexene or 3-methylcyclohexene. Electrophilic quench of 27 , 28
and 29 (HCI for mixture analysis) would produce cis-2-heptene,
ethylcyclopentane and methylcyclohexane respectively.

Treatment of 27 with 2.0 equivalents of EtAlClz at ~78 0C for 2
hours, followed by HCI/MeOH quench at -78 oC, produced a 1:98:1
ratio of cis-2-heptene, ethylcyclopentane and methylcyclohexane
(Table 1, entry 4) in 79% yield from 27 , by GLC analysis. When 27

was submitted to the same conditions for 29 hours, the same product

20

ratio was observed. However, treatment with 2.0 equivalents of
EtAlClz at ~78 0C for 2 hours, followed by removal of the cold bath
for 0.5 hour and quenching at ~78 °C, produced a 99:1 ratio of
ethylcyclopentane and methylcyclohexane, with only a trace amount
of cis-2-heptene. The absence of vinylcyclopentane and any products
resulting from B-hydride elimination is noteworthy.

trans-S-Hepten-l-yltitanocene chloride (30) was obtained
according to the method just described. trans-5-Hepten-l-
ylmagnesium bromide produced from 21, gave a l:94:4:1 ratio of
trans-1,5-heptadiene, trans-2-heptene, ethylcyclopentane and
vinylcyclopentane when quenched with a 10% aqueous HCI solution
at 0 0C (Table 2, entry 1). Here also, the ratio was somewhat different
when the corresponding titanocene species 30 was quenched with
HCI/MeOH at ~78 oC. trans-Z-Heptene, ethylcyclopentane and
vinylcyclopentane amounted to» a 98:1:1 distribution (Table 2, entry
2).

Table 2. Product Distribution from Quench of trans-2-Hepten-l-yl
metal Species and Isomers.

entry quenched : \ \ Or\ 0’ m
l species 1 _ ‘

 

 

 

 

 

 

 

 

 

 

 

1 Grignard R. 1 9 4 4 - 1
2 3 0 - 9 8 1 ~ 1
3 30+EtAlC12 ~ 3 4 6 4 l 1
4 30+EtAlCl2 - - 9 8 2 ~
5 ”+3.11% - - 9 3 5 1

 

21

Cyclization of 30 proved to be more difficult than the
corresponding cis isomer 27 . This is in accord with Schwartz's
observation of olefin reactivity with hydrochlorozirconocene.51
Treatment of a 0.1 M solution of 30 with 2.0 equivalents of EtAlClz at
~78 0C for 2 hours, followed by protonolysis, produced a 34:64:1zl
ratioof trans-2-heptene, ethylcyclopentane, methylcyclohexane and
vinylcyclopentane (Table 2, entry 3). This ratio changed to a 4:94:2
distribution of trans-2-heptene, ethylcyclopentane and methyl
cyclohexane when the solution was Stirred for one additional hour
after removal of the cold bath. Complete cyclization was achieved
after 2.5 hours of reaction at 23 0C (Table 3, entry 4),
ethylcyclopentane being produced in 59% yield from 30 (GLC
analysis). The use of 10.0 equivalents of EtAlClz for reaction at ~78 0C
for 2 hours on 30 drove the cyclization to completion (Table 2, entry
5), but endo cyclization occurred to a larger extent to form
methylcyclohexane after protonolysis.

In order to avoid the long and tedious process of concentration
in vacuo and filtration to obtain 30 as a pure complex in toluene,
free of magnesium salts and Lewis basic solvents (THF and CH2C12),
30 was produced and cyclized according to the following procedure.
A 1.0 M solution of trans-5-hepten-l~ylmagnesium bromide in the
less Lewis basic EtzO was transferred to 1.2 equivalent of szTiClz in
toluene at ~40 °C. After 45 minutes at ~40 0C and 5.5 hours at 23 °C,
the reaction mixture was diluted to a 0.1 M solution by addition of
toluene.

Subsequent protonolysis at ~78 0C gave a 88:12 ratio of acyclic

olefins and cyclic products (Table 3, entry 1). In the presence of the

22

less Lewis basic Et20, the magnesium dihalide salts produced during
the transmetalation step appeared to have acted as a Lewis acid by
promoting the cyclization reaction. The presence of the Lewis base
EtzO is thought to promote fi-hydride elimination as the temperature
was raised from ~78 °C to 23 0C during protonolysis, thus explaining
the formation of trans-1,5-heptadiene, vinylcyclopentane and
ethylidenecyclopentane. If the 0.1 M solution of crude 30 was
treated with 10.0 equivalents of EtAlC12 at ~78 °C for 2.5 hours and
quenched at ~78 oC, GLC analysis showed a 85% cyclization rate with,

here also, an appreciable amount of B-hydride elimination products

(Table 3, entry 2).

Table 3. Product Distribution from Quench of Crude 30 and Isomers.

 

entry M M O" H O“ .1

l 2 86 8 3 1 ~
2 3 13 13 9 33 2

In conclusion, this more convenient and direct procedure was
not as efficient as the standard method. The presence of the Lewis
acids and Lewis bases greatly promoted unwanted reactions and
decomposition pathways of complex 30. A pure and stable solution
of 30 in toluene proved to be the best starting material to obtain
clean and efficient intramolecular olefin insertion upon addition of

EtAlClz.

4. 11‘ ' 21' ' 201 0 -11‘ 1 ._- 'XI" -_- ' 210116

911191111:

Cyclization of the 5-methyl-5-hexen-1-yl ligand is of great
interest because it produces a quaternary carbon center by exo
insertion of the terminal olefin into the carbon-titanium bond
(Scheme 4). In the alternative endo cyclization mode, the metal
center would be positioned on a tertiary carbon, a process which is

not sterically and energetically favored.

(Kg M

II B-H elim. 11 11H “"1“

 

 

 

 

 

 

31

 

 

1161sz /\/\/k exo
0L endo szcm \ O</T'C1sz

l HCI Inc: I HCI
(I M o<

Scheme 4. Potential Reaction Pathways of 31 with EtAlClz.

Species 31 was obtained from alkene bromide 26 in 59% yield
(GLC analysis), as a 0.1 M solution in toluene It underwent facile and
regioselective cyclization when treated with 2.0 equivalents of
EtAlC12 at ~78 0C for 4 hours. Protonolysis (HCl/MeOH,-78 oC) gave a
99:1 ratio of 1,1-dimethylcyclopentane (93% yield from 31 by GLC

24

analysis) and methylcyclohexane with only a trace amount (< 0.5%) of
2~methyl~l~hexene generated from 31. If the cold bath was
removed for 1 hour, after 4 hours of reaction at ~78 oC, protonolysis
of the solution under the same conditions, yielded the same products,

in identical amount.

5.: lSli” 'llE BI'IESH-IHI
Ringglgsgre

Because our method for forming five-membered carbocycles
utilizes bromoalkenes as starting material, it was interesting to
compare it, in terms of selectivity, with the well established
nBu3SnH-induced free radical cyclization. Treatment of 0.05 M
solutions of cis-l-bromo-S-heptene (20).or trans-1-bromo-5-
heptene (21) in benzene at 70 °C, with 1.2 equivalents of nBu3SnH
and a catalytic amount of AIBN radical initiator gave the following
results. Selective free radical cyclization of 20 and 21 produced
ethylcyclopentane and methylcyclohexane in a 99:1 and 98:252 ratio
respectively. In both cases, the alkene bromide was completely
reduced by nBu3SnH. However, the reaction mixture contained 9-12%
of acyclic olefin, generated by nBu3SnH quench of the uncyclized free
radical by hydrogen abstraction. Closure of 1-bromo-5-methy1-5-
hexene (26) mediated by nBu3SnH has been reported.23 Cyclization
predominantly went via an endo mode of cyclization, 1,1~
dimethylcyclopentane and methylcyclohexane were generated in a

40:60 ratio. Our method is of special interest since the

25

regioselectivity is reversed to yield the exo product almost

exclusively.

6mm

From our studies on simple substrates such as 20, 21, and 26,
several features are noteworthy. The alkenyltitanocene 'chlorides 27 ,
30, and 31 were obtained from the readily accessible Grignard
reagents, by transmetalation on szTiClz in CH2C12. Once purified, by
removal of all Lewis acids and Lewis bases involved in the synthesis,
they showed a good stability in toluene solutions stored under inert
atmosphere. Even if the EtAlC12~induced cyclization required longer
reaction times and a larger amount of co-catalyst, compared to the
parent S-hexen-l-yltitanocene chloride system (1), total ring closure
occurred at low temperature. This is of importance, especially for
more elaborate substrates. Complete cyclization of the organic ligand
has to take place before the carbon framework is released from the
metal center, by external quench. Methods in which the reactive
species is neutralized prior to cyclization in a competitive reaction
(hydrogen abstraction on nBu3SnH for the free radical process) can
cause extensive waste of a valuable organic ligand.

Syn addition to the olefin occurred with an exceptional
regioselectivity. The substitution pattern of the double bond had no
dramatic influence. Alkenyltitanocene chlorides 27,30 and 31 gave

exo to endo product ratios of 99:1, 98:2 and 99:1 respectively.

26
Finally, decomposition of the alkenyltitanocene chlorides by 13-
hydride elimination did not occur under optimum reaction
conditions. Quite concentrated solutions could be employed with no
problem of intermolecular olefin polymerization.
To extend the scope of this methodology, more elaborate
substrates were tested in the szTiC12~mediated cyclization. A

detailed study is presented in Chapter 2.

Selective Formation of Bicyclic Compounds Mediated by

Titanocene Chloride

1.1mm

Because the number of known condensed cyclopentanoid
natural products continues to grow, and despite the fact that a
collection of synthetic methods has been elaborated, new approaches
are needed.53 The application of our cyclization methodology in
natural product synthesis will often require the construction of
bicyclic structures. The cis-bicyclo[3.3.0]octane, cis-l-methyl
bicyclo[3.3.0]octane, and cis-l~methylbicyclo[4.3.0]nonane systems
are of special interest Since they often constitute a part of the
skeleton of cyclopentanoid compounds.

There are two ways in which the activated tether can be
connected in an intramolecular exo fashion to produce a fused [3.3.0]

bicyclic system. One way involves the cyclization of the activated

27

carbon onto a cyclopentene ring. With the tether attached at the
allylic position, exo cyclization of 32 produces the cis-
bicyclo[3.3.0]octane with the stereochemistry defined by the syn
addition to the double bond and the cis constraint of the bicyclic
system. Another route to these systems is achieved by the cyclization
of 33. Formation of a fused five-membered ring unit with a
bridgehead methyl substituent is especially valuable. This
framework is found in the carbon skeleton of triquinanes, a class of
naturally occuring sesquiterpenes.

The fused bicyclo[4.3.0]nonane framework can potentially be
prepared by ring closure of the analogous substituted cyclohexane
system 34. Cyclization of 34 in an exo manner generates the
hydrindane carbon skeleton. Futhermore, the methyl substituted
bridgehead carbon atom is identical to the C~13 quaternary center of

the C-D ring system of steroids.

O/\/\ TiCle2 M TICle2 w 110'sz
3 4

32 33

Our study started with the synthesis and cyclization of 3-

(2-cyclopentenyl)propen~1~yltitanocene chloride (32).

28
2. nhi an! -101 f - ~Br urn 11m

The alcohol precursor 35 was reported by Weber et al. 54

(Equation 12)

G 1.HSiCI3,(PhCN)2PdCI2 31M°a oxetane W014 (12)
2. MeMgBr, 15120 “C14

35

 

 

Hydrosilylation of cyclopentadiene with
trichlorosilane, catalyzed by (PhCN)2PdC12, at 105 0C for 65 hours
gave 2~cyclo pentenyltrichlorosilane in 84% yield.55 Methylation with
methylmagnesium bromide in EtzO afforded 2~cyclopentenyl
trimethylsilane in 77% yield, which was converted to 35 as follows.
Nucleophilic attack of 2~cyclopentenyltrimethylsilane on TiCl4~
activated oxetane resulted in the formation of 35, along with
appreciable amounts of 3~chloro~1~propanol (generated by
competitive chloride ion attack of the activated oxetane). However,
good yields of pure 35 could not be obtained by fractional distillation
or flash column chromatography. A more classical route is presented

in Scheme 5.

29

OACOOH ”NH“ O/VOH N33 131% 1. Mg.THF
E120 OA/B'
3 6

01112012 2. C02

 

 

Scheme 5. Synthetic Route to 39.

One-carbon homologation of 2~cyclopentene~1~acetic acid to
carboxylic acid 38 was achieved by sequential LiAlH4 reduction to
alcohol 36 and bromination of 36 according to the standard
NB S /PPh3 method to the alkene bromide 37. Treatment of a THF
solution of the Grignard reagent of 37 with C02 (dry-ice) at ~78 oC
afforded the carboxylic acid 38. LiAlH4 reduction of 38 in E120,

followed by bromination, yielded 39 as a pure compound.

 

 

 

 

 

 

 

1101sz endo (3920117.:
[6 ‘— OM11» CO
3 2
4 1 4 0

[HCI

l HCI l HCI

ON CO

Scheme 6. Most Probable Reaction Pathway of 32 with EtAlClz.

(2

30

Intramolecular carbon-titanium bond syn addition onto the
olefin can potentially result in the formation of 40 and 41 from 32
(Scheme 6). Potential B-hydride elimination products are not shown
and quenched reaction mixtures were not analyzed for these
compounds. Based on our previous results, the alkenyltitanocene
chloride species do not decompose by B-hydride elimination under
optimum reaction conditions. The non commercially available
standard bicyclo[3.2.l]octane, resulting from protonolysis of 41, was
obtained from bicyclo[3.2.1]~2~octene, by Hz-hydrogenation on Pd/C
at one atmosphere.56 Hydrolysis of the Grignard reagent of 39
produced a sample of 3-propylcyclopentene.

Upon treatment of a 0.1 M toluene solution of 32 with 2.0
equivalents of EtAlC12 and subsequent protonolysis, a 97:3 mixture of
cis-bicyclo[3.3.0]octane (83% yield from 32 by GLC analysis) and
uncyclized product was observed. The closure regioselectivity was
excellent since no endo type product occurred, no bicyclo[3.2.l]octane
was detected in the reaction mixture. However, the cyclization
reaction could not be driven to completion; treatment of 32 with 4.0
equivalents of EtAlC12 for 5 hours at ~78 0C gave no better

conversion.

3. 11‘ 91' .1010 - -=,01100 00 “1171 '1‘

2~(3-Bromopropyl)~1~methylenecyclopentane (42) was

prepared according to the synthetic sequence shown in Scheme 7.

31

Condensation of pyrrolidinocyc10pentane (obtained from
cyclopentanone according to the method of Stork57) on
methylacrylate gave methyl 3~(2~oxocyclopentenyl)propionate (43).
Selective olefination of this keto-ester with methylene
triphenylphosphane, generated by action of NaH on
methyltriphenylphosphonium iodide in DMSO,53 yielded the ester 44,
which was reduced to the alcohol 45 with LiAlH4. Bromination of 45
with NBS/PPh3 in CH2C12 at0°C, resulted in complete isomerization
of the double bond. However, bromination of the mesyl derivative of
45 with LiBr in THF according to general methods59 provided 42 as a

pure compound.

 

 

 

 

O
O
é 1. pyrrolidine, PTSA COOMe CHgPPha homing
2. methylacrylate
LiAlH4 MO“ 1. M98020, TEA, CHzclz w Br
H29 4 5 2. LiBr, THF 4 2

Scheme 7. Synthetic Route to 42.

The chlorotitanocene 33 was generated in 75% yield (GLC
analysis) from 42 as a 0.1 M solution in toluene. Most probable
reaction pathways of 33, upon treatment with EtAlClz, are shown in
Scheme 8. Addition of 2.0 equivalents of EtAlClz at ~78 0C for 1 hour

produced a 1:99 ratio of 1~methylene-2~propylcyclopentane and cis-

32
1~methy1bicyclo[3.3.0]octane (84% yield from 33 by GLC analysis).

As the major product was not commercially available, easy
comparison of retention time, by GLC analysis, with an authentic
sample could not be performed. An analytical sample was isolated as
described in the Experimental section and gave satisfactory 1H and
13C NMR and MS spectra. cis- and trans-Bicyclo[4.3.0]nonane,
resulting from endo closure by syn addition of the carbon-titanium

bond on the or and [3 face respectively, were not formed during the

 

 

 

 

 

 

 

 

reaction.
_. 1101sz
1101sz exo
. endo 1'10sz
3 3
1 HCI l HCI l HCI
H

Scheme 8. Most Probable Reaction Pathways of 33 with
EtAlClz.

4 11' =1 3.010 - -H_"‘=01H--mhln

2-(3-Bromopropyl)~ l ~methylenecyclohexane (46) was

obtained by a method analogous to the synthesis of 42 (Scheme 9).50

33

O O

1. pyrrolidine, PTSA so cute CH2PPh3 : : Me
2. methylacrylate DMSO

LiAlH4 wort 1. MeSOzCI. TEA. CH20|2 we»

E120 2. LiBr, THF 4 6

Scheme 9. Synthetic Route to 46.

 

 

 

A 0.1 M solution of the chlorotitanocene derivative 34 was
produced under the usual experimental conditions in 81% yield from
46 (GLC analysis). Reaction with 1.0 equivalent of EtAlClz for 3 hours
at ~78 oC generated cis-1~methylbicyclo[4.3.0]nonane as a single
product, and in 74% yield (GLC analysis), after protonolysis (Scheme
10). It cerresponded to a syn addition of the carbon-titanium bond

onto the olefin in an exo fashion.

 

 

 

 

 

 

TiCICp2
'11C10p2
ee .. —»
3 4
I HCI l HCI I HCI

am

Scheme 10. Most Probable Reaction Pathways of 34 with
EtAlClz.

34
5. 011-1. 0 f h ° '1' w'

Free radical ring closure mediated by nBu3SnH was performed
on bromoalkenes 39, 42, and 46 in benzene solutions, as described

in the Experimental section. Results are given in Table 4.

Table 4. Compared Selectivities with Free Radical Cyclization.

 

 

 

X
W ON <33
x = TiClez 3 97 o
X = Br 97 0
CH3 H
{SMX AN 03
x =TiClsz 1 99 0
X = Br 11 15 50:24 (cisztrans)
CH3 H
x &N (D (I)
X= TiClez 0 100 O
X = Br 47 17 5:31 (cis:trans)20

 

In each case,

the bromoalkene

completely consumed under

However, radical quench by hydrogen abstraction prior to cyclization
appeared to be a major drawback of this method, as uncyclized

species composed 3 to 47%

the

of the product mixtures.

reaction

starting materials

conditions

 

utilized.

Another

35

limitation was the lack of selectivity. Exo- to endo-product ratios of
17:83 and 1:2 for 42 and 46 respectively, reflected the poor

regioselectivity of the radical addition on the olefin.

6.9911211sz

The szTiClz—induced ring closure of 39,42 and 46 is a
valuable and efficient process. cis-Bicyclo[3.3.0]octane, cis-1-
methylbicyclo[3.3.0]octane and cis-l-methylbicyclo[4.3.0]nonane
were obtained regioselectively and in high yields. The fused
bicyclo[3.3.0] system was generated in the cis form exclusively by
both nBu3SnH- and szTiClz-initiated methods. 3-
Propylcyclopentene occurred in the reaction mixture to an extent of
3% in both cases. However, a major difference in product distribution
was observed for the ring closure of 42 and 46. The radical
mediated cyclization of 42 favored the quite stable bicyclic products,
cis-bicyclo[4.3.0]nonane (strain energy 8.9 kcal/mol76), whereas the
szTiClz based method leads to the exclusive formation of the more
constrained cis-l-methylbicyclo[3.3.0]octane system (strain energy
for cis-bicyclo[3.3.0]octane 12.0 kcal/mol75). The same tendency was
observed in the cyclization of 46. Radical cyclization formed the
stable trans-decalin as the major cyclized product. The titanium
method, instead, produced the relatively instable cis-1-
methylbicyclo[4.3.0]nonane system by effective irreversible

cyclization.

36

A similar outcome was observed for anionic cyclizations
performed on analogous substrates.31a 2-(3-Iodopropyl)-l-
methylenecyclopentane and 2-(3-iodopropyl)-1~methylene
cyclohexane underwent regio- and stereoselective isomerization to
cis-1-methylbicyclo[3.3.0]octane and cis-1-methylbicyclo[4.3.0]
nonane respectively, upon treatment with tBuLi in pentane/Etzo
solutions. However, the poor rate of isomerization represented a
major problem for this method. Uncyclized products amounted 84%
and 35% of the reaction mixture for 2-(3-iodopropyl)-l-
methylenecyclopentane and 2-(3-iodopropyl)-l-methylene

cyclohexane.

Six-membered Ring and Attempted Seven-membered Ring

Formation Mediated by Titanocene Chloride

1. Introduction

According to Baldwin's rules,11 favored processes for six-
membered ring closure are 6-exo-tet, 6-exo-trig, 6-endo-trig and 6-
endo-dig. Seven-membered ring formation via 7-exo-tet, 7-exo-trig,
7-endo-trig or 7-endo-dig closures are also favored. Although each
mode of cyclization possesses literature precedents, existing methods
have not, to date, been as versatile and numerous as those
employed for five-membered ring closure. Intramolecular insertion

of unactivated olefin into the carbon-titanium bond performed on

37

appropriate substrates is expected to generate 6- and 7-membered
carbocycles in a regioselective fashion via 6-exo-trig and 7-exo-trig
modes respectively. Thus, the methodology under investigation
should complement and even improve the existing methods. The first
tests were carried on the simplest system, 6-hepten-1-y1titanocene

chloride (2).

2. n ‘ . :1. 1i .9 . 9'I_" ‘ "' . -_ 0 ‘n’ [,0 I“

l Vri Lw'Ai

The organic precursor 50 to 6-hepten-1-yltitanocene chloride
(2) was obtained by one-carbon homologation of 6-bromo-l-hexene
(47) as depicted in Scheme 11. A solution of 5-hexen-l-
ylmagnesium bromide in THF was treated with C02 (dry—ice) at -78
oC and acidified to generate carboxylic acid 48. Reduction with
LiAlH4 provided 49, which was brominated to 50 with NBS/ PPh3 in
CH2C12.

1.M ,THF -
War ———g_—. /\/\/\cooH Mg.
4 7 2. 002 4 8
WOH M War
4 9 CHzc'e S 0

Scheme 11. Synthetic Route to 1-Bromo-7-octene (50)

38

Grignard reagent formation of 50 in THF, followed by
transmetalation on szTiC12 according to the general procedure
yielded 2 in 74% yield (GLC analysis) from 50. Upon treatment with
EtA1C12 or other Lewis acids, 6-hepten-l-yltitanocene chloride (2)
could potentially generate the six products shown in Scheme 12, by
protonolysis or decomposition by B-hydride elimination of the
titanocene species. Reaction mixtures were analyzed for all
compounds, except cycloheptene. Since endo cyclization of 2m 52 is

disfavored, only trace amounts of cycloheptene should appear, if any.

(k Ml °"m’ Q/ HCI (l
hemp2 -—-
5 l

 

 

 

 

 

 

 

 

 

 

exo
\ \ 2 \
endo

 

 

 

 

 

5 2

Scheme 12. Potential Reaction Pathways of 2 with EtAlClz.

Protonolysis of the 0.1 M toluene solution of 2 gave a 98:2 ratio

of l-heptene and methylcyclohexane. EtAlClz-induced cyclization by

39
addition of 2.0 equivalents of EtAlC12 at -78 0C for 1 hour afforded a

l:96:3 distribution of l-heptene, methylcyclohexane, and
methylenecyclohexane, after protonolysis at -78 °C. In this particular
case, yields were somewhat dependent upon the concentration of 2.
Cyclization occurred in 45-55% yields (GLC analysis) at 0.1 M
concentration of 2, but in 83% yield if a 0.01 M solution of 2 was
employed.

In an effort to overcome decomposition by B-hydride
elimination, another Lewis acid was tested. Methylalumoxanes have
been used extensively with Zr or Ti transition metals as catalysts for
butene or propene polymerization, and the study of the
stereochemical outcome of such reactions.61 Thus, treatment of 2
with 3.0 equivalents of methylalumoxane, prepared according to
published procedures,62 at -78 0C resulted in an almost complete
conversion to 51. A 6:86:6 ratio of l-heptene, methylcyclohexane
and methylenecyclohexane resulted after protonolysis. The three
products accounted for 80% of the starting material 2. If the cold
bath was removed and the solution allowed to warm up to ambient
temperature, this ratio changed to 1:75:24. Although the three
products were obtained in identical yield, decomposition of 51 by B-
hydride elimination became a major problem, methylenecyclohexane
accounted for 24% of the product mixture.

In the study of the carbotitanation of trimethyl(phenylethynyl)
silane by titanocenedichloride in the presence of MeAlClz, Eisch et al
63 discussed the solvent influence on the following equilibria

(Equation 13).

40

‘Cl,, + —
0921102 +MeAIc12 :cpzni "'AlMeCl2 _ szfi-Me NCL: (13)

°' 53 54

 

While Lewis basic solvents prevent the formation of
53 by coordination with MeAlClz, aromatic solvents, such as toluene,
have a tendency to form complexes with 53, thus pulling the first
equilibrium to the left. Coordination of these u-bases to the cationic
site of 54 also retards the olefin or acetylene insertion. However,
polar and weakly donor solvents, such as haloalkanes, were shown to
accelerate ethylene insertion process into 54. Consequently,
treatment of 2 in a 1,2-dichloroethane solution with 0.4 equivalent
of EtAlClz (1.0 M in n-pentane) at -32 0C resulted in complete
cyclization of 2. Protonolysis of the solution with 1 M HCl in EtzO, 0.2
hour after the addition gave methylcyclohexane as the only product,
in 64% yield from 2. However, the reactive species were more prone

to polymerization as the yields dropped at longer reaction times.

In view of the potential synthetic utility of our approach to
cyclohexane ring formation, it was of interest to test a more
elaborated substrate in the cyclization process. Alkene bromide 59
should preferentially undergo exo closure to form a gemdimethyl
substituted cyclohexane ring. Such a skeleton is especially valuable

in terpenoid chemistry, since it is often part of the carbon framework

41

of these naturally occurring compounds. Based on our results for
five-membered ring formation, the external olefin should insert
quite readily into the carbon-titanium bond. Finally, B-hydride
elimination, which was of concern for the parent system 2, does not
take place on the exo cyclized species 61 (Scheme 14). Scheme 13

shows our approach to substrate 59 from l-methylcyclohexene.

 

 

0/ 1.03,MeOH,CH2012 OMOCHa cuzppna, DMSO
2. M623, stOH

55 OCHa

00H3 $302 CH20|2

We...
Mel-1 NBS, PPh3 We,

5 8 “W2

LiAlH4
E120

 

 

Scheme 13. Synthetic Route to S9.

Ozonolysis of l-methylcyclohexene and MeZS-reduction of the
hydroperoxide product yielded the ketoacetal 55.64 Wittig
olefination of 55 according to the Corey modification65 produced the
acetal 56, which was reduced to aldehyde 57 under mild acidic
conditions.66 LiAlH4 reduction to 58 and bromination afforded 59 as
a pure compound. Grignard reagent formation of 59 and
transmetalation on szTiClz produced 60 in 63% yield by GLC
analysis. Exo-ring closure and endo-ring closure could generate 61

and 62 respectively (Scheme 14).

42

. 110'sz _endo M1700» exo
6 o 'I'tCICp2

.3: ... 1.2.1

M

Scheme 14. Potential Reaction Pathways of 60 with Lewis
Acids.

 

 

 

 

<32

 

 

 

CR

In this case, the olefin insertion did not occur as readily as for
the parent system 50. The steric hindrance caused by the methyl
substituent probably made the required conformation for olefin
insertion less favored. A variety of reaction conditions to form 61

were tested, our best results are given in Table 5.

Table 5. Cyclization of 60: Experimental Conditions and Results

 

 

 

 

 

 

 

 

catalyst solventa temp. reficutlicon c 210;“! rgsfiétb yieldC
EtAlClz, 2 eq toluene -78 °C 13 h 95 5 87%
EtAlClz, 2 eq toluene ~20 0C 12 h 8 8 12 73%
EtAlC12,1eq Cl(CH2)2Cl -30 0C 15 mn 15 85 23%
MezAlCl, 0.3 eq Cl(CH2)2Cl -30 0C 15 mu 1 8 8 2 72%
(CH3A10)n , 1 eq Cl(CHa2rC1 -30 0C 1.3 h 100 - low

 

 

 

aAll reactions were performed with 0.1 M solutions of 60. bNo endo-product
was observed under these conditions. CYields refer to both products (non
cyclized and exo-product) and were obtained by GLC analysis of the
hydrolyzed reaction mixtures.

43

In toluene, 60 underwent only partial cyclization upon
treatment with 2.0 equivalents of EtAlClz. This process was
somewhat promoted at higher temperature, since reaction at -20 0C
for 12 hours resulted in a 12% conversion of 60 to 1,1-
dimethylcyclohexane, after protonolysis. In 1,2-dichloroethane
solvent and at -30 0C, the reactive species was more subject to
decomposition, probably by intermolecular polymerization of 60.
Treatment of 60 with 1.0 equivalent of EtAlClz for 15 minutes and
subsequent quenching gave a 15:85 ratio of 2-methyl-1-heptene and
1,1-dimethylcyclohexane. However, this strong Lewis acid induced
decomposition of 60, 2-methyl-1-heptene and 1,1-
dimethylcyclohexane accounted only for 23% of the initial material.
The less Lewis acidic MezAlCl induced cyclization to the same extent,
but in higher yield. Finally, methylalumoxane had no influence on
the ring closure and destroyed most of the starting material. In all
cases, a temperature rise of the 1,2-dichloroethane solution resulted
in almost a complete disappearence of 2-methyl-1-heptene or 1,1-

dimethylcyclohexane, by decomposition of the reactive species 60.

The two-carbon homologation of 37 as shown in Scheme 15,
provided a synthesis of 66. Monoalkylation of diethylmalonate by
37 in DMF provided the diethyl ester 63, which was
deethoxycarboxylated to ethyl ester 64. LiAlH4 reduction of 64 to

44

the alcohol 65, followed by bromination with NBS/PPh3 afforded 3-
(4-bromobutyl)cyclopentane (66) in 53% overall yield.

ooze:

Br .
m CH2(COOE1)2, NaH OA/kcoza LICI, H20, DMSO
6 3

3 DMF

7
co 25, LiAlH4 ©/\/\/°H NBS,PPh3 GA/VB'
4 B20 6 5 CH5» 6 6

 

 

 

6

Scheme 15. Synthetic Route to 66.

The corresponding 4-(2-cyclopentenyl)but-1-yltitanocene
chloride (67) can potentially generate cis-bicyclo[4.3.0]nonane and
trans-bicyclo[4.3.0]nonane via exo type ring closure and
bicyclo[4.2.1]nonane via endo ring closure. However, syn addition of
the carbon-titanium bond onto the olefin, in an exo manner, should
produce cis-bicyclo[4.3.0]nonane after acidic quench. trans-
Bicyclo[4.3.0]nonane and bicyclo[4.2.1]nonane result from exo ring
closure on the a face, and endo ring closure respectively. These

processes are disfavored based on our previous results.

 

 

 

 

 

 

 

 

TiCle2
endo T'C'sz exo
6 9 6 8

Scheme 16. Most Probable Cyclization Pathways of 67.

45

Cyclization induced by addition of 2.0 equivalents of EtAlClz at
-78 0C to a 0.1 M solution of 67 in toluene did not occur after 18
hours. A 93:7 ratio of 3-butyl-l-cyclopentene and cis-
bicyclo[4.3.0]nonane reflected the poor reaction mixture, if the
solution was stirred an additional 0.5 hour at 0 0C. The two products
were generated in 70% yield from 67 after HCl protonolysis. Longer
reaction times did not give a better conversion; the structure of 67

was confirmed by 13C NMR performed on a sample diluted in D6-

benzene.67
5. Synthesis and Attempted Cyclization of 7-Octgn-l-yltitanocene
111191191:

8-Bromo-l-octene (70) was prepared as follows. Alkylation of
diethylmalonate with 47 in DMF afforded the diethyl ester 71, which
was deethoxycarboxylated to ethyl ester 72, in presence of LiCl and
water in DMSO. Reduction of 72 to 7-octen-l-ol (73) and
bromination of 73 with NBS/ PPh3 in CH2C12 gave 70 in 57% overall
yield (Scheme 17).

 

CH C El
W3, £1.33}: / 00251 LICI, H20, DMso
4 7 NaH, DMF 7 1 0025:
“NH NBS, PPh
WCOZEtl—f—WOH OH I 3 70
7 2 5‘20 7 3 2Cz

Scheme 17. Synthetic Routes to 70.

46

Treatment of 7-octen-l-yltitanocene chloride (71) with a
Lewis acid can potentially generate 75 and 76, which giVe
methylcycloheptane and cyclooctane upon protonolysis (Scheme 18).
The reaction mixture was also analyzed for methylenecycloheptane

which resulted from the decomposition of 75 by B-hydride

 

 

 

 

 

 

 

elimination.
TICIsz
endo exo
_. WWCICpZ .
7 4
7 6 7 5
I HCI HCI I HCI

O W

Scheme 18. Exo and Endo Cyclization Products of 7 4.

A variety of experimental conditions were tested (Table 6).
Reaction of 74 with EtAlClz or methylalumoxane in toluene or in 1,2-
dichloroethane solutions did not result in ring closure. No
methylcycloheptane product from exo-cyclized 74 was detected.
Polymerization of 74 catalyzed by EtAlClz accounted for low yields in
l-octene (0-5%). Methylalumoxane did not induce starting material
decomposition when used at -78 0C in toluene, but it did not promote
cyclization either. Since no trace of methylcycloheptane was

observed under any reaction conditions, the 6-carbon chain

47

connecting the olefin to the titanium center is probably too long for

an adequate conformation to be reached prior to olefin insertion.

Table 6. Reaction Conditions for Attempted Cyclization of 74.

 

 

 

 

 

 

 

 

 

solvent concentration catalyst reaction
time
toluene 0.1 M EtAlClz, 2 cq -78 0C 0.2 h low
toluene 0.01 M EtAlClz. 2 cq -78 0C 1 h low
toluene 0.1 M (CH3A10)n. 0.6 cq -78 OC 4 h 89%
toluene 0.1 M (CH3A10)n, 1.2 cq -78 0C 11 h 75%
A Cl(CH3)zCl 0.1 M Bunch. 1 cq -30 0C 0.54: low

 

aRefers to yield of l-octene from 74 obtained by GLC analysis.

Trialkylsilyl groups are known for exerting a strong
stabilization of electron deficient carbon atoms at the [3 position to
the silicon center (Si [S-effect).68 The initial insertion product of
trimethyl(phenylethynyl)silane onto the Ziegler-Natta catalyst
system, generated by reaction of equimolar amounts of Cp2TiC12 and
MeAlClz in chloroform was isolated and characterized.69 The
carbometalation step was eased by the trimethylsilyl activating
substituent, explained in terms of hyperconjugation effect. More

recently, in a regiochemical study of the allyltrimethylsilane

48

insertion into a carbon-zirconium bond,70 the outcome of the reaction
of allyltrimethylsilane with Cp22r(pyridyl)+ resulted from the Me3Si-
stabilization of the polar 4-center transition state.

For six- and seven-membered ring formation, a Me3Si
substituent positioned on the olefin tether as depicted by 7 7
(Scheme 19) should cause a rate enhancement for the olefin insertion
into the carbon-titanium bond, by interaction of the silicon atom with

the [3 developing positive charge.

 

M0381 7 7

Scheme 19. TMS-Accelerated Olefin Insertion into C-Ti Bond.

By its remote position from the olefin, the MegSi substituent
should not cause any unnecessary steric interactions with the
crowded titanium center, contrarily to a vinyltrimethylsilane moiety
for example. Thus EtAlClz-induced intramolecular olefin insertion
was performed on the simplest systems, 7-bromo-3-(trimethylsilyl)—

l-heptene (78) and 8-bromo-3-(trimethylsilyl)-1-octene (79).

49
7. nhi 1!. 1'. u 0 -l‘-3uu - u‘ t , ' -- ‘o -n-

7-Bromo-3-(trimethylsilyl)-l-heptene (78) was obtained as
follows. Trimethylsilylation of propargyl alcohol71 in THF afforded
80, which was reduced to 81 with Red-Al in toluene according to the
method of Denmark.72 Treatment of 81 with triethylorthoacetate
under acidic conditions following a published procedure,73 generated
the Ortho Claisen type product 82. Reduction with LiAlH4 to 83 and
bromination by action of LiBr on the corresponding mesylate
completed the synthesis of intermediate 84. The 2-carbon
homologation of 84 by reaction on diethylmalonate provided 78 as

shown in Scheme 20.

50

 

 

 

 

 

 

 

 

 

. - ,T I , E
= CHZOH 1. EtMgBr, THF TMS CHZOH 1 Red Al ouene 120
2. TMSCI 8 0 2. 3.6 MH2804
TMS CH30(OEt)3 LCOZEI LiAlH4, E120
\ TMS
CH H
8 l 20 Proplonic acid 8 2
g 1. Mesoch TEA, CH20l2 L CH2(002Et)2
TMS OH 2. LiBr, THF TMS Br NaH, DMF
8 3 8 4
gouge: LiCl. H20. DMSO £/\/°° Et LiAlH4. 5120
W3 ms 2
/(/\/\ 1. Mesozoi, TEA, CH2C|2 L\/\
TMS OH 2. LiBr THF TMS Br
8 7 ’ 7 8

Scheme 20. Synthetic Route to 78.

Action of 78 on Mg at 64 0C resulted solely in complete
Grignard reagent formation.74 Transmetalation on Cp2TiC12 to
generate 5-(trimethylsily1)—6-hepten-l-yltitanocene chloride (88)
and work up produced a solution of 88 in toluene (approximately 0.1
M). Treatment with EtAlC12 for 1 hour at -78 oC resulted in complete
and clean cyclization of the organic ligand, as evidenced by HCI
quench at -78 °C and GLC analysis of the crude mixture (Equation
14). In 1,2-dichloroethane, addition of 0.4 equivalent of EtAlClz over
a 15 minutes period at -30 0C was sufficient to induce complete ring

closure.

51

TMS

x’ .
1M Laws Add “0|sz ( 14)
TMS 110le2

88 89

 

To measure the rate enhancement caused by the TMS
substituent, an equimolar solution of 88 and 6-hepten-l-
yltitanocene chloride (2) (0.14 M in toluene) was treated over a 15
minutes period with 0.4 equivalent of EtAlC12 at -78 0C. Immediate
quench of an aliquot gave a 48:52 and a 84:16 ratio of uncyclized
versus cyclized products for 88 and 2 respectively. After 41 hours,
they changed to 5:95 and 60:40 (Scheme 21). Thus, introduction of a
trimethylsilyl group on the tether resulted in an acceleration of the
olefin insertion, probably by stabilizing the polar four-center

transition state.

 

 

 

 

 

1“) j;
2‘)

80 I X-H
§ 0 X-TMS
if", 60
>6
0
1::
g 40 u
'U
0
E
"‘ 20
‘>’. a
O

0 l ' r ' l ' I ' I '

10 20 30 4O 50

Time (hours)

Scheme 21. Compared Rate of Cyclization of 88 (X=TMS) and 2 (X=H).

52

8. nh i n iz i - - -
r' i1 -1- n

 

3-Carbon chain elongation of 84 was performed according to

the synthetic sequence shown in Scheme 22.

 

 

/ /
LA 1. Mg, 5120 LiAlH4, 320
ms TMS ooze:

3' 2. CuCI, Ethylacrylate
8 4 9 0

/ /
OH 1. MBSOZCI. TEA. CH2C|2 Br
TMS TMS

9 l 2. LiBr, THF 7 9

Scheme 22. Synthetic Route to 79.

Action of 84 on Mg, in Et20 solution under reflux, generated
the Grignard reagent, which was treated with ethylacrylate under
CuCl catalysis75 to give the 1,4-Michael addition product 90. Ethyl
ester 90 was converted to 79 by usual procedures.

6-(Trimethylsilyl)-7-octen-1-y1titanocene chloride (92) could
generate, by exo insertion of the olefin, the substituted

cycloheptylmethyltitanocene chloride 93 (Equation 15).

TMS

/
- - TICI
Mm. 6...... c... (15)

92 93

 

53

However, action of 2.0 equivalents of EtAlClz at ~78 0C on a 0.1
M solution of 92 in toluene had no effect after 12 hours. Raising the
temperature to 23 oC resulted in oligomerization after 0.5 hour.
Polymerized material also resulted when 1.0 equivalent of EtAlC12

was added to a 0.1 M solution of 92 in 1,2-dichloroethane at -30 0C.

9.9mm

We have shown that six-membered ring closure is a valuable
process. The szTiClz based methodology offered several advantages
over the existing methods. Contrarily to the carbocationic
cyclizations, the closure operated by exo insertion of the olefin. This
process could be of special importance when endo ring closure did
not fulfill the requirement of a synthetic sequence. Reactions were
regioselective, the cycloheptane endo product did not occur under
our reaction conditions. Activation of the double bond was not
necessary. However, the reaction rates were enhanced when the 4-
center transition state was stabilized by a suitably positioned
trimethylsilyl group. Decomposition of the insertion product by B-
hydride elimination was more of a concern, compared to the five-
membered ring formation. It could nevertheless be minimized by
careful operating conditions. Steric environment of the alkene had a
major influence upon the success of the cyclization. Disubstituted
olefins gave only partial ring closure, whereas trisubstituted tethered

olefins were unreactive.

54

Seven-membered ring formation was not favored. Adequate
conformations for the olefin insertion could not be reached. Electronic
effects induced by a trimethylsilyl activating group did not overcome
the steric effects. However 5- versus 7-membered ring formation can
be beneficially employed for tandem type cyclization. 4-Vinyl-7-
octen-l-yltitanocene chloride should preferentially undergo 5-exo
type cyclization, followed by a 6-exo closure to the hydrindane

system.

CONCLUSION

The present study on regioselective carbocyclic ring formation
mediated by szTiClz offers a new and quite general method for
generating five- and six-membered rings.

The alkenyltitanocene chlorides were readily accessible.
Transmetalation of the Grignard reagent of alkene bromide
substrates on szTiClz produced the organometallic species, which
underwent cyclization upon treatment with a Lewis acidic co-
catalyst.

The closure was typically a syn exo-addition of the carbon-
titanium bond on the olefin tether. Acyclic substrates containing an
internal or terminal carbon-carbon double bond, as well as cyclic
substrates of the same nature, all showed great regioselectivity in
the closure process. All reactions went near or to completion,
depending on the concentration in organometallic species, the solvent
and the co-catalyst utilized.

Following ring closure, the newly formed carbon-titanium bond
is a potential handle for product functionalization,79 and more work
has to be accomplished in this area. Tandem type olefin insertion into
carbon-titanium bond should have great potential for polycycle

formation and natural product synthesis.

55

EXPERIMENTAL

General. Melting points were measured in glass capillary tubes on a
Thomas Hoover melting point apparatus and are uncorrected.
Infrared (IR) spectra were recorded on a Nicolet PC/IR Fourier
transform spectrometer system equipped with a Nicolet IR/42
optical bench. 1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded on a Varian VXR-300 S spectrometer. Chemical shifts are
reported in parts per million (8 scale) from residual proton resonance
(CHC13, 5 7.24 ppm) or from 13C resonance (CHC13, 8 77.00 ppm).
Multiplicities are recorded by the following abbreviations: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet. Electron impact (70 eV)
mass spectra (MS) were recorded on a Finnigan 400 with an Incos
4021 data system, or on a Hewlett Packard GC/MS system 5970 B
equipped with a capillary DB-S column. Gas chromatography (GLC)
was conducted on a Perkin-Elmer 8500 using a 50-meter capillary
column, SE-54 type (column A), or a Hewlett-Packard 5880 A using a
25-meter long capillary column (ID = 0.25 nm), liquid phase GB-l
(column B). Both chromatographs were equipped with flame
ionization detectors and helium was used as a carrier gas, unless
noted otherwise. Preparative gas chromatography was performed on
a Varian Aerograph 90-P instrument with a gas conductivity type

detector and a one-meter long column packed with SE-30 Chrom W.

56

57

Helium was used as a carrier gas. Thin layer chromatography was
performed on glass precoated Merck Silica Gel 60 F254 plates (0.25
mm thick) and an aqueous potassium permanganate solution was
used as a visualisation reagent. Flash chromatography was
performed with Merk Silica Gel 60 (230-400 mesh, ASTM) according
to the method of Still.77 Elemental analyses were performed by
Galbraith Laboratories, Knoxville, TN.

Unless overwise indicated, all reagents were obtained from
commercial suppliers and used without purification. Ethylaluminum
dichloride in toluene was purchased from Aldrich Chemical Co. and
used as a known molarity, EtAlC12 refers to a 1.8 M solution of
ethylaluminum dichloride in toluene unless overwise stated.
Dimethylsulfoxide (DMSO) and dimethylformamide (DMF) were
purchased from Aldrich Chemical Co. as 99+% pure chemicals. N-
bromosuccinimide (NBS) was recrystallized from water (600 ml of
water for 70 g of NBS) and dried under vacuum overnight. For
Grignard reactions, Mg was activated by sequential treatment of
magnesium turnings with a 10% aqueous HCI solution, water and
Et20, and was dried while heated under high vacuum. For ozonolysis
reactions, ozone was generated by a Welsbach ozonator. Quenched
reaction mixtures were compared with authentic samples, whenever
possible. Analytical samples of 1,5-hexadiene, l-hexene,
methylcyclopentane, methylenecyclopentane, cyclohexane,
cyclohexene, 3-methyl-l-cyclohexene, 2-methyl-l,5-hexadiene,
methylenecyclohexane, cis-decalin, trans-decalin, l-heptene, 1,6-
heptadiene, l-octene, cyclooctane, and 1,1-dimethylcyclohexane

were obtained from Aldrich Chemical Co. trans-1,5-Heptadiene, cis-

58

1,5-heptadiene, trans-Z-heptene, cis-Z-heptene, vinylcyclopentane,
ethylcyclopentane, ethylidenecyclopentane, 1,1-dimethylcyclo
pentane, 2-methyl-1-hexene, trans-bicyclo[4.3.0]nonane, cis-
bicyclo[4.3.0]nonane, cis-bicyclo[3.3.0]octane, cycloheptane, and
methylcycloheptane were obtained from Wiley Organics.
Methylcyclohexane was purchased from Fisher, and l-methyl-l-
cyclohexene from Chemical Samples Co. Other standards were
obtained from the corresponding Grignard reagents or synthesized
from commercially available compounds. Tetrahydrofuran (THF),
diethylether (EtzO), toluene, benzene, n-pentane and n-hexane were
distilled under nitrogen from sodium/benzophenone ketyl
immediately prior to use. CH2C12, triethylamine and 1,2-
dichloroethane were distilled from calcium hydride immediately
before use. All reactions were performed under a positive pressure
of N2 in flame-dried glass apparatus. Alkenyltitanocene chloride
syntheses and cyclization reactions were performed under an
atmosphere of dry, oxygen-free argon that had been passed through
a 6-cm x 60-cm glass column containing an activated copper catalyst,
using standard Schlenk line techniques. Brine refers to a saturated
aqueous solution of NaCl. For extractions, EtzO was purchased from
Columbus Chemical Industries Inc. and petroleum ether (35-60 0C

boiling fraction) was purchased from E.M. Science Co.

Methyltriphenylphosphonium Iodide. A solution of 13.1 g (50
mmol) of triphenylphosphine and 16.2 g (115 mmol) of methyliodide
in 50 ml of benzene was heated under reflux overnight. The

voluminous precipitate was filtered, washed with 200 ml of benzene

59

and dried under high vacuum at 55 0C overnight. A quantitative
yield of methyltriphenylphosphonium iodide (46.9 g) was obtained.
Melting point 185-185.5 °C.

Pyridinium p-Toluenesulfonate (PPTS). A solution of 3.8 g (20
mmol) of p-toluenesulfonic acid in 8.1 ml (100 mmol) of pyridine
was stirred at ambient temperature for 20 minutes. The excess of
pyridine was removed by rotatory evaporation and the residue was
recrystallized from acetone. The white crystals were dried under
vacuum to afford 3.77 g (75% yield) of PPTS. Melting point 118-119
0C.

l-(Tetrahydropyranyloxy)-S-hexyne (15). Into a 500-ml,
three-necked round-bottomed flask equipped with a condenser, was
placed a solution of 9.81 g (0.1 mol) of 5-hexyn-l-ol, 12.62 g (0.15
mol) of dihydropyran and 2.51 g (0.01 mol) of PPTS in CH2C12 (300
ml). The solution was stirred at room temperature until completion.
The solvent was removed and the residue was partitioned between
Et20 (100 m1) and brine (100 ml). The aqueous layer was extracted
with Et20 (3 x 30 ml), the organics were combined and dried on
MgSO4. Concentration and distillation under reduced pressure gave
17.6 g (97% yield) of a colorless oil. Boiling point 99-100 oC (7
mmHg).

l-(Tetrahydropyranyloxy)-5-heptyne (16). A 200-ml three-
necked round-bottomed flask was fitted with a condenser and a

thermometer. A solution of 10 g (54.9 mmol) of 15 in 90 ml of THF

60

was introduced via syringe. To this solution, cooled to -78 °C, 24.2 ml
of a 2.5 M solution of nBuLi in hexanes (60.4 mmol) were added
slowly and allowed to react for 1.5 hour. The cold bath was removed
for 10 minutes to allow complete metalation. It was then replaced,
and 4.1 ml (65.9 mmol) of methyliodide were added for reaction at -
78 oC. The temperature was increased to 23 0C 0.5 hour after, and
the reaction was complete after 2 hours. The mixture was partitioned
between brine (200 ml) and Et20 (200 ml). The aqueous layer was
extracted with Et20 (2 x 50 ml). The organics were combined, washed
with water (100 ml) and dried on MgSO4. Distillation under reduced
pressure yielded 11 g of 16 (91% of theorical). Boiling point 92 °C
(11 mmHg).

S-Heptyn-l-ol (17). A solution of 14.64 g (74.6 mmol) of 16 and
1.88 g (7.5 mmol) of PPTS in 500 ml of anhydrous methanol was
stirred at 55 0C until complete consumption of the starting material
(about 4 hours). The solution was concentrated, partitioned between
Et20 (100 ml) and brine (100 ml). The aqueous phase was extracted
with Et20 (2 x 80 ml). The organics were washed with water (50 ml)
and dried (MgSO4). Distillation afforded 4.15 g (92% of the theorical
yield) of 17 as a colorless oil. Boiling point 83-85 0C (7 mmHg).

cis-S-Hepten-l-ol (18). A 250-ml round-bottomed flask fitted
with a hydrogen inlet and a rubber septum was flashed with
hydrogen and charged with 0.56 g (2.25 mmol) of nickel acetate
tetrahydrate in 80 ml of 95% ethanol. To this suspension was added

2.25 ml (2.25 mmol) of a 1 M solution of sodium borohydride in

61

ethanol. When gas evolution ceased, the black suspension obtained
was treated with 0.31 ml (4.5 mmol) of ethylenediamine, followed by
2.02 g (18 mmol) of 17. The rubber septum was replaced ‘by a new
one to avoid any leak, and the solution was stirred under a positive
pressure of H2. All of the starting material was reduced when 470 ml
of H2 approximately were consumed. The crude solution was filtered
through a pad of silica gel, washed with 100 ml of a 50% saturated
aqueous NaCl solution and 40 ml of water. The aqueous phase was
extracted with Et20 (2 x 50 ml) and the combined organic phases
were dried on MgSO4. After distillation, 3.87 g (86% yield) of 18
were obtained. Boiling point 83-86 0C (15 mmHg). Purity by GLC 96%,

the remaining 4% were l-heptanol.

cis-l-Bromo-S-heptene (20). A one—liter round-bottomed flask
was charged with 12.31 g (46.9 mmol) of triphenylphosphine, 4.46 g
(39.1 mmol) of 18 and 300 ml of CH2C12. The flask was fitted with an
addition funnel for solids containing 8.35 g (46.9 mmol) of NBS, and
cooled to 0 oC. NBS was added in small portions and the solution was
stirred until completion of the reaction. After concentration under
reduced pressure, petroleum ether (200 ml) was added to precipitate
the byproducts. The solution was filtered and the filtrate was cooled
to —20 0C overnight to precipitate more solids. The solution was
filtered again, dried on MgSO4, passed through a small pad of basic
alumina (Brockman Activity 1, 80-200 mesh) and concentrated.
Distillation under reduced pressure gave 3.66 g (53% yield) of 20.
Boiling point 85-90 0C (33 mmHg); IR (neat) v max 3013, 2961, 2936,
2859, 1655, 1456, 1439, 1404, 1372, 1287, 1250, 1032, 739, 700,

62

644 cm'l; 1H NMR (CDC13) 8 5.41 (m, 2 H), 3.40 (t, J = 6.9 Hz, 2 H),
2.05 (q, J = 7.2 Hz, 2 H), 1.86 (quintet, J = 7.2 Hz, 2 H), 1.59 (dd, J =
6.4 Hz, J = 0.5 Hz, 3 H), 1.48 (quintet, J = 7.5 Hz, 2 H) ppm; 13C NMR
(CDC13) 8 129.78, 124.46, 33.71, 32.33, 28.00, 25.89, 12.72 ppm; MS
(El-70 eV) m/e (relative intensity) 178 (M+2, 11), 176 (M, 12), 137
(5), 135 (5), 109 (7), 97 (84), 95 (24), 83 (25), 81 (30), 69 (57), 68
(11), 67 (22), 57 (15), 56 (8), 55 (100). Anal. Calcd for C7H13Br: C,
47.48; H, 7.40. Found: C, 47.30; H, 7.51.

trans-S-Hepten-l-ol (19). A one-liter round-bottomed flask
fitted with a Claisen adapter, a dry-ice condenser and a drying tube
was immersed into a dry-ice/isopropanol bath (-78 0C). NH3 was
introduced into the flask until 440 ml were liquified, followed by
5.52 g (240 mmol) of dry and clean sodium, cut in small pieces. Into
the dark blue solution produced, 4.48 g (40 mmol) of 17 were
injected by syringe. After 3 hours of reaction, the excess of sodium
was destroyed by addition of NH4C1 and the ammonia was allowed to
evaporate slowly. The reaction mixture was partitioned between 75
ml of a saturated aqueous NH4C1 solution and 150 ml of Et2O. The
aqueous phase was extracted with 100 ml of Et2O. The organics were
washed with brine (100 ml), water (80 ml) and dried on MgSO4.
Distillation gave 4.15 g of a colorless liquid (91% yield). Boiling point
84-85 0C (14 mmHg).

trans-l-Bromo-S-heptene (21). Treatment of 5.72 g (50.1 mmol)
of 19 with 15.76 g (60.1 mmol) of triphenylphosphine and 10.69 g
(60.1 mmol) of NBS in 370 ml of CH2C12 was done according to the

63

general procedure. By distillation under reduced pressure, 7.79 g
(88% yield) of 21 were collected. Boiling point 88-89 0C (34 mmHg);
IR (neat) v max 3025, 2963, 2936, 2857, 1453, 1439, 1377, 1283,
1250, 1200, 1074, 966, 733, 641 cm-1;1H NMR (CDC13) 8 5.39 (m, 2
H), 3.38 (t, J = 6.9 Hz, 2 H), 1.99 (q, = 6.8 Hz, 2 H), 1.85 (quintet, J =
7.2 Hz, 2 H), 1.62 (d, J = 4.6 Hz, 3 H), 1.47 (quintet, J = 7.3 Hz, 2 H)
ppm; 13C NMR (CDC13) 8 130.59, 125.46, 33.75, 32.24, 31.62, 28.03,
17.86 ppm; MS (El-70 eV) m/e (relative intensity) 178 (M+2, 2), 176
(M, 2), 136 (2), 134 (2), 97 (12), 81 (11), 70 (4), 69 (26), 67 (11), 56
(7), 55 (100).

4-Bromo-2-methyl-l-butene (22). Reaction of 10 g (116.0
mmol) of 3-methyl-3-buten-1-ol with 36.51 g (139.2 mmol) of
triphenylphosphine and 24.78 g (139.2 mmol) of NBS in CH2C12 (600
m1) according to the general procedure gave 12.96 g (75% yield) of
22 after work up and distillation under reduced pressure. Boiling
point 83-86 0C (200 mmHg); 1H NMR (CDC13) 8 4.84 (m, 1 H), 4.75 (m,
1 H), 3.45 (t, J = 7.4 Hz, 2 H), 2.56 (t, J = 7.4 Hz, 2 H), 1.73 (m, 3 H)
ppm; 13C NMR (CDC13) 8 142.37, 112.61, 40.88, 30.71, 21.90 ppm.

Diethyl (3-Methyl-3-buten-l-yl)propanedioate (23). To a
suspension of 0.78 g (32.4 mmol) of NaH in 30 ml of DMF maintained
at 0 °C, 4.93 ml (32.4 mmol) of diethylmalonate were added
dropwise, and were allowed to react for 2 hours at room
temperature. The solution was then cooled to 0 °C, treated with 4.40
g (29.5 mmol) of 22 and stirred at room temperature until complete

consumption of the starting material. Water (75 ml) and Et2O (50 ml)

64

were added. The aqueous phase was extracted with Et20 (3 x 20 ml).
The organic extracts were combined, washed with water (50 ml),
dried on MgSO4 and concentrated. Distillation under reduced
pressure yielded 6.53 g (97% of theorical) of a colorless oil. Boiling
point 90-95 0C (1 mmHg); IR (neat) v max 3077, 2982, 2940, 2876,
1736, 1651, 1449, 1370, 1323, 1298, 1221, 1152, 1098, 1030, 891,
862 cm'l; 1H NMR (CDC13) 8 4.72 (broad s, 1 H), 4.67 (broad s, 1 H),
4.16 (q, = 7.2 Hz, 4 H), 3.30 (m, 1 H), 2.02 (m, 4 H), 1.69 (s, 3 H),
1.24 (t, J = 7.1 Hz, 6 H) ppm; 13C NMR (CDC13) 8 169.41, 144.06,
111.14, 61.25, 51.33, 35.21, 26.62, 22.13, 14.04 ppm; MS (BI-70 eV)
m/e (relative intensity) 228 (6), 183 (20), 182 (11), 173 (20), 161
(8), 160 (100), 155 (8), 154 (18), 139 (15), 137 (59), 136 (11), 133
(53), 132 (18), 127 (7), 115 (9), 114 (18), 111 (7), 109 (44), 108 (14),
105 (13), 119 (14), 99 (7), 88 (27), 87 (8), 86 (33), 82 (6), 81 (42), 80
(19), 79 (13), 73 (12), 69 (13), 68 (32), 67 (20), 58 (5), 55 (63), 53
(14), 45 (10), 43 (10).

Ethyl S-Methyl-S-hexenoate (24). A 100-ml round-bottomed
flask was charged with 44 ml of DMSO, 1.77 g (41.8 mmol) of LiCl, 0.4
ml (22.0 mmol) of water and 5.61 g (22.0 mmol) of 23. The solution
was heated to reflux and stirred until complete comsumption of the
starting material. The mixture was poured into cold water (30 ml)
and Et2O (30 ml), extracted with Et2O (2 x 30 ml). The organics were
washed with a saturated aqueous NaHCO3 solution (40 ml), water (40
ml) and dried on MgSO4. After distillation, 2.52 g (74% yield) of 24
were obtained. Boiling point 79-80 0C (16 mmHg); 1H NMR (CDC13) 8
4.69 (m, 1 H), 4.65 (m, 1 H), 4.09 (q, J = 7.1 Hz, 2 H), 2.25 (t, J = 7.5

65
Hz, 2 H), 2.01 (t, J = 7.4 Hz, 2 H), 1.73 (m, 2 H), 1.69 (s, 3 H), 1.22 (t, J
= 7.1 Hz, 3 H) ppm; 13C NMR (CDC13) 8 173.61, 144.76, 110.57, 60.15,
37.03, 33.71, 22.76, 22.13, 14.20 ppm.

S-Methyl-S-hexen-l-ol (25). To a suspension of 2.7 g (71.1
mmol) of LiAlH4 in 200 ml of Et20 maintained at 0 0C, 10.1 g (64.6
mmol) of 24 in 50 ml of Et20 were added. After complete reaction,
water (2.7 ml), a 15% aqueous NaOH solution (2.7 ml) and water (8.1
ml) were successively added at 0 °C. The white precipitate was
removed by suction filtration and the solution was dried on MgSO4
and concentrated. Distillation under reduced pressure afforded 6.57 g
(89% yield) of 25. Boiling point 92-93 0C (16 mmHg); 1H NMR (CDC13)
8 4.66 (m, 1 H), 4.63 (m, l H), 3.57 (t, J = 6.3 Hz, 2 H), 2.06 (broad s
removed by D20 exchange, 1 H), 1.98 (t, J = 7.0 Hz, 2 H), 1.66 (s, 3 H),
1.38-1.58 (m, 4 H) ppm; 13C NMR (CDC13)8 145.65, 109.86, 62.64,
37.43, 32.25, 23.65, 22.22 ppm.

l-Bromo-5-methyl-5-hexene (26). Treatment of 6.49 g (56.8
mmol) of 25 with 17.89 g (68.2 mmol) of triphenylphosphine and
12.14 g (68.2 mmol) of NBS in CH2C12 (100 ml) was done according to
the general procedure. After distillation under reduced pressure,
8.21 g (82% yield) of 26 were collected. Boiling point 67-69 0C (31
mmHg); IR (neat) v max 3075, 2967, 2938, 2865, 1653, 1456, 1439,
1375, 1250, 889, 733, 644 cm'l; 1H NMR (CDC13) 8 4.68 (m, 2 H), 3.40
(t, J = 6.7 Hz, 2 H), 2.02 (t, J = 7.5 Hz, 2 H), 1.84 (quintet, J = 7.1 Hz, 2
H), 1.70 (s, 3 H), 1.56 (quintet, J = 7.5 Hz, 2 H) ppm; 13C NMR (CDC13) 8
145.11, 110.32, 36.80, 33.69, 32.26, 25.98, 22.19 ppm; MS (El-70 eV)

66

m/e (relative intensity) 178 (M+2, 2), 176 (M, 2), 137 (1), 123 (1),
109 (1), 98 (3), 97 (39), 96 (36), 95 (10), 83 (7), 81 (100), 79 (34), 77
(11).

2-Cyclopentene-1-ethanol (36). Treatment of 15.0 g (118.9
mmol) of 2-cyclopentene-1-acetic acid with 4.96 g (130.8 mmol) of
LiAlH4 in 220 ml of Et20 according to the general procedure ga've
10.36 g (78% yield) of 36 after distillation. Boiling point 85-87 0C (14
mmHg); IR (neat) v max 3335, 3052, 2932, 2853, 1653, 1615, 1458,
1431, 1360, 1200, 1059, 1010, 910, 876, 719 cm'1;1H NMR (CDC13) 8
5.71 (dq, J = 5.7 Hz, J = 2.0 Hz, 1 H), 5.65 (dq, J = 5.6 Hz, J = 2.0 Hz, 1
H), 3.65 (two t, J = 6.8 Hz, 2 H), 2.63-2.80 (broad m, 1 H), 2.15-2.40
(m, 2 H), 2.03 (ddt, J = 4.9 Hz, J = 12.7 Hz, J = 8.2 Hz, 1 H), 1.8 (broad s
exchanded with D20, 1 H), 1.30-1.75 (three m, 3 H) ppm; 13C NMR
(CDC13) 8 134.85, 130.82, 61.68, 41.94, 38.69, 31.72, 29.56 ppm; MS
(El-70 eV) m/e (relative intensity) 112 (1), 94 (30), 93 (7), 91 (4),
80 (8), 79 (100), 78 (4), 77 (15), 68 (6), 67 (82), 66 (27), 65 (14), 55
(4), 53 (12), 51 (7), 50 (4).

3-(2-Bromoethyl)cyclopentene (37). Treatment of 5.38 g (48.0
mmol) of 36 with 15.11 g (57.6 mmol) of triphenylphosphine and
10.25 g (57.6 mmol) of NBS in CH2C12 (100 ml) according to the
general procedure, gave 6.97 g (83% yield) of 37 after distillation
under reduced pressure. Boiling point 69-70 0C (15 mmHg); IR (neat)
v max 3052, 2934, 2851, 1439, 1362, 1256, 1211, 912, 721, 563
cm-1; 1H NMR (CDC13) 8 5.75 (dq, J = 5.9 Hz, J = 2.2 Hz, 1 H), 5.64 (dq, J
= 5.7 Hz, J = 2.0 Hz, 1 H), 3.41 (two t, J = 7.3 Hz, 2 H), 2.7-2.9 (broad

67

m, 1 H), 2.2-2.4 (broad m, 2 H), 1.7-2.2 (three m, 3 H), 1.3-1.5 (m, 1
H) ppm; 13C NMR (CDC13) 8 133.42, 131.28, 44.25, 39.06, 32.09, 31.87,
29.26 ppm; MS (El-70 eV) m/e (relative intensity) 176 (M+2, 5), 174
(M, 5), 95 (4), 93 (2), 91 (2), 81 (2), 79 (8), 77 (5), 68 (5), 67 (100),
66 (5), 65 (9), 63 (2), 55 (2), 53 (4), 51 (3).

3-(2-Cyclopenten-l-yl)propanoic acid (38). A 100-ml round-
bottomed flask equipped with a condenser was charged with 2.74 g
. (112.8 mmol) of Mg and 40 ml of THF. The flask was heated to 45 oC
and 4.95 g (28.2 mmol) of 37 were added in small portions over a
2.5-hour period. The solution was stirred for 5 hours at 60 °C, cooled
to ambient temperature and added by cannula to a large excess of
C02 (dry ice) in 50 ml of THF at -78 0C. The cold bath was removed,
and CO2 bubbled through the solution while reacting with the
Grignard reagent. After complete evaporation of C02, the solution was
diluted with Et20 (100 ml), treated with a 10% aqueous HCl solution
(20 ml), extracted with Et20 (2 x 40 ml), washed with brine (40 ml)
and dried on Na2S04. Concentration and distillation under reduced
pressure gave 3.21 g (81% yield) of 38. Boiling point 95-98 0C (3
mmHg); IR (neat) v max 3052, 2940, 2855, 2674, 1709, 1453, 1414,
1287, 1260, 1211, 1073, 939, 721 cm'l; 1H NMR (CDC13) 8 5.68 (dq, J
= 5.9 Hz, J = 2.2 Hz, 1H), 5.63 (dq, J = 5.9 Hz, J = 2.0 Hz, 1 H), 2.68 (m,
1 H), 2.15-2.50 (m with one t at 2.36 ppm, J = 7.7 Hz, 4 H), 2.04 (ddt,
J = 5.0 Hz, J = 12.8 Hz, J = 8.4 Hz, 1 H), 1.54-1.82 (m, 2 H), 1.20-1.50
(m, 2 H) ppm; 13C NMR (CDC13) 8 180.45, 133.89, 131.20, 44.77, 32.35,
31.95, 30.58, 29.33 ppm; MS (El-70 eV) m/e (relative intensity) 140
(4), 122 (18), 95 (3), 94 (7), 93 (3), 91 (4), 81 (25), 80 (88), 79 (40),

68

78 (3), 77 (13), 68 (7), 67 (100), 66 (12), 65 (17), 63 (3), 60 (3), 55
(6), 54 (3), 53 (9), 52 (4), 51 (7), 50 (4), 45 (14). Anal. Calcd for
C3H1202: C, 68.54; H, 8.63. Found: C, 68.76; H, 8.88.

2-Cyclopentene-l-propanol (35). Treatment of 3.21 g (22.9
mmol) of 38 with 0.87 g (22.9 mmol) of LiAlH4 in 40 ml of Et20
according to the general procedure gave 2.45 g (85% yield) of 35
after distillation. Boiling point 82-85 0C (10 mmHg); IR (neat) v max
3341, 3052, 2936, 2851, 1453, 1362, 1055, 1013, 914, 718 cm'1;1H
NMR (CDC13) 8 5.69 (dq, J = 5.7 Hz, J = 2.0 Hz, 1 H), 5.64 (dq, J = 5.7 Hz,
J = 1.9 Hz, 1 H), 3.62 (t, J = 6.6 Hz, 2 H), 2.55-2.70 (m, 1 H), 2.15-2.40
(m, 2 H), 2.02 (ddt, J = 5.0 Hz, J = 12.8 Hz, J = 8.3 Hz, 1 H), 1.50-1.63
(m, 2 H), 1.20-1.50 (m, 4 H) ppm; 13C NMR (CDC13) 8 134.87, 130.42,
63.16, 45.28, 32.04, 31.95, 31.08, 29.75 ppm; MS (El-70 eV) m/e
(relative intensity) 126 (3), 108 (7), 93 (15), 91 (6), 82 (6), 81 (5), 80
(59), 79 (26), 77 (9), 68 (6), 67 (100), 66 (17), 65 (14), 55 (4), 53 (7),
51 (5).

3-(3-Bromopropyl)cyclopentene (39). Treatment of 2.45 g (19.4
mmol) of 35 with 6.11 g (23.3 mmol) of triphenylphosphine and 4.15
g (23.3 mmol) of NBS in CH2C12 (80 ml) according to the general
procedure gave 2.80 g (76% yield) of 39 after distillation. Boiling
point 81-82 0C (11 mmHg); IR (neat) v max 3052, 3005, 2938, 2949,
1653, 1612, 1458, 1439, 1359, 1277, 1246, 1203, 1036, 910, 775,
720, 642, 561 cm-1; 1H NMR (CDC13) 8 5.71 (dq, J = 5.6 Hz, J = 2.2 Hz, 1
H), 5.63 (dq, J = 5.7 Hz, J = 2.0 Hz, 1 H), 3.39 (t, J = 6.8 Hz, 2 H), 2.55-
2.70 (m, l H), 2.15-2.40 (m, 2 H), 2.03 (ddt, J = 12.8 Hz, J = 5.0 Hz, J =

69

8.4 Hz, 1 H), 1.87 (quintet, J = 7.3 Hz, 2 H), 1.30-1.60 (two m, 3 H)
ppm; 13C NMR (CDC13) 8' 134.47, 130.77, 44.83, 34.53, 34.06, 31.97.
31.25, 29.68 ppm; MS (El-70 eV) m/e (relative intensity) 190 (4),
188 (4), 109 (3), 95 (3), 93 (1), 91 (2), 82 (10), 81 (5), 80 (3), 79 (7),
77 (4), 68 (6), 67 (100), 66 (9), 65 (7), 53 (4), 52 (2), 51 (3). Anal.
Calcd for C3H13Br: C, 50.81; H, 6.93. Found: C, 50.95; H, 7.05.

Methyl 3-(2-Oxocyclopentyl)propionate (43). A solution of
42.06 g (500 mmol) of cyclopentanone, 60.45 g (820 mmol) of
pyrrolidine and 0.95 g (5 mmol) of p-toluenesulfonic acid in 150 ml
of benzene was heated to reflux until complete removal of the water
by azeotropic distillation. Most of the solvent was evaporated and the
yellow residue was distilled under reduced pressure to give 52.64 g
(77% yield) of pynolidinocyclopentanone. Boiling point 85-89 0C (12
mmHg). A solution of 47.8 g (555 mmol) of methylacrylate and 43.20
g (315 mmol) of pynolidinocyclopentanone in dioxane (120 ml) was
stirred for 2 hours and heated to reflux for 10 minutes. Water (24
ml) was then added and allowed to react for 15 hours under reflux.
Concentration to an oil, dilution in Et20 (800 ml), washing with a 5%
aqueous HCl solution (2 x 200 ml) and water (300 ml) gave a
colorless liquid which was dried on Na2SO4. Concentration and
distillation under reduced pressure yielded 32.23 g (60% of theorical)
of 43. Boiling point 100-101 0C (2.5 mmHg); 1H NMR (CDC13) 8 3.62 (s,
3 H), 2.38 (t, J = 7.4 Hz, 2 H), 1.40-2.35 (several m, 9 H) ppm; 13C
NMR (CDC13)8 220.22, 173.59, 51.50, 48.17, 37.90, 31.87, 29.47,
24.86, 20.55 ppm.

7O

Methyl 3-(2-Methylenecyclopentyl)propionate (44). To 40 ml
of DMSO, 1.44 g (66 mmol) of NaH were added and stirred at 80 0C
until complete evolution of H2. A solution of 24.25 g (60 mmol) of
methyltriphenylphosphonium iodide in warm DMSO (80 ml) was
injected at 0 0C and allowed to react at ambient temperature for 15
minutes. To the reactive methylenetriphenylphosphane produced,
8.51 g (50 mmol) of 43 were added for overnigth reaction at room
temperature. The crude solution was poured onto 40 ml of cold water
and extracted with petroleum ether (5 x 100 ml). The organic
extracts were combined and washed with water (20 ml), a 75%
methanol solution in water (20 ml) and water (20 ml), dried on
Na2804 and concentrated. Fractional distillation gave 4.12 g (49%
yield) of 44. Boiling point 85-87 0C (8 mmHg); 1H NMR (CDC13) 8 4.87
(broad s, 1 H), 4.77 (broad s, 1 H), 3.64 (s, 3 H), 2.20-2.40 (broad m, 5
H), 1.20-2.0 (broad m, 6 H) ppm; 13C NMR (CDC13)8 174.27, 155.68,
104.87, 51.45, 43.31, 32.97, 32.34, 29.29, 24.06 ppm; MS (El-70 eV)
m/e (relative intensity) 168 (2), 137 (14), 136 (13), 108 (48), 95
(66), 94 (60), 93 (52), 79 (100), 55 (56).

3-(2-Methylenecyclopentyl)propanol (45). A solution of 11.59
g (68.9 mmol) of 44 in 50 ml of Et20 was added slowly to a
suspension of 2.87 g (75.8 mmol) of LiAlH4 in 200 ml of Et20 at 0 0C.
After completion of the reaction, the solution was treated
successively with water (2.87 ml), a 15% NaOH aqueous solution
(2.87 ml) and water (8.6 ml) at 0 0C. The voluminous white
precipitate formed was filtered, and the filtrate was dried on MgS04

and concentrated to an oil. Pure 45 was obtained by distillation, 9.25

71

g (96% yield) were collected. Boiling point 99-100 0C (7 mmHg); 1H
NMR (CDC13) 8 4.84 (m, 1 H), 4.75 (m, 1 H), 3.63 (t, J = 6.6 Hz, 2 H),
2.15-2.40 (m, 3 H), 1.80-2.00 (m, 1 H), 1.40-1.75 (m and one s at
1.62 ppm removed by D20 exchange, 6 H), 1.10-1.35 (m, 2 H) ppm;
13C NMR (CDC13) 8 156.68, 104.21, 63.18, 43.69, 33.13, 32.66, 30.99.
30.41, 24.14 ppm.

2-(3-Bromopropyl)-l-methylenecyclopentane (42). To a
solution of 1.83 g (13.1 mmol) of 45 and 2.7 m1 (19.6 mmol) of
triethylamine in 65 ml of CH2C12 cooled to -10 0C, 1.12 ml (14.4
mmol) of freshly distilled methanesulfonyl chloride was added
slowly. After 15 minutes of reaction at -10 °C, the solution was
diluted with 50 m1 of CH2C12 , washed with a 10% HCl aqueous
solution (40 m1), a NaHC03 saturated aqueous solution (25 ml) and
brine (40 ml). Mesyl 3-(2-methylenecyclopentyl)propanol in CH2C12
was dried (MgSO4), concentrated, added via syringe to 2.68 g (26.1
mmol) of lithium bromide dissolved in 40 ml of THF at 0 °C, and
allowed to react at room temperature until completion. The crude
mixture was diluted in Et20 (100 ml) and washed with a NaHC03
saturated aqueous solution (2 x 200 ml) and brine (20 ml). The
organic phase was dried on MgSO4, concentrated and purified by
flash column chromatography on silica gel using petroleum ether as
eluant. 20-ml fractions were collected and those containing the
product were combined and concentrated. The residue was distilled
under reduced pressure using a Kugehlrohr apparatus and gave 1.90
g (72% yield) of 42 as a colorless liquid. Boiling point 60-65 0C (5
mmHg); IR (neat) v max 3071, 2955, 2868, 1653, 1450, 1433, 1285,

72

1246, 1202, 880, 646 cm'l; 1H NMR (CDC13) 8 4.86 (m, 1 H), 4.77 (m, 1
H), 3.40 (two t, J = 6.8 Hz, 2 H), 2.30 (m, 3 H), 1.80-2.00 (m, 3 H),
1.60-1.80 (m, 2 H), 1.18-1.60 (m, 3 H) ppm; 13C NMR (CDC13) 8 156.20,
104.51, 43.20, 34.02, 33.06, 32.91, 32.62, 31.12, 24.15 ppm; MS (EI-
70 eV) m/e (relative intensity) 204 (M+2, 3), 202 (M, 3), 123 (3), 109
(3), 107 (3), 96 (16), 95 (35), 94 (3), 93 (6), 91 (5), 82 (31), 81 (100),
80 (9), 79 (31), 78 (3), 77 (11), 68 (6), 67 (35), 65 (7), 55 (11), 54
(6), 53 (18), 52 (5), 51 (7). Anal. Calcd for C9H15Br: C, 53.22; H, 7.44.
Found: C, 52.94; H, 7.24.

2-(3-Bromopropyl)-1-methylenecyclohexane (46). Boiling
point 70-72 0C (1 mmHg); IR (neat) v max 3081, 3069, 2932, 2855,
1645, 1444, 1292, 1254, 891, 652, 558 cm°1;1H NMR (CDC13) 8 4.64
(broad s, 1 H), 4.55 (broad s, 1 H), 3.40 (t, J = 6.7 Hz, 2 H), 2.13-2.47
(m, 1 H), 1.93-2.10 (m, 2 H), 1.2-1.9 (several m, 10 H) ppm; 13C NMR
(CDC13)8 152.21, 106.00, 42.52, 34.46, 34.23, 33.87, 30.89, 30.64,
28.72, 24.00 ppm; MS (El-70 eV) m/e (relative intensity) 218 (M+2,
1), 216 (M, 1), 137 (5), 110 (6), 109 (15), 96 (72), 95 (100), 93 (13),
91 (11), 82 (11), 81 (54), 79 (25), 77 (16), 68 (13), 67 (65), 65 (11),
55 (26), 53 (18). Anal. Calcd for C10H17Br: C, 55.31; H, 7.89. Found: C,
55.20; H, 7.88.

6-Bromo-1-hexene (47). Treatment of 7.01 g (70.0 mmol) of 5-
hexen-l-ol with 20.20 g (77.0 mmol) of triphenylphosphine and
13.70 g (77.0 mmol) of NBS in CH2C12 (100 ml) according to the

general procedure gave 9.08 g (80% yield) of 47 after distillation.
Boiling point 64-65 0C (35 mmHg); IR (neat) v max 3079, 2938, 2859,

73
1642, 1455, 1439, 1284, 1252, 991, 914, 739 cm'1;13C NMR (CDC13) 8
137.02, 115.52, 50.83, 40.13, 31.87, 26.39 ppm.

6-Heptenoic acid (48). 5-Hexen-l-ylmagnesium bromide was
obtained by reacting 8.15 g (50.0 mmol) of 47 with 4.86 g (200.0
mmol) of Mg in 60 ml of THF. Treatment with C02 (dry-ice) at -78 0C
according to the general procedure gave 5.21 g (82% yield) of 47
after distillation. Boiling point 95-97 0C (8 mmHg); IR (neat) v max
3081, 2978, 2940, 2658, 1705, 1642, 1466, 1418, 1292, 1242, 1204,
995, 912 cm'1;13C NMR (CDC13)8 183.45, 137.65, 115.18, 38.71,
32.50, 31.20, 16.70 ppm; MS (El-70 eV) m/e (relative intensity) 128
(3), 87 (5), 82 (5), 75 (3), 74 (100), 73 (13), 67 (9), 56 (12), 55 (26),
53 (5), 45 (13).

6-Hepten-l-ol (49). Treatment of 5.00 g (39.0 mmol) of 48 with
1.48 g (39.0 mmol) of LiAlH4 in 100 m1 of Et20 according to the
general procedure gave 3.81 g (86% yield) of 49 after distillation.
Boiling point 80-81 0C (8 mmHg); IR (neat) v max 3337, 3079, 2959,
2924, 2876, 1822, 1642, 1458, 1379, 1040, 993, 909, 764, 637 cm-1;
13C NMR (CDC13) 8 138.86, 114.32, 68.06, 35.16, 32.27, 31.12, 16.39
ppm; MS (El-70 eV) m/e (relative intensity) 114 (<1), 96 (12), 82 (7),
81 (96), 79 (10), 71 (33), 68 (13), 67 (28), 58 (18), 57 (35), 56 (16),
55 (100), 54 (73), 53 (17).

7-Bromo-1-heptene (50). Treatment of 2.10 g (18.4 mmol) of 49
with 5.80 g (22.1 mmol) of triphenylphosphine and 3.93 g (22.1
mmol) of NBS in CH2C12 (80 ml) according to the general procedure

74

afforded 1.33 g (41% yield) of 50 after distillation. Boiling point 68-
70 0C (17 mmHg); IR (neat) v max 3077, 3000, 2961, 2936, 2859,
1642, 1460, 1439, 1269, 1242, 1200, 993, 912, 729, 644, 563 cm'l;
1H NMR (CDC13) 8 5.80 (ddt, J = 17.0 Hz, J = 10.3 Hz, J = 6.7 Hz, 1 H),
5.00 (ddt, J = 17.1 Hz, J = 1.7 Hz, J = 1.8 Hz, 1 H), 4.94 (ddt, J = 10.3
Hz, J = 2.0 Hz, J = 1.1 Hz, 1 H), 3.40 (t, J = 6.8 Hz, 2 H), 2.06 (broad q, J
= 6.7 Hz, 2 H), 1.86 (quintet, J = 7.1 Hz, 2 H), 1.3-1.5 (broad m, 4 H)
ppm; 13C NMR (CDC13)8 138.56, 114.58, 33.79, 33.50, 32.65, 28.01,
27.62 ppm; MS (El-70 eV) m/e (relative intensity) 178 (M+2, <1),
176 (M, <1), 148 (3), 137 (6), 135 (6), 134 (5), 107 (3), 97 (31), 95
(3), 81 (9), 79 (2), 69 (28), 68 (8), 67 (14), 56 (7), 55 (100), 54 (13),
53 (13), 51 (4).

1,l-Dimethoxyheptan-6-one (55). A solution of 14.43 g (150
mmol) of l-methyl-l-cyclohexene in 75 ml of methanol and 40 ml of
CH2C12 was treated with ozone at -78 0C until a blue color persisted.
The solution was degassed with N2 and poured into 0.37 g of p-
toluenesulfonic acid dissolved in 45 ml of dimethylsulfur at -78 0C.
The mixture was stirred at ambient temperature for 3 hours, diluted
with 400 ml of CH2C12, washed successively with a 3 N HCl aqueous
solution (120 ml), water (3 x 150 m1) and dried on Na2S04.
Concentration and bulb-to-bulb distillation under reduced pressure
gave 19.23 g (74% yield) of 55. Boiling point 75-85 °C.(0.l mmHg); IR
(neat) v max 2946, 2832, 1717, 1364, 1161, 1129, 1074, 1053 cm'l;
1H NMR (CDC13) 8 4.30 (t, J = 5.7 Hz, 1 H), 3.26 (s, 6 H), 2.39 (t, J = 7.4
Hz, 2 H), 2.09 (s, 3 H), 1.5-1.6 (m, 4 H), 1.2-1.4 (m, 2 H) ppm; 13C NMR
(CDC13)8 209.25, 104.36, 52.54, 43.35, 32.05, 29.59, 23.84, 23.27

75

ppm; MS (El-70 eV) m/e (relative intensity) 173 (M-l, <1), 143 (2),
111(2), 85 (3), 84 (9), 83 (15), 75 (100), 71 (8), 67 (5), 61 (12), 58
(5), 55 (6), 47 (14), 45 (8), 43 (46).

7,7-Dimethoxy-2-methyl-l-heptene (56). A suspension of 3.12
g (130 mmol) of NaH in 90 ml of DMSO was stirred at 0 0C for one
hour. A solution of 52.55 g (130 mmol) of
methyltriphenylphosphonium iodide dissolved in warm DMSO (180
ml) was added to the yellow sodium methylsulfinyl carbanion
solution cooled to 0 oC, and was allowed to react at room temperature
for 15 minutes. Addition of 17.42 g (100 mmol) of 55 via syringe
and overnight reaction at 22 0C gave the crude olefinated product.
The reaction mixture was poured into iced water (250 ml) and
methanol (50 ml) and extracted with n-pentane (3 x 200 ml). The
organics were washed with 80 ml of a 3:1 mixture of methanol and
water, 50 ml of water and dried on Na2S04. Concentration to an oil
followed by bulb-to-bulb distillation afforded 14.30 g (83% yield) of
56. Boiling point 60-70 0C (0.1 mmHg); IR (neat) v max 3075, 2942,
2863, 2830, 1651, 1456, 1387, 1375, 1192, 1161, 1129, 1078, 1053.
961, 887 cm-1; 1H NMR (CDC13) 8 4.65 (m, 1 H), 4.62 (m, 1H), 4.32 (t, J
= 5.7 Hz, 1 H), 3.27 (s, 6 H), 1.96 (t, J = 7.5 Hz, 2 H), 1.67 (s, 3 H), 1.57
(q, J = 7.1 Hz, 2 H), 1.2-1.5 (m, 5 H) ppm; 13C NMR (CDC13) 8 146.06,
109.89, 104.56, 52.43, 37.49, 32.14, 27.19, 24.01, 22.07 ppm; MS (EI-
70 eV) m/e (relative intensity) 172 (<1), 140 (1), 109 (22), 108 (15),
93 (9), 84 (9), 81 (5), 75 (100), 71 (13), 69 (4), 67 (17), 58 (7), 55
(11), 53 (5), 47 (15), 45 (8), 43 (7). Anal. Calcd for C10H202: C, 69.72;
H, 11.70. Found: C, 69.73; H, 11.44.

76

6-Methyl-6-heptenal (57). To a suspension of 8102 (80 g) in
CH2C12 (180 ml), were added 8 ml of a 15% H2804 aqueous solution.
After adsorption on the silica gel (5 minutes), 8.0 g (46.4 mmol) of
56 were injected for overnight reaction at ambient temperature. The
mixture was quenched with 1.0 g of NaHC03 and the solids were
removed by suction filtration. The filtrate was washed with water
(100 m1) and dried on Na2804. After evaporation of the solvent, 7.56
g of a yellow oil were obtained. It was utilized for the next step
without further purification. IR (neat) v max 3075, 2936, 2863, 1727,
1653, 1456, 1375, 1127, 1080, 887 cm-1; 1H NMR (CDC13) 8 9.73 (t, J =
1.8 Hz, 1 H), 4.67 (broad s, 1 H), 4.63 (broad s, 1 H), 2.41 (td, J = 7.1
Hz, J = 1.9 Hz, 2 H), 1.99 (t, J = 7.4 Hz, 2 Hz), 1.67 (s, 3 H), 1.3-1.6 (two
m, 4 H) ppm; 13C NMR (CDC13) 8 202.62, 145.23, 110.12, 43.69, 37.37,
26.93, 22.20, 21.59 ppm.

6-Methyl-6-hepten-l-ol (58). A solution of 7.6 g of crude 57 in
Et20 (100 ml) was stirred at 0 0C with 1.76 g (46.4 mmol) of LiAlH4.
After usual workup and concentration, 4.61 g (78% yield) of 58 were
obtained by distillation. Boiling point 95-97 0C (15 mmHg); IR (neat)
v max 3345, 3075, 2936, 2861, 1651, 1456, 1375, 1128, 1053, 885
cm'l; 1H NMR (CDC13) 8 4.67 (m, 1 H), 4.64 (m, 1 H), 3.62 (t, J = 6.7 Hz,
2 H), 2.00 (t, J = 7.4 Hz, 2 H), 1.68 (s, 3 H), 1.56 (quintet, J = 7.0 Hz, 5
H) ppm; 13C NMR (CDC13) 8 145.93, 109.75, 62.95, 37.71, 32.63, 27.34,
25.36, 22.32 ppm.

77

7-Bromo-2-methyl-l-heptene (59). By following the general
procedure, 3.49 g (27.0 mmol) of 58 were treated with 8.50 g (32.4
mmol) of triphenylphosphine and 5.77 g (32.4 mmol) of NBS in
CH2C12 (100 ml). After distillation, 3.03 g (59% yield) of 59 were
obtained. Boiling point 75-77 0C (15 mmHg); IR (neat) v max 3075,
2936, 2859, 1649, 1454, 1441, 1375, 1262, 887, 646 cm'1;1H NMR
(CDC13) 8 4.68 (m, 1 H), 4.65 (m, 1 H), 3.39 (t, J = 6.8 Hz, 2 H), 2.00 (t, J
= 6.7 Hz, 2 H), 1.85 (q, = 7.0 Hz, 2 H), 1.69 (s, 3 H), 1.35-1.50 (m, 4
H) ppm; 13C NMR (CDC13) 8 145.65, 109.93, 37.52, 33.82, 32.70, 27.78,
26.68, 22.31 ppm; MS (El-70 eV) m/e (relative intensity) 192 (M+2,
<1), 190 (M, <1), 137 (1), 135 (1), 111 (14), 109 (1), 107 (1), 95 (2),
79 (l), 70 (2), 69 (32), 68 (3), 67 (8), 65 (1), 57 (11), 56 (100), 55
(38), 54 (4), 53 (8), 52 (1), 51 (2). Anal. Calcd for C3H15Br: C, 50.28; H,
7.91. Found: C, 50.84; H, 8.30.

Diethyl 2-[2-(2-Cyclopenten-l-yl)ethyl]propanedioate (63).
A solution of 6.7 ml (44 mmol) of diethylmalonate in DMF (60 ml)
was treated with 1.06 g (44.0 mmol) of NaH. Alkylation by 7.00 g (40
mmol) of 37 produced 8.81 g (82% yield) of 63 after distillation.
Boiling point 100-103 0C (0.2 mmHg); IR (neat) v max 3050, 2982,
2940, 2909, 2853, 1753, 1736, 1453, 1370, 1337, 1298, 1279, 1246,
1221, 1177, 1156, 1098, 1030, 914, 860, 721 cm'l; 1H NMR (CDC13) 8
5.69 (dq, J = 5.7 Hz, J = 2.2 Hz, 1 H), 5.62 (dq, J = 5.7 Hz, J = 2.0 Hz, 1
H), 4.16 (q, J = 7.0 Hz, 4 H), 3.27 (t, J = 7.5 Hz, 1 H), 2.55-2.70 (m, 1
H), 2.15-2.40 (m, 2 H), 1.95-2.10 (m, 1 H), 1.85-1.95 (m, 2 H), 1.30-
1.50 (m, 3 H), 1.24 (t, J = 7.1 Hz, 6 H) ppm; 13C NMR (CDC13) 8 169.48,
134.38, 130.71, 61.23, 52.23, 45.19, 33.56, 31.93, 29.51, 27.08, 14.06

78

ppm; MS (El-70 eV) m/e (relative intensity) 208 (M-46, 2), 191 (4),
180 (4), 173 (27), 163 (6), 162 (5), 161 (9), 160 (12), 135 (3), 134
(9), 133 (11), 127 (2), 117 (14), 115 (3), 114 (3), 107 (4), 106 (7),
105 (5), 101 (8), 94 (7), 93 (22), 92 (12), 91 (9), 88 (3), 86 (6), 81
(9), 80 (100), 79 (27), 77 (11), 73 (8), 69 (4), 67 (46), 66 (7), 65 (9),
55 (16), 53 (6), 51 (3).

Ethyl 4-(2-Cyclopenten-1-yl)butanoate (64). A solution of
3.88 g (15.3 mmol) of 63, 1.23 g (29.0 mmol) of LiCl and 0.28 ml
(15.3 mmol) of water in 40 ml of DMF was heated to reflux until
completion of the reaction. Distillation under reduced pressure
afforded 2.18 g (78% yield) of 64. Boiling point 90-93 0C (6 mmHg);
IR (neat) v max 3052, 2980, 2942, 2851, 1738, 1460, 1373, 1238,
1177, 1134, 1034, 719 cm'l; 1H NMR (CDC13) 8 5.69 (dq, J = 5.7 Hz, J =
2 Hz, 1 H), 5.64 (dq, J = 5.6 Hz, J = 2.0 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2
H), 2.15-2.40 (m with t at 2.27 ppm , J = 7.3 Hz, 4 H), 2.55-2.70 (m, 1
H), 2.01 (ddt, J = 5.0 Hz, J = 12.8 Hz, J = 8.3 Hz, 1 H), 1.63 (quintet, J =
7.6 Hz, 2 H), 1.18-1.50 (m with t at 1.23 ppm, J = 7.1 Hz, 6 H) ppm;
13C NMR (CDC13) 8 173.74, 134.77, 130.41, 60.14, 45.26, 35.52, 34.56,
31.94, 29.69, 23.34, 14.23 ppm; MS (El-70 eV) m/e (relative
intensity) 182 (2), 137 (5), 136 (32), 135 (6), 121 (2), 119 (13), 108
(7), 107 (3), 101 (6), 95 (9), 94 (35), 93 (32), 92 (7), 91 (12), 88 (17),
87 (4), 81 (6), 80 (19), 79 (27), 77 (13), 73 (5), 70 (7), 68 (6), 67
(100), 66 (12), 65 (14), 61 (7), 60 (10), 55 (9), 53 (10), 52 (4), 51 (5).
Anal. Calcd for C11H1302: C, 72.49; H, 9.95. Found: C, 71.82; H, 9.94.

79

4-(2-Cyclopenten-l-yl)butanol (65). A Solution of 4.43 g (24.3
mmol) of 64 in Et20 (40 ml), (was stirred with 0.93 g (24.3 mmol) of
LiAlH4. Distillation gave 3.25 g (96% yield) of 65. Boiling point 82-85
0C (5 mmHg); IR (neat) v max 3329, 3052, 2934, 2851, 1458, 1360,
1057, 1036, 912, 718 cm'l; 1H NMR (CDC13) 8 5.69 (dq, J = 5.7 Hz,'J =
1.9 Hz, 1 H), 5.65 (dq, J = 5.7 Hz, J = 1.9 Hz, 1 H), 3.63 (t, J = 6.6 Hz, 2
H), 2.55-2.70 (broad m, 1 H), 2.15-2.40 (m, 2 H), 2.01 (ddt, J = 4.8 Hz,
J = 12.8 Hz, J = 8.4 Hz, 1 H), 1.55 (quintet, J = 6.9 Hz, 2 H), 1.20-1.45
(m, 6 H) ppm; 13C NMR (CDC13) 8 135.11, 130.23, 45.54, 35.89, 33.03,
31.96, 29.79, 24.10 ppm; MS (El-70 eV) m/e (relative intensity) 140
(1), 122 (8), 107 (3), 95 (2), 94 (11), 93 (25), 91 (4), 81 (9), 80 (32),
79 (26), 78 (2), 77 (8), 68 (7), 67 (100), 66 (16), 65 (11), 55 (7), 53
(7), 51 (4).

3-(4-Bromobutyl)cyclopentene (66). A solution of 3.25 g (23.2
mmol) of 65 in CH2C12 (100 ml) was treated with 7.29 g (27.8 mmol)
of triphenylphosphine and 4.95 g (27.8 mmol) of NBS according to
the general procedure. After distillation, 4.09 g (87% yield) of 66
were obtained. Boiling point 90-95 0C (10 mmHg); IR (neat) v max
3052, 3005, 2940, 2849, 1651, 1613, 1458, 1439, 1360, 1267, 1237,
1111, 1049, 986, 719, 846, 719, 646, 563 cm'l; 1H NMR (CDC13) 8 5.70
(dq, J = 5.7 Hz, J = 2.0 Hz, 1 H), 5.65 (dq, J = 5,7 Hz, J = 1.9 Hz, 1 H),
3.40 (t, J = 6.8 Hz, 2 H), 2.62 (broad m, 1 H), 2.18-2.40 (m, 2 H), 2.02
(ddt, J = 4.9 Hz, J = 12.7 Hz, J = 8.4 Hz, 1 H), 1.85 (broad quintet, J =
7.0 Hz, 2 H), 1.20-1.50 (m, 5 H) ppm; 13C NMR (CDC13) 8 134.88,
130.40, 45.37, 35.16, 33.89, 33.02, 31.96, 29.76, 26.50 ppm; MS (EI-
70 eV) m/e (relative intensity) 204 (M+2, 1), 202 (M, 1), 137 (2), 135

80

(2), 123 (9), 95 (4), 82 (3), 81 (14), 80 (2), 79 (6), 77 (4), 68 (6), 67
(100), 66 (10), 65 (6), 55 (4), 54 (2), 53 (4), 51 (2). Anal. Calcd for
C9H1sBr: C, 53.22; H, 7.44. Found: C, 53.04; H, 7.27.

Diethyl 2-(5-Hexen-l-yl)propanedioate (71). Treatment of
7.22 g (44.3 mmol) of 47 with 7.40 g (48.7 mmol) of diethylmalonate
and 1.17 g (48.7 mmol) of NaH in 45 ml of DMF under the usual
conditions gave 8.66 g (81% yield) of 71. Boiling point 74-78 0C (0.2
mmHg); IR (neat) v max 3079, 2982, 2938, 2878, 1752, 1642, 1466,
1449, 1269, 1304, 1230, 1152, 1034, 997, 912, 864 cm‘l; 1H NMR
(CDC13) 8 5.75 (ddt, J = 10.3 Hz, J = 17.0 Hz, J = 6.7 Hz, 1 H), 4.96 (ddt,
J = 17.0 Hz, J = 2.2 Hz, J = 1.7 Hz, 1 H), 4.91 (ddt, J = 10.1 Hz, J = 2.2
Hz, J = 1.1 Hz, 1 H), 4.16 (q, J = 5.3 Hz, 4 H), 3.28 (t, J = 7.4 Hz, 1 H),
2.02 (q, J = 7.0 Hz, 2 H), 1.87 (q, J = 7.6 Hz, 2 H), 1.17-1.50 (m and one
t at 1.24 ppm, J = 7.1 Hz, 10 H) ppm; 13C NMR (CDC13) 8 169.49,
138.52, 114.53, 61.22, 52.01, 33.36, 28.55, 28.43, 26.73, 14.05 ppm;
MS (El-70 eV) m/e (relative intensity) 201 (M-41, 3), 198 (3), 197
(22), 196 (7), 187 (53), 169 (9), 161 (36), 160 (100), 151 (77), 155
(33), 141 (35), 139 (9), 135 (15), 133 (56), 132 (16), 127 (31), 123
(33), 122 (66), 115 (53), 114 (22), 113 (11), 105 (19), 104 (16), 99
(26), 95 (52), 94 (27), 93 (13), 88 (29), 87 (63), 86 (41), 85 (10), 83
(21), 82 (67), 81 (51), 80 (13), 79 (24), 77 (9), 71 (8), 70 (7), 69 (91),
68 (14), 67 (67), 65 (5), 58 (6), 55 (90), 54 (44), 53 (30), 51 (6), 45
(27). Anal. Calcd for C13H2204: C, 64.44; H, 9.15. Found: C, 64.63; H,
9.26.

81

Ethyl 7-0ctenoate (72). Reaction of 8.66 g (35.7 mmol) of 71 with
2.87 g (67.8 mmol) of LiCl and 0.64 ml (35.7 mmol) of water in 90 ml
of DMSO under the usual conditions gave 5.30 g (87% yield) of 72.
Boiling point 85-88 0C (12 mmHg); IR (neat) v max 3079, 2978, 2932,
2876, 2853, 1738, 1642, 1460, 1371, 1290, 1117, 1096, 1034, 995,
912 cm'l; 1H NMR (CDC13) 8 5.77 (ddt, J = 17.0 Hz, J = 10.3 Hz, J = 6.7
Hz, 1 H), 4.97 (ddt, J = 17.0 Hz, J = 2.2 Hz, J = 1.7 Hz, 1 H), 4.91 (ddt, J
= 10.0 Hz, J = 2.0 Hz, J = 1.1 Hz, 1 H), 4.10 (q, J = 7.2 Hz, 2 H), 2.26 (t, J
= 7.5 Hz, 2 H), 2.02 (q, J = 7.0 Hz, 2 H), 1.60 (quintet, J = 7.4 Hz, 2 H),
1.26-1.44 (m with one t at 1.23 ppm , J = 7.1 Hz, 7 H) ppm; 13C NMR
(CDC13)8 173.77, 138.80, 114.36, 60.14, 34.31, 33.52, 28.57, 28.50,
24.81, 14.23 ppm; MS (El-70 eV) m/e (relative intensity) 170 (l),
155 (4), 128 (7), 125 (16), 115 (6), 101 (5), 97 (14), 96 (17), 95 (7),
89 (6), 88 (56), 87 (17), 83 (27), 82 (80), 81 (22), 79 (6), 73 (12), 71
(5), 70 (25), 69 (23), 68 (6), 67 (27), 61 (24), 60 (30), 59 (14), 57 (6),
56 (21), 55 (100), 54 (15).

7-0cten-1-ol (7.3). Treatment of 5.30 g (31.1 mmol) of 72 with a
suspension of 1.30 g (34.3 mmol) of LiAlH4 in Et20 (60 ml) produced
3.64 g (91% yield) of 73. Boiling point 88-91 0C (15 mmHg); IR (neat)
v max 3333, 3079, 2959, 2928, 2874, 1642, 1458, 1379, 1059, 995,
963, 909, 633 cm-1; 1H NMR (CDC13) 8 5.78 (ddt, J = 17.0 Hz, J = 10.3
Hz, J = 6.7 Hz, 1 H), 4.97 (ddt, J = 17.3 Hz, J = 2.0 Hz, J = 1.7 Hz, 1 H),
4.91 (ddt, J = 10.3 Hz, J = 2.0 Hz, J = 1.2 Hz, 1 H), 3.61 (t, J = 6.6 Hz, 2
H), 2.02 (q, J = 7.3 Hz, 2 H), 1.55 (quintet, J = 7.0 Hz, 2 H), 1.20-1.45
(m and one s at 1.35 ppm exchanged by D20, 7 H) ppm; 13C NMR
(CDC13)8 139 02, 114.22, 62.99, 33.67, 32.71, 28.86, 28.83, 25.57

82

ppm; MS (El-70 eV) m/e (relative intensity) 110 (M-18, 5), 96 (4),
95 (43), 86 (8), 83 (6), 82 (27), 81 (71), 79 (7), 71 (44), 70 (5), 69
(46), 68 (61), 67 (72), 57 (18), 56 (64), 55 (100), 54 (38), 53 (22), 51
(7), 45 (13), 43 (45).

8-Bromo-1-octene (70). Treatment of 3.64 g (28.4 mmol) of 73
were treated with 8.94 g (34.1 mmol) of triphenylphosphine and
6.06 g (34.1 mmol) of NBS in CH2C12 (40 ml) according to the general
procedure produced 4.81 g (89% yield) of 70 after distillation. Boiling
point 80-84 0C (15 mmHg); IR (neat) v max 3077, 2998, 2930, 2857,
1642, 1462, 1439, 1292, 1258, 1221, 993, 910, 727, 646, 561 cm'l;
1H NMR (CDC13) 8 5.78 (ddt, J = 17.1 Hz, J = 10.3 Hz, J = 6.7 Hz, 1 H),
4.98 (ddt, J = 17.1 Hz, J = 2.2 Hz, J = 1.7 Hz, 1 H), 4.51 (ddt, J = 10.2
Hz, J = 2.2 Hz, J = 1.1 Hz, 1 H), 3.39 (t, J = 6.8,Hz, 2 H), 2.03 (q, J = 7.0
Hz, 2 H), 1.84 (quintet, J = 7.0 Hz, 2 H), 1.2-1.5 (m, 6 H) ppm; 13C NMR
(CDC13)8 138.86, 114.37, 33.90, 33.61, 32.76, 28.67, 28.20, 28.00
ppm; MS (El-70 eV) m/e (relative intensity) 192 (M+2, 1), 190 (M,
1), 150 (56), 148 (64), 69 (68), 55 (55), 41 (100).

3-Trimethylsilyl-2-propyn-1-ol(80). A three-liter, three-
necked, round-bottomed flask equipped with a thermometer, was
fitted with a Claisen adapter, on which was mounted a 250-ml
pressure equalizing addition funnel and a reflux condenser. The flask
was charged with 48.7 g (2.0 mol) of magnesium turnings and 1 liter
of THF. To the stirred suspension were added dropwise 149.5 ml (2.0
mol) of bromoethane over a 4-hour period, maintaining the

temperature below 50 oC. The solution was heated with a steam bath

83

at 50 0C for one hour and then cooled to 5 0C on ice. 41.6 ml (0.72
mol) of propargyl alcohol in 42 ml of THF was added over 4 hours at
5-10 oC and was allowed to react at ambient temperature for 20
hours. The resulting solution was cooled to 5 0C and treated with 254
ml (2.0 mol) of chlorotrimethylsilane at 5-10 0C. The suspension was
then heated to reflux for 2.5 hours with a steam bath, cooled to 22 0C
and quenched with 800 ml of 1.4 M aqueous H2804, maintaining the
temperature below 45 °C. The resulting solution was stirred for an
additional hour and was diluted in 600 m1 of Et20. The aqueous
phase was extracted with Et20 (2 x 400 ml), the organic extracts
were washed with water (2 x 1 liter) and brine (800 ml), and dried
on Mg804. After concentration, the residue was distilled under
reduced pressure to give 79.95 g (86% yield) of 80. Boiling point 73-
78 0C (20 mmHg); IR (neat) v max 3366, 2961, 2901, 2178, 1636,
1410, 1250, 1038, 985, 837, 760, 700, 648 cm'1;1H NMR (CDC13) 8
4.23 (s, 2 H), 1.95 (broad s, 1 H), 0.15 (s, 9 H) ppm; 13C NMR (CDC13) 8
103.86, 90.61, 51.55, -0.25 ppm; MS (El-70 eV) m/e (relative
intensity) 115 (M-15, 83), 99 (4), 97 (7), 87 (20), 85 (18), 83 (4), 76
(7), 75 (100), 74 (7), 73 (71), 67 (4), 61 (52), 60 (5), 59 (45), 58 (11),
57 (6), 55 (10), 53 (9), 47 (13), 45 (36).

(E)-3-Trimethylsilyl-2-propen-l-ol (81). A solution of 25.7 g
(0.2 mol) of 80 in 120 ml of Et20 was added dropwise over a two-
hour period to 82 ml (0.28 mol) of a 3.4 M solution of Red-Al in
toluene, diluted in Et20 (120 m1), at ice-bath temperature. After 2
hours of reaction at 22 0C, the reaction mixture was treated with 600

ml of a 3.5 M aqueous solution of H2804 at 0 oC. The aqueous phase

84

was extracted with Et20 (200 + 150 ml), the organics were washed
with water (2 x 150 ml), brine (150 ml), dried on Mg804 and
concentrated. Distillation of the residue under reduced pressure
afforded 22 g (85% yield) of 81 as a colorless liquid. Boiling point 74-
77 0C (18 mmHg); IR (neat) v max 3326, 2957, 2899, 2859, 1622,
1420, 1248, 1073, 991, 864, 841, 768, 692, 613 cm-1;1H NMR (CDC13)
8 6.14 (dt, J = 18.7 Hz, J = 4.4 Hz, 1 H), 5.88 (dt, J = 18.7 Hz, J = 1.7 Hz,
1 H), 4.13 (dd, J = 1.7 Hz, J = 4.4 Hz, 2 H), 1.92 (s, l H), -0.04 (s, 9 H)
ppm; 13C NMR (CDC13) 8 144.78, 129.47, 65.41, -1.40 ppm; MS (El-70
eV) m/e (relative intensity) 115 (M-15, 83), 99 (4), 97 (7), 87 (20),
85 (18), 83 (4), 76 (7), 75 (100), 74 (7), 73 (71), 67 (4), 61 (52), 60
(5), 59 (45), 58 (11), 57 (6), 55 (10), 53 (9), 47 (13), 45 (36).

Ethyl 3-(Trimethylsilyl)-4-pentanoate (82). A 100-ml round-
bottomed flask equipped with a short-path distillation head was
charged with 2.61 g (20 mmol) of 81, 25.7 ml (140 mmol) of
triethylorthoacetate and a few drops of propionic acid. The flask was
slowly heated to 140 0C over a 4-hour period during which 2.5 ml of
liquid were collected (boiling point 70 oC). Most of the solvent was
evaporated and the residue was distilled under reduced pressure. A
low boiling fraction was collected at 40 0C (10 mmHg) and 3.35 g
(84% yield) of 82 distilled at 67-70 0C (6 mmHg). IR (neat) v max
3080, 2975, 1740, 1628, 1370, 1250, 1179, 1094, 1038, 999, 899,
839, 752, 693, 637 cm-1; 1H NMR (CDC13) 8 5.70 (ddd, J = 17.0 Hz, J =
10.6 Hz, J = 8.4 Hz, 1 H), 4.87 (ddd, J = 10.5 Hz, J = 1.5 Hz, J = 1.0 Hz, 1
H), 4.82 (dt, J = 17.0 Hz, J = 1.4 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 2.36
(d, J = 6.7 Hz, 1 H), 2.35 (d, J = 8.9 Hz, 1 H), 2.05 (tddd, J = 7.7 Hz, J =

85
8.5 Hz, J =1.1 Hz, J = 1.1 Hz, 1 H), 1.21 (t, J = 7.1 Hz, 3 H), -0.03 (s, 9H)
ppm; 13C NMR (CDC13) 8 173.47, 138.23, 112.14, 60.24, 33.72, 30.74,
14.26, -3.48 ppm; MS (El-70 eV) m/e (relative intensity) 200 (1),
185 (2), 157 (3), 155 (4), 119 (8), 117 (4), 103 (6), 97 (4), 82 (13), 81
(2), 75 (31), 74 (9), 73 (100), 61 (2), '59 (5), 58 (3), 57 (2), 55 (5), 54
(29), 53 (4), 47 (3), 45 (20).

3-(Trimethylsilyl)-4-penten-l-ol (83). Treatment of 26.33 g
(131.4 mmol) of 82 with 5.00 g (131.4 mmol) of LiAlH4 in 260 ml of

Et20 gave 18.05 g (87% yield) of 83. Boiling point 78—80 0C (8
mmHg); IR (neat) v max 3333, 3079, 2901, 1626, 1412, 1248, 1040,

995, 897, 856, 839, 750, 690, 637 cm'l; 1H NMR (CDC13) 8 5.62 (ddd, J
= 16.7 Hz, J = 10.6 Hz, J = 9.2 Hz, 1 H), 4.86 (dd, J = 10.6 Hz, J = 2.0 Hz,
1 H), 4.84 (ddd, J = 16.7 Hz, J = 2.0 Hz, J = 0.6 Hz, 1 H), 3.50-3.70 (two
111, 2 H), 1.54-1.74 (m with broad s exchanged by D20 at 1.57 ppm, 4
H), -0.04 (s, 9 H) ppm; 13C NMR (CDC13) 8 139.69, 112.39, 62.81,
31.48, 31.26, -3.46 ppm; MS (El-70 eV) m/e (relative intensity) 143
(M-15, 1), 103 (3), 97 (3), 75 (48), 74 (9), 73 (100), 69 (5), 68 (65),
67 (77), 61 (5), 59 (7), 58 (3), 55 (5), 54 (3), 53 (15), 47 (5), 45 (30),
43 (17).

5-Bromo-3-(trimethylsilyl)-l-pentene (84). Treatment of
13.09 g (82.7 mmol) of 83 with 7.1 ml (91.0 mmol) of freshly
distilled methanesulfonyl chloride in 400 m1 of CH2C12 according to
the general method produced the mesylate derivative of 80 after
work up. This mesylate was added to a solution of 17.02 g (165.4

mmol) of LiBr in 250 ml of THF. Distillation under reduced pressure

11

86

gave 15.69 g (86% yield) of 84. Boiling point 75-77 0C (11 mmHg); IR
(neat) v max 3079, 2959, 2899, 1628, 1429, 1305, 1250, 1215, 1074,
999, 901, 839, 752, 692, 638 cm'l; 1H NMR (CDC13) 8 5.53 (ddd, J =
17.0 Hz, J = 10.3 Hz, J' = 9.5 Hz, 1 H), 4.93 (ddd, J = 10.3 Hz, J = 1.7 Hz,
J = 0.6 Hz, 1 H), 4.87 (ddd, J = 17.0 Hz, J = 1.8 Hz, J = 1.0 Hz, 1 H), 3.50
(m, 1 H), 3.28 (dt, J = 9.5 Hz, J = 8.1 Hz, 1 H), 1.83-2.00 (m, 2 H), 1.68
(td, J = 9.8 Hz, J = 4.7 Hz, 1 H), -0.03 (s, 9 H) ppm; 13C NMR (CDC13) 8
137.92, 113.44, 33.89, 33.87, 31.94, -3.44 ppm; MS (El-70 eV) m/e
(relative intensity) 222 (M+2, <1), 139 (18), 137 (18), 109 (3), 75 (3),
74 (8), 73 (100), 69 (5), 68 (90), 67 (54), 54 (6), 58 (3), 55 (4), 54
(3), 53 (12), 45 (26). Anal. Calcd for C3H17BrSi: C, 43.44; H, 7.75.
Found: C, 43.35; H, 7.86.

Diethyl 2-(3-Trimethy1silyl-4-pentenyl)propionate (85).
Treatment of 3.78 g (17.1 mmol) of 84 with 2.86 g (18.8 mmol) of
diethylmalonate and 0.45 g (18.8 mmol) of NaH in 40 ml of DMF
under the usual conditions, gave 4.13 g (81% yield) of 85. Boiling
point 111-118 0C (0.1 mmHg); IR (neat) v max 3077, 2959, 2909,
1752, 1734, 1626, 1448, 1370, 1333, 1250, 1107, 1038, 895, 858,
839, 639 cm-1; 1H NMR (CDC13) 8 5.56 (ddd, J = 17.0 Hz, J = 10.3 Hz, J =
8.9 Hz, 1 H), 4.88 (dd, J = 10.3 Hz, J = 2.0 Hz, 1 H), 4.81 (ddd, J = 17.0
Hz, J = 2.0 Hz, J = 0.8 Hz, 1 H), 4.15 (m, 4 H), 3.28 (dd, J = 8.4 Hz, J =
7.0 Hz, 1 H), 2.02 (m, 1 H), 1.74 (m, 1 H), 1.43 (broad m, 3 H), 1.24 (t,
J = 7.1 Hz, 3 H), 1.23 (t, J = 7.2 Hz, 3 H), -0.06 (s, 9 H) ppm; 13C NMR
(CDC13) 8 169.56, 169.45, 139.21, 112.54, 61.22, 61.19, 51.82, 34.55,
28.52, 26.02, 14.09, 14.07, -3.94 ppm; M8 (El-70 eV) m/e (relative
intensity) 300 (<1), 285 (1), 246 (3), 245 (13), 233 (5), 217 (5), 209

87

(4), 181 (6), 173 (10), 171 (7), 167 (S), 140 (18), 137 (6), 136 (7),
129 (5), 127 (19), 119 (6), 117 (4), 115 (5), 109 (9), 108 (12), 81 (8),
80 (8), 79 (6), 75 (16), 74 (9), 73 (100), 67 (12), 59 (7), 55 (20), 54
(11). Anal. Calcd for C15H2304Si: C, 59.96; H, 9.39. Found: C, 59.94; H,
9.53.

Ethyl 5-(Trimethylsilyl)-6-heptenoate (86). Reaction of 4.02 g
(13.4 mmol) of 85 with 1.08 g (25.5 mmol) of LiCl and 0.24 ml (13.4
mmol) of water in 40 ml of DMSO under the usual conditions gave
2.52 g (83% yield) of 86. Boiling point 100-105 °C (8 mmHg); IR
(neat) v max 3077, 2957, 1734, 1626, 1373, 1248, 1177, 1099, 1034,
999, 895, 837, 750, 691, 638 cm'l; 1H NMR (CDC13) 8 5.56 (ddd, J =
17.0 Hz, J = 10.3 Hz, J = 9.2 Hz, 1 H), 4.86 (dd, J = 10.6 Hz, J = 2.0 Hz, 1
H), 4. 80 (ddd, J = 17.0 Hz, J = 2.0 Hz, J = 0.8 Hz, 1 H), 4.10 (q, J = 7.1
Hz, 2 H), 2.24 (m, 2 H), 1.30-1.80 (broad m, 5 H), 1.22 (t, J = 7.1 Hz, 3
H), -0.06 (s, 9 H) ppm; 13C NMR (CDC13) 8 173.76, 139.70, 112.19,
60.13, 34.59, 34.59, 34.11, 27.82, 24.71, 14.25, -3.37 ppm; MS (El-70
eV) m/e (relative intensity) 228 (<1), 183 (3), 174 (5), 173 (35), 129
(9), 117 (10), 103 (6), 101 (4), 93 (5), 82 (8), 81 (6), 79 (3), 75 (20),
74 (9), 73 (100), 68 (6), 67 (11), 59 (7), 58 (3), 55 (27), 54 (8). Anal.
Calcd for C12H2402Si: C, 63.10; H, 10.59. Found: C, 62.07; H, 10.38.

5-(Trimethylsilyl)-6-hepten-l-ol (87). Treatment of 2.41 g
(10.6 mmol) of 86 with 0.44 g (11.6 mmol) of LiAlH4 in suspension
in Et20 (20 ml) produced 1.87 g (95% yield) of 87. Boiling point 105-
107 °C (8 mmHg); IR (neat) v max 3333, 3077, 2934, 2859, 1626,
1412, 1248, 1055, 997, 895, 837, 748, 691, 638 cm-1; 1H NMR (CDC13)

1

88
8 5.57 (ddd, J = 17.0 Hz, J = 10.3 Hz, J = 9.2 Hz, 1 H), 4.85 (dd, J = 10.3
Hz, J = 2.0 Hz, 1 H), 4.79 (ddd, J = 17.0 Hz, J = 2.1 Hz, J = 0.8 Hz, 1 H),
3.60 (t, J = 6.4 Hz, 2 H), 1.15-1.70 (m, 8 H), -0.06 (s, 9 H) ppm; 13C
NMR (CDC13) 8 140.14, 111.91, 62.93, 34.89, 32.57, 28.18, 25.43, -3.34
ppm; MS (El-70 eV) m/e (relative intensity) 186 (<1), 171 (1), 143
(1), 129 (3), 96 (2), 95 (2), 91 (2), 81 (14), 77 (2), 76 (3), 75 (35), 74
(9), 73 (100), 68 (13), 67 (39), 66 (4), 59 (7), 55 (9), 54 (32), 53 (4).
Anal. Calcd for C10H2208i: C, 64.45; H, 11.90. Found: C, 64.18; H, 12.03.

7-Bromo-3-(trimethysilyl)-1-heptene (78). A solution of 1.75
g (9.4 mmol) of 87 in CH2C12 (75 ml) was treated with 1.06 ml (13.7
mmol) of freshly distilled methanesulfonyl chloride according to the
general procedure. The mesylate obtained was added to a solution of
2.55 g (24.8 mmol) of LiBr in 50 m1 of THF and 2.15 g (92% yield) of
a colorless oil were collected by distillation. Boiling point 94-95 0C (7
mmHg); IR (neat) v max 3077, 2959, 2857, 1626, 1458, 1439, 1412,
1248, 997, 897, 837, 750, 691, 638, 563 cm'l; 1H NMR (CDC13) 8 5.57
(ddd, J = 17.0 Hz, J = 10.3 Hz, J = 8.9 Hz, 1 H), 4.86 (dd, J = 10.3 Hz, J =
2.0 Hz, 1 H), 4.80 (ddd, J = 17.0 Hz, J = 2.0 Hz, J = 0.6 Hz, 1 H), 3.37 (t,
J = 7.0 Hz, 2 II), 1.65-1.95 (m, 2 H), 1.40-1.65 (m, 5 H), -0.05 (s, 9 H)
ppm; 13C NMR (CDC13)8 139.86, 112.12, 34.73, 33.79, 32.70, 27.92,
27.59, -3.33 ppm; MS (El-70 eV) m/e (relative intensity) 250 (<1),
248 (<1), 193 (1), 191 (1), 139 (10), 137 (10), 109 (2), 107 (1), 96
(2), 95 (5), 93 (2), 83 (2), 81 (16), 79 (3), 75 (5), 74 (13), 73 (100),
71 (2), 69 (2), 68 (12), 67 (58), 66 (8), 59 (9), 58 (5), 55 (12), 54
(32). Anal. Calcd for C10H21Br8i: C, 48.18; H, 8.49. Found: C, 48.06; H,
8.57.

89

Ethyl 6-(Trimethylsilyl)-7-octenoate (90). A solution of 4.43 g
(20.0 mmol) of 84 in 10 ml of Et20 was added in small portions over
a two-hour period to 1.94 g (80.0 mmol) of Mg in 20 ml of Et20 at 34
0C. The funnel was rinsed with 5 ml of Et20. After 4 hours of reaction
under reflux, the solution was transferred into a Schlenck tube,
cooled to -40 °C and treated with 1.09 ml (10.0 mmol) of
ethylacrylate over a three-hour period. During the addition, catalytic
amounts of CuCl were added (5 times). Stirring for 1 hour at -40 oC
and 15 min at 23 0C completed the reaction. 10% aqueous HCl
solution (40 ml) cooled to 0 °C was added and the two-phase solution
was extracted with Et20 (2 x 60 ml), washed with saturated aqueous
NaHC03 (40 ml), water (40 ml) and dried on Na2804. The solution was
concentrated and the oil was passed through a column of silica gel
(eluent n-pentane, followed by Et20). The fractions containing 90
(Et20) were combined and concentrated. Distillation under reduced
pressure gave 1.89 g (78% yield) of 90. Boiling point 110-113 0C
(7mmHg); IR (neat) v max 3077, 2959, 2859, 1734, 1626, 1373,
1250, 1177, 1034, 997, 895, 839, 750, 691, 638 cm'l; 1H NMR (CDC13)
8 5.56 (ddd, J = 17.0 Hz, J = 10.3 Hz, J = 9.2 Hz, 1 H), 4.84 (dd, J = 10.3
Hz, J = 2.0 Hz, 1 H), 4.76 (ddd, J =17.0 Hz, J = 2.1 Hz, J :10 Hz, 1 H),
4.09 (q, J = 7.2 Hz, 2 H), 2.25 (t, J = 7.6 Hz, 2 H), 1.4-1.7 (m, 6 H), 1.22
(t, J = 7.1 Hz, 4 H), -0.06 (s, 9 H) ppm; 13C NMR (CDC13) 8 173.85,
140.10, 111.90, 60.14, 34.72, 34.32, 28.83, 28.04, 24.82, 14.24, -3.32
ppm; MS (El-70 eV) m/e (relative intensity) 242 (8), 197 (14), 173
(53), 160 (7), 129 (9), 117 (20), 103 (6), 95 (8), 81 (7), 80 (16), 75

90

(16), 73 (100), 55 (15). Anal. Calcd for C13H26028i: C, 64.41; H, 10.81.
Found: C, 64.42; H, 10.87.

6-(Trimethylsilyl)-7-octen-l-ol (91). Treatment of 2.13 g (8.8
mmol) of 90 with 0.37 g (9.7 mmol) of LiAlH4 in suspension in Et20
(20 ml) produced 1.66 g (95% yield) of 87 . Boiling point 108-110 0C
(6 mmHg); IR (neat) v max 3337, 3077, 2932, 2857, 1626, 1458,
1412, 1248, 1057, 997, 895, 858, 837, 691, 638 cm'l; 1H NMR (CDC13)
8 5.57 (ddd, J = 17.0 Hz, J = 10.3 Hz, J = 9.2 Hz, 1 H), 4.84 (dd, J = 10.4
Hz, J = 2.1 Hz, 1 H), 4.78 (ddd, J =17.0 Hz, J = 2.0 Hz, J = 1.0 Hz, 1 H),
3.61 (t, J = 6.6 Hz, 2 H), 1.1-1.6 (m, 9 H), 1.64 (broad s exchanged by
D20, 1 H), -0.06 (s, 9 H) ppm; 13C NMR (CDC13) 8 140.30, 111.71, 62.76,
34.82, 32.58, 29.06, 28.31, 25.50, -3.34 ppm; MS (El-70 eV) m/e
(relative intensity) 200 (17), 185 (9), 157 (17), 129 (17), 110 (6),
109 (7), 95 (23), 91 (14), 82 (33), 81 (54), 75 (77), 74 (31), 73 (100),
69 (17), 68 (49), 67 (49), 59 (22), 55 (21), 54 (77). Anal. Calcd for
C11H24OSi: C, 65.93; H, 12.07. Found: C, 65.83; H, 11.66.

8-Bromo-3-(trimethylsilyl)-1-octene (79). A solution of 1.55 g
(7.7 mmol) of 91 in CH2C12 (40 ml) was treated with 0.67 ml (8.6
mmol) of freshly distilled methanesulfonyl chloride according to the
general procedure. The mesylate obtained was added to a solution of
1.59 g (15.4 mmol) of LiBr in 25 ml of THF, and 1.66 g (82% yield) of
a colorless oil were collected. Boiling point 105-108 0C (6 mmHg); IR
(neat) v max 3077, 2930, 2855, 1626, 1460, 1248, 997, 895, 837,
750, 691, 638, 563 cm'l; 1H NMR (CDC13) 8 5.57 (ddd, J = 17.0 Hz, J =
10.2 Hz, J = 9.4 Hz, 1 H), 4.84 (dd, J = 10.4 Hz, J = 2.1 Hz, 1 H), 4.78

91

(ddd, J = 17.0 Hz, J = 2.0 Hz, J = 0.8 Hz, 1 H), 3.38 (t, J = 6.8 Hz, 2 H),
1.83 (quintet, J = 6.7 Hz, 2 H), 1.1-1.5 (m, 7 H), -0.05 (s, 9 H) ppm; 13C
NMR (CDC13)8 140.17, 111.89, 34.84, 34.00, 32.79, 28.48, 28.22,
28.01, -3.31 ppm; MS (El-70 eV) m/e (relative intensity) 264 (M+2,
8), 262 (M, 8), 139 (31), 137 (31), 110 (5), 109 (5), 95 (18), 82 (40),
81 (54), 75 (12), 74 (26), 73 (100), 69 (9), 68 (25), 67 (28), 59 (16),
55 (15), 54 (59). Anal. Calcd for C11H23Br8i: C, 50.18; H, 8.80. Found:
C, 50.66; H, 9.20.

Bicyclo[3.2.l]octane. A solution of 1.39 g (12.8 mmol) of
bicyclo[3.2.l]octene in 7 ml of anhydrous methanol was treated with
0.14 g of 10% Pd on C, with stirring, under a positive pressure of H2.
After completion of the reaction monitored by GLC, the mixture was

filtered through Celite and purified by preparative GC (oven
temperature 100 0C). A white solid was obtained. 13C NMR (CDC13) 8

39.66, 35.16, 32.81, 28.86, 19.15 [lit7313C NMR (CDC13) 8 39.7, 35.2,
32.8, 28.9, 19.1 ppm].

Methylenecycloheptane. A suspension of 0.13 g (5.5 mmol) of
NaH in 10 ml of DMSO was stirred at 0 °C for 45 minutes. A solution
of 2.22 g (5.5 mmol) of methyltriphenylphosphonium iodide in warm
DMSO (5 ml) was added to the yellow sodium methylsulfinyl
carbanion solution, cooled to 0 0C, and was allowed to react at room
temperature for 15 minutes. Addition of 0.59 ml (5.0 mmol) of
cycloheptanone via syringe and reaction at 22 0C for 1.5 hour gave
the crude olefinated product. After usual workup the solution was

concentrated by distillation under atmospheric pressure and an

[I

92

analytical sample of methylenecycloheptane was obtained by
preparative G. C. (oven temperature 120 0C). IR (neat) v max 3071,
2980, 2934, 2853, 1638, 1447, 882 cm'1;1H NMR (CDC13)84.66
(quintet, J = 1.0 Hz, 2 H), 2.26 (m, 4 H), 1.45-1.60 (broad m, 8 H) ppm;
13C NMR (CDC13) 8 152.26, 110.27, 36.17, 29.48, 28.40 ppm; MS (EI-
70 eV) m/e (relative intensity) 110 (20), 96 (4), 95 (55), 91 (3), 83
(4), 82 (72), 81 (37), 79 (15), 77 (8), 69 (13), 68 (41), 67 (100), 66
(6), 65 (10), 63 (3), 56 (26), 55 (31), 54 (53), 53 (26), 52 (6), 51 (11),
50 (5).

General Procedure for the Preparation of the
Alkenyltitanocene Chloride Solutions. Synthesis of cis-5-
Hepten-l-yltitanocene Chloride (27). Addition of 0.356 g (2.0
mmol) of cis-l-bromo-S-heptene (20) in small portions, to 0.199 g
(8.0 mmol) of activated magnesium in 2 ml of THF, maintained at 65
0C was accomplished over a 1 hour period. After 5 hours of reaction,
the solution mixture was cooled to 23 0C and slowly transferred to a
stirred suspension of 0.598 g (2.4 mmol) of Cp2TiCl2 in 8 ml of CH2C12
at -45 oC. The red brick solution was stirred at -45 0C for 0.5 hour,
after what the cold bath was removed for reaction at ambient
temperature during 3.5 hours. The solution was concentrated in
vacuo to a volume of 1-2 ml, diluted in n-hexane (5 ml) and toluene
(8 m1) prior to filtration under argon. The solids were washed with
toluene (3 x 5 ml) and the combined fractions were concentrated in
vacuo until complete evaporation of THF, CH2C12, n-hexane and
toluene. The red brick paste obtained, was then diluted in toluene to

a 0.1 M solution of 27 . Compound 27 was produced in 61% from 20

93

by comparison of the GLC peak area of the quenched material with
that of an internal standard (n-octane; response factor 1.14). It was
stored under argon at -20 °C, although it was quite stable at ambient

temperature under an inert atmosphere.

General Procedure for the Cyclization of the
Alkenyltitanocene Chlorides. Cyclization of cis-S-Hepten-l-
yltitanocene Chloride (27). In a Sclenck tube cooled to -78 OC, 2
ml (0.2 mmol) of the 0.1 M solution of 27 in toluene were treated by
slow addition of 0.22 ml (0.4 mmol) of a 1.8 M solution of EtAlCl2 in
toluene. The initially red brick solution turned to dark green in
presence of EtAlCl2. Two hours of reaction at -78 oC and subsequent
protonolysis, by slow addition of a HCI solution in methanol at -78 oC,
afforded an orange reaction mixture, which was analyzed by GLC
without purification. Column A was used under the following
condition: oven temperature 100 °C. For identification of the product
mixture, a solution of authentic standards in toluene was injected
and gave the following retention times (minutes): cis-1,5-heptadiene
(17.8); cis-2-heptene (19.1); vinylcyclopentane (20.8);
methylcyclohexane (21.2); ethylcyclopentane (22.1); 3-
methylcyclohexene (22.7); toluene (25.0); l-methylcyclohexene
(26.4); ethylidenecyclopentane (27.2); n-octane (internal standard,
30.0). Thus, analysis of the crude solution revealed the following
mixture: cis-2-heptene (1%); ethylcyclopentane (98%);
methylcyclohexane (1%) in 79% yield from 27 (internal standard n-

octane).

94

Synthesis and Cyclization of trans-S-Hepten-1-yltitanocene
Chloride (30). A 0.1M solution of 30 in toluene was produced
according to the general procedure. Treatment of 2 ml (0.2 mmol) of
this solution with 0.22 ml (0.4 mmol) of EtAlCl2 in toluene at -78 0C
for 2 hours and at 23 0C for 2.5 hours, followed by protonolysis
(HCl/MeOH) produced ethylcyclopentane (98%) and
methylcyclohexane (2%). This distribution was obtained by GLC
analysis under the experimental conditions described above and by
comparison of retention times (minutes) with those of authentic
samples: trans-1,5-heptadiene (17.0); trans-Z-heptene (18.1);
vinylcyclopentane (20.8); methylcyclohexane (21.2);
ethylcyclopentane (22.1); 3-methylcyclohexene (22.7); toluene (25.0);
l-methylcyclohexene (26.4); ethylidenecyclopentane (27.2); n-octane
(internal standard, 30.0).

Synthesis and Cyclization of 5-Methyl-5-hexenyltitanocene
Chloride (31). A 0.1M solution of 31 in toluene was produced
according to the general procedure. Treatment of 2 ml (0.2 mmol) of
this solution with 0.22 ml (0.4 mmol) of EtAlCl2 in toluene at -78 0C
for 4 hours resulted in complete ring closure to 1,1-
dimethylcyclopentane and methylcyclohexane in a 99:1 ratio and in
93% yield from 31 determined by GLC analysis (internal standard n-
octane; response factor 1.14). Mixture analyses were run on column
A under the following conditions: oven temperature 70 0C; carrier gas
H2. Retention times (minutes) were compared with those of authentic
samples: 2-methyl-1,5-hexadiene (15.3); 1,1-dimethylcyclopentane
(15.7); 2-methyl-1-hexene (16.6); methylcyclohexane (21.9);

95

methylenecyclohexane (24.5); toluene (27.4); 1-methylcyclohexene

(29.5); n-octane (internal standard, 36.5).

Synthesis and Cyclization of 3-(2-Cyclopentenyl)prop-1-
yltitanocene Chloride (32). Four ml (0.4 mmol) of a 0.1 M
solution of 32 in toluene, produced according to the general
procedure were treated at -78 °C with 0.43 ml (0.4 mmol) of EtAlCl2
in toluene. A 97:3 ratio of cis-bicyclo[3.3.0]octane and 3-
propylcyclopentene was obtained after 1 hour of reaction at -78 0C
and protonolysis. cis-Bicyclo[3.3.0]octane was generated in 83% yield
(determined by GLC analysis) from 32 (internal standard n-octane;
response factor 1.00). Mixtures were analyzed by GLC on column A at
oven temperature 130 OC. Authentic samples had the following
retention times (minutes): toluene (12.3); n-octane (13.6); 3-
propylcyclopentene (15.3); cis-bicyclo[3.3.0]octane (19.8);
bicyclo[3.2.l]octane (20.6).

Synthesis and Cyclization of 3-(2-Methylenecyclopentyl)
prop-l-yltitanocene Chloride (33). Over a 80-minutes period,
0.401 g (1.97 mmol) of 42 was added in small portions to 0.193 g
(7.95 mmol) of Mg in 3 ml of THF maintained at 60 0C. After 4 hours
of reaction, the reaction was cooled to 23 oC and transferred to a
suspension of 0.599 g (2.4 mmol) of Cp2TiCl2 in 8 ml of CH2C12 at -50
oC, and allowed to react at 23 °C for 3.5 hours. Usual work up gave a
red brick paste which was diluted in 8 ml of toluene. 1.1 ml (1.98
mmol) of EtAlCl2 was added in small portions over a 70-minute

period to this solution at -78 0C. After one hour at -78 °C, 5% HCl in

96

MeOH (3 ml) was added slowly at -78 oC and the temperature was
raised to 23 oC. The crude mixture was extracted with n-pentane (5
ml) and filtered through a small pad of alumina. Analyzis by GLC on
column B (oven temperature 50 oC) revealed the presence of cis-1-
methylbicyclo[3.3.0]octane as the only product. Under the same
conditions, authentic standards gave the following retention times
(minutes): cis-1-methylbicyclo[3.3.0]octane (see below for isolation,
4.7); n-nonane (internal standard; response factor 1.00, 5.2); 1-
methylene-2-propylcyclopentane (5.6). An analytical sample of cis-
1-methylbicyclo[3.3.0]octane was obtained by preparative GC at oven
temperature 110 0C. A volatile and colorless liquid was collected. 1H
NMR (CDC13) 8 1.05 (s, 3 H), 1.1-1.9 (four m, 13 H) ppm [lit31a 1H NMR
(CDC13) 8 1.05 (s, 3 H), 1.27-1.81 (m, 13 H) ppm]; 13C NMR (CDC13) 8
25.91, 29.13, 34.48, 41.81, 49.71, 50.81 ppm [lit312l 13C NMR (CDC13) 8
25.94, 29.10, 34.50, 41.86, 49.74, 50.90 ppm]; MS (EI-70eV) m/e
(relative intensity) 124 (4), 109 (4), 95 (27), 81 (100), 67 (35), 55
(20), 53 (11), 41 (30).

Synthesis and Cyclization of 3-(2-Methylenecyclohexyl)
prop-l-yltitanocene Chloride (34). To 0.148 g (6.1 mmol) of Mg
in 2 m1 of THF maintained at 60 0C, was added 0.324 g (1.49 mmol)
of 46 over a one hour period. After 6 hours at 60 oC, transmetalation
with 0.448 g (1.18 mmol) of Cp2TiCl2 for 5.5 hours according to the
general procedure afforded a solution of 34 in toluene (15 m1).
Cyclization was induced by addition of 1.0 ml (1.8 mmol) of EtAlC12 at
-78 0C and was complete within 3 hours. After HCl/MeOH quench.

The crude mixture was analyzed by GLC with column B at oven

97

temperature of 60 °C. Authentic samples in toluene, eluted from the
column with the following retention times (minutes): n-decane
(internal standard; response factor 1.00, 7.3); l-methylene-2-
propylcyclohexane (7.4); cis-1-methylbicyclo[4.3.0]nonane (see below
for isolation, 8.3); trans-1-methylbicyclo[4.3.0]nonane (9.2); trans-
decalin (9.7); cis-decalin (12.8). An analytical sample of cis-1-
methylbicyclo[4.3.0]nonane was purified by preparative GLC at oven
temperature 130 °C. A colorless liquid was obtained. 1H NMR (CDC13)
8 0.93 (s, 3 H), 1.1-1.9 (m, 15 H) ppm [lit3121 1H NMR (CDC13) 8 0.93 (s,
3 H), 0.85-1.69 (m, 15 H) ppm]; 13C NMR (CDC13) 8 20.65, 22.43, 22.79,
26.73, 26.80, 28.97, 33.79, 38.19, 40.50, 44.98 ppm [lit31a 13C NMR
(CDC13) 8 20.69, 22.46, 22.82, 26.80, 29.03, 33.85, 38.24, 40.53, 45.04

[313111]-

Synthesis and Cyclization of 6-Hepten-l-yltitanocene
Chloride (2). The Grignard reagent of 50 was obtained by reaction
of 0.361 g (2.03 mmol) of 50 with 0.198 g (8.10 mmol) of Mg in 3 ml
of THF. Transmetalation on 0.61 g (2.44 mmol) of Cp2TiCl2 in 3 m1 of
CH2C12 and work up produced 2 in 74% yield from 50 by GLC
analysis (internal standard n-heptane; response factor 1.00). To 10
ml (0.2 mmol) of a 0.01 M solution of 2 in toluene was added 0.22 ml
(0.4 mmol) of EtAlCl2 for reaction at -78 0C during 1 hour, followed
by HCl/MeOH quench. GLC analyses were conducted at oven
temperature 100 0C on column A. Retention times (minutes) of the
various standards ordered as follow: 1,6-heptadiene (12.4); 1-
heptene (13.1); n-heptane (13.8); methylcyclohexane (16.3);
methylenecyclohexane (17.6); toluene (19.2); cycloheptane (23.7). A

1

98

96:1:3 distribution of methylcyclohexane, l-heptene and

methylenecyclohexane resulted.

Synthesis and Cyclization of 6-Methyl-6-hepten-l-
yltitanocene Chloride (60). 6-Methy1-6-hepten-1-ylmagnesium
bromide was obtained by reaction of 0.380 g (2.0 mmol) of 59 on
0.199 g (8.2 mmol) of Mg in THF (2 m1) and was added to 0.598 g
(2.4 mmol) of Cp2TiCl2 in CH2C12 (8 ml). After work up a 63% yield
(by GLC analysis and comparison with an internal standard n-
nonane; response factor 1.12) of 60 resulted. Product mixture
analyses were performed at oven temperature 100 0C with column
A. Authentic samples eluted from the column with the retention
times (minutes): toluene (17.7); 2-methyl-1-heptene (19.5); 1,1-
dimethylcyclohexane (20.8); methylcycloheptane (30.4); n-nonane
(36.5). All cyclizations were carried on 1-2 ml sample of 60 (0.1 M in
toluene). Then necessary, toluene was completely evaporated and
replaced by 1,2-dichloroethane. Thus addition of 14 01 (0.025 mmol,
1.8 M solution in n-hexane) of Me2AlCl to 2.5 ml (0.1 mmol) of 60 in
1,2-dichloroethane at -30 0C produced a dark green solution which
was quenched by slow addition of a 1 M HCl solution in Et20, after 15
minutes of reaction. GLC analysis gave a 18:82 ratio of 2-methyl-l-
heptene and 1,1-dimethylcyclohexane, which accounted for 72% of
the starting material. Ring closures induced by other Lewis acids in
other solvents were conducted in a similar way (see Table 5 in

Results and Discussion section).

99

Synthesis and Cyclization of 4-(2-Cyclopeutenyl)but-1-
yltitanocene Chloride (53). A 0.1 M solution of 67 in toluene
(82% yield from 66 by GLC analysis; internal standard n-nonane;
response factor 1.00) was generated by action of 0.411 g (2.02 mmol)
of 66 on 0.204 g (8.40 mmol) of Mg in 2 ml of THF, transmetalation
on 0.605 g (2.43 mmol) of Cp2TiC12 in 8 ml of CH2C12 and work up
according to the general procedure. GLC analyses were conducted on
column B under the following condition: oven temperature 50 0C. n-
Nonane, 3-butyl-1-cyclopentene, trans-bicyclo[4.3.0]nonane and cis-
bicyclo[4.3.0]nonane eluted from the column at 5.6, 6.1, 7.6 and 9.4
minutes respectively. Cyclizations were run according to the general

procedure.

Synthesis of 7-0cten-l-yltitanocene Chloride (74). Reaction
of 0.383 g (2.0 mmol) of 70 on 0.202 g (8.3 mmol) of Mg in THF (2
m1) at 60 0C for 6 hours and transmetalation on 0.598 g (2.4 mmol)
of Cp2TiCl2 afforded 74 in 80% yield (by GLC analysis, internal
standard n-octane; response factor 1.00). Cyclizations were carried on
a 0.1 M solution of 74 in toluene. For reaction mixture analyses,
authentic samples gave the following retention times (minutes): 1-
octene (12.3); n-octane (12.9); methylcycloheptane (17.7);
methylenecycloheptane (18.1); cyclooctane (23.2) for elution through

column A at oven temperature 130 oC.

Synthesis and Cyclization of 5-(Trimethylsilyl)-6-hepten-1-
yltitanocene Chloride (88). The Grignard reagent of 78 was
prepared by addition of 0.25 g (1.0 mmol) of 78 on 0.10 g (4.0

100

mmol) of Mg in THF (2 ml) at 44 oC, followed by reaction at 64 °C for
10 hours. Transmetalation on 0.29 g (1.2 mmol) of Cp2TiCl2 in CH2C12
(5 ml) for 4 hours afforded 88 in toluene (10 ml) after usual work
up. Analysis of the solution by GLC after HCI/Et20 quench, revealed
one single peak at 8.7 mn (column A, oven temperature 200 oC ).
This retention time was identical to the product obtained by quench
of the Grignard reagent. To a Schlenck tube cooled to -78 0C and
containing 2 ml (0.2 mmol) of 88 in toluene, was added 0.22 ml (0.4
mmol) of EtAlCl2, for reaction at -78 0C for 1 hour. The solution was
quenched with HCI/Et20 at -78 oC. GLC analysis showed one single

peak at 11.5 mn under the same operating conditions.

General Procedure for the nBu3SnH Free Radical Cyclization
of Disubstituted Bromo Alkenes. Cyclization of cis-l-Bromo-
5-heptene (20). A solution of 0.177 g (1.0 mmol) of 20, 0.33 ml
(1.2 mmol) of nBu3SnH and 0.01 g of AIBN in benzene (20 ml) was
introduced into a 100-ml glass tube. Under external cooling with
liquid nitrogen, the tube was degassed by applying high vacuum, and
closed. The solution was stirred at 70 °C for 14 hours, cooled to
ambient temperature and analyzed by GLC. Experimental conditions
identical to those utilized for the titanium based methodology, gave a
12:87:1 distribution of cis-Z-heptene, ethylcyclopentane and

methylcyclohexane.

Free Radical Cyclization of trans-l-Bromo-S-heptene (21). A
solution of 0.177 g (1.0 mmol) of 21, 0.33 ml (1.2 mmol) of nBu3SnH
and 0.01 g of AIBN in 20 ml of benzene was submitted to the

101

mentioned above reaction conditions for 14 hours. GLC analysis of
the crude mixture gave a 9:89:2 distribution of trans-Z-heptene,

ethylcyclopentane and methylcyclohexane.

Free Radical Cyclization of 3-(3-Bromopropyl)cyclopantene
(39). A solution of 0.04 g (0.2 mmol) of 39, 0.07 ml (0.24 mmol) of
nBu3SnH and 0.01 g of AIBN in benzene (20 ml) was submitted to the
usual reaction conditions for 6 hours. GLC analysis of the crude
mixture gave a 3:97 ratio of 3-propylcyclopentene and cis-

bicyclo[3.3.0]octane.

Free Radical Cyclization of 1-(3-Bromopropyl)-2-methylene
cyclopentane (42). A solution of 0.03 g (0.15 mmol) of 42, 0.05 ml
(0.18 mmol) of nBu38nH and 0.01 g of AIBN in 15 ml of benzene was
submitted to the usual reaction conditions for 5 hours. GLC analysis
of the crude mixture gave the following product distribution: 1-
methylene-3-propylcyclopentane (11%), cis-1-methylbicyclo[3.3.0]
octane (15%), cis-bicyclo[4.3.0]nonane (50%) and trans-
bicyclo[4.3.0]nonane (24%).

Free Radical Cyclization of l-(3-Bromopropyl)-2-methylene
cyclohexane (46). A solution of 0.043 g (0.20 mmol) of 46, 0.07 ml
(0.18 mmol) of nBu3SnH and 0.01 g of AIBN in 20 ml of benzene was
heated to 70 0C for 12 hours according to the general procedure. GLC
analysis conducted on column B at 60 0C gave the following results.
1-methylene-2-propylcyclohexane (47%), cis-1-methylbicyclo[4.3.0]

nonane (17%), trans-decalin (31%), and cis-decalin (5%) eluted from

102

the column at 7.5, 8.5, 9.9 and 13.1 minutes respectively [lit20 1-
methylene-2-propylcyclohexane (56%); cis-1-methylbicyclo[4.3.0]

nonane (15%), trans-decalin (25%), and cis-decalin (4%)].

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29.

30.

31.

32.

33.
34.
35.
36.

37

38.

39.
40.
41.

42.

43.

106

(a) Bailey, W. F.; Patricia, J. J.; DelGobbo, V. C.; Jarret, R. M.;
Okarma, P. J. J. Org. Chem. 1985,50, 1999. (b) Bailey, W. F.;
Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.

Bailey, W. F.; Patricia, J. J.; Nurmi, T. T. Tetrahedron Lett. 1986,
27, 1865.

(a) Bailey, W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am. Chem.
Soc. 1987, 109, 2442. (b) Bailey, W. F.; Khanolkar, A. D. J. Org.
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Beckwith, A. L. J.; Phillipou, G.; Serelis, A. K. Tetrahedron Lett.
1981,22, 2811.

Bailey, W. F.; Khanolkar, A. D. Tetrahedron Lett. 1990, 31, 5993.
Hata, G.; Miyake, A. J. Org. Chem. 1963,28, 3237.
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Lamb, R. C.; Ayers, P. W.; Toney, M. K.; Garst, J. F. J. Am. Chem.
Soc. 1966, 88, 4261.

Utimoto, K.; Imi, K.; Shiragami, H.; Fujikura, 8.; Nozarki, H.
Tetrahedron Lett. 1985,26, 2101.

(a) Abelman, M. M.; Overman, L. E. J. Am. Chem. Soc. 1988, 110,
2328. (b) O'Connor, 8.; Zhang, Y.; Negishi, E.; Luo, F. -T.; Cheng, J. -
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Rigollier, P.; Young, J. R.; Fowley, L. A.; Stille, J. R. J. Am. Chem.
Soc. 1990, 112, 7709.

Ligand cyclization during Grignard formation and hydrolysis, to
an extend of 2 to 5%, has been well documented by Ashby, E. C.;
Oswald, J. J. Org. Chem. 1988,53, 6068, and references therein.

A full procedure is described for the EtAlCl2-induced cyclization .
of disubstituted alkenyltitanocene chlorides in the Experimental
section.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.
55.

56.

107

(a) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
42, 3772. (b) Vesato, 8.; Kobayashi, K.; Inouye, H. Chem. Pharm.
Bull. 1982, 30, 927.

Semmelhack, M. F.; Bozell, J. J.; Keller, L.; Sato, T.; Spiess, E. J.;
Wulff, W.; Zask, A. Tetrahedron 1985, 41, 5803.

Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem. Commun. 1973,
553.

Rossi, R.; Carpita, A. Synthesis 1977, 561. (b) Ohloff, G.; Vial, C.;
Niif, F.; Pawlak, M. Helv. Chim. Acta 1977, 60, 1161.

(a) Kocienski, P. J.; Ostrow, R. W. J. Org. Chem. 1976, 41, 398. (b)
Doolitle, R. B.; Proveaux, A. T.; Heath, R. R. J. Chem. Ecol. 1980, 6,
271.

(a) Trippett, S. J. Chem. Soc. 1962, 2337. (b) Bose, A. K.; Lal, B.
Tetrahedron Lett. 1973, 3957.

(a) Sato, F.; Sato, 8.; Kodama, H.; Sato, M. J. Organomet. Chem.
1977, 142, 71. (b) Sato, F.; Haga, 8.; Sato, M. Chem. Letters 1978,
999.

(a) Can, D. B.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 638. (b)
Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1979, 101, 3521. (c)
Miller, J. A.; Negishi, E. Isr. J. Chem. 1984, 24, 76.

Julia, M.; Descoins, C.; Baillarge, M.; Jacquet, B. Tetrahedron,
1975,31, 1737.

(a) Trost, B. M. Chem. Soc. Rev. 1982, II, 141. (b) Paquette, L. A.
Polyquinane Chemistry, Syntheses and Reactions in Reactivity
and Structure concepts in Organic Chemistry; Hafner, K.; Rees, C.
W.; Trost, B. M.; Lehn, J. M.; von Ragué Schleyer, P.; Zahradnik, R.,
Editors; Springer-Verlag, Berlin, Volume 26, 1987.

Carr, 8. A.; Weber, W. P. J. Org. Chem. 1985, 50, 2782.

Kiso, Y.; Yamamoto, K.; Tamao, K.; Kumada, M. J. Am. Chem. Soc.
1972, 94, 4373.

Siege], 8.; Smith, G. V. J. Am. Chem. Soc. 1960, 82, 6087.

57.

58.
59.
60.

61.

62.

63.

64.

65.

66.

67.

68.

108

Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell,
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Gream, G. B.; Serelis, A. K. Aust. J. Chem. 1974, 27, 629.
Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, 35 , 3195.

Lissa Fowley is acknowledged for the synthesis of 46.
Spectroscopic data for 46 are given in the Experimental section,
and are in agreement with those reported: Gream, G. B.; Serelis,
A. K. Aust. J. Chem. 1974, 27, 629.

(a) Ewen, J. A. J. Am. Chem. Soc. 1984, 106, 6355. (b) Kaminsky,
W.; Kiilper, K.; Brintzinger, H. -H.; Wild, F. R. W. P. Angew. Chem.
Int. Ed. Engl. 1985, 24, 507. (c) Gassman, P. G.; Callstrom, M. R. J.
Am. Chem. Soc. 1987, 109, 7875. (d) R811, W.; Brintzinger, H. -H.;
Rieger, B.; Zolk, R. Angew. Chem. Int. Ed. Engl. 1990, 29, 279.

Methylalumoxane (CH3AlO)n, n = 20.2, was prepared by action of
hydrated aluminum sulfate on trimethylaluminum in toluene
according to U. 8. Patent 4,544,762 Oct. 1, 1985.

Eisch, J. J.; Baleslawski, M. P.; Piotrowski, A. M. in: Transition
Metal Catalyzed Polymerizations. Ziegler-Natta and Metathesis
Polymerizations; Quirk, R. P. Editor; Cambridge University Press,
Cambridge, 1988, 210.

(a) Hudlicky, T.; Ranu, B. C. J. Org. Chem. 1985,50, 123. (b)
Pappas, J. J.; Keaveney, W. P. Tetrahedron Lett. 1966, 4273.

(a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 866.
(b) Greenwald, R.; Chaykovsky, M.; Corey, E. J. J. Org. Chem. 1963,
28, 1128.

Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J. M. Synthesis 1978,
63.

Olefinic signals (8 = 135.7 and 130.2 ppm) of identical intensity
appeared at chemical shifts similar to those of the bromoalkene
66 (8 = 134.9 and 130.4 ppm). Thus, the double bond did not

isomerize to produce a more substituted olefin at any stage of
the synthesis.

Lambert, J. B. Tetrahedron 1990, 46, 2677.

69.

70.
71.
72.
73.
74.

75.
76.

77.
78.
79.

109

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

Guram, A. 8.; Jordan, R. F. Organometallics 1990, 9, 2190.
ku, J. R.; Furth, P. S. J. Am. Chem. Soc. 1989, III, 8834.
Denmark, 8. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595.
Wilson, 8. R.; Zucker, P. A. J. Org. Chem. 1988, 53, 4682.

Six-membered ring formation by intramolecular carbometalation
of a Grignard reagent has been reported by Fujikura, 8.; Inoue,
M.; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984,25, 1999.
However, an internal acetylene activated by a trimethylsilyl
group was necessary for the cyclization to occur.

Liu, S. -H. J. Org. Chem. 1977, 42, 3209.

Chang, S.; McNally, D.; Shary-Tehrany, S.; Hickey, M. J.; Boyd, R. H.
J. Am. Chem. Soc. 1970, 92, 3109.

Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
Stothers, J. B.; Tan, C. T. Can. J. Chem. 1977,55, 841.

Carbon monoxide insertion into carbon-titanium bonds has been
reported: Fachinetti, G.; Floriani, C. J. Chem. Soc., Chem. Commun.
1972, 654. For formation of a carbon-halogen bond, see
reference 41. For formation of a carbon-phosphorus bond, see:
Doxsee, K. M.; Shen, G. S. J. Am. Chem. Soc. 1989, III, 9129.

APPENDIX

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