RADIOLABELLING OF ORGANIC MOLECULES WITH

SHORT-LIVED RADIONUCLIDES (“C, F)18

Julius Alexander Balatoni

B.Sc., The University of British Columbia, 1981

M.Sc., The University of British Columbia, 1985

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF

THE REQUIREMENTS FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

in

THE FACULTY OF GRADUATE STUDIES

DEPARTMENT OF CHEMISTRY

We accept this thesis as conforming

to the required standard

THE UNIVERSITY OF BRITISH COLUMBIA

August 1994

© Julius Alexander Balatoni, 1994

Date:

Vancouver,

2036 The

Department

his

financial

In

of

available at

this

presenting

the

or

University

Main

her

thesis

University

gain

for

representatives.

b.

Mall

Canada

of

for

reference

this

shall

Chemistry

of

scholarly

thesis

30)

British

of

not

British

and

jq

be

in

Columbia

purposes

partial

allowed

It

study.

Columbia,

is

understood

fulfillment

I

without

may

further

be

I

agree

granted

that

my

agree

of

the

written

copying

that

that

requirements

by

the

the

permission

permission.

or

head

Library

publication

of

for

for

my

shall

an

extensive

department

advanced

of

make

this

thesis

it

copying

degree

freely

or

for by

in

vinyl-tin

proceeded

was

to

fluorine

separate

liberated

reaction

elevated

cyanide. systems.

incorporation

to

electrophilic

of

lived The

The

A

organometallic

19%

yield

facilitate

found

primary

range

radionudides

reactivity

radiochemical

and

bonds.

temperature.

oxidative

of

an

Fluorine

Non-radioactive

from

in

to

of

complexes

acetyl

isomeric

9.0%

aim

fluorination

simple

be

aromatic

of

For

the

of

the

of

intermediates:

[ 11 Cjcyanide

yield

was

hypofluorite

decomplexation

(E)-vinylstannanes

( 11 C,

this

example,

chromium

(, 6 -arene)tricarbonylchroniium

most

yield

mixture

found

Under

1,

at

study

18 F)

nucleophilic

reactions

4,

best.

and

effective

(based

5,

into

to

31

was

the

11 C-labelled anion,

under

and

of

Subsequently,

tricarbonyl

be

(i)

was

organic

to

reaction

39

the

step. (i 1 6 -arene)tricarbonylchromium

on

to

fluorinating

6

develop

fluorinated

varied

and

with

produce

30,

and

starting

substitution

only

Abstract

molecules.

31,

11

(ii)

aryl

conditions

40

[ 12 Cjcyanide

moiety

leaving

conditions.

new

32,

31

vinyl-tin

[ 18 F]F 2 ).

in

F-

nitriles

with agent

was

33,

methods

41-42%

and

group

thereby

complexes

of

and

radiofluorinated

CH 3 COOF,

This

used,

for

were

derivatives

18 F-labelled

the

and

Generally,

34

that

the

was

for

yield;

was

the

prepared

obviating

[ 11 C]cyanide

attached

the

electrophilic

was

accomplished

were

aryl

studied

at

introduction

fluorination

complexes

readily

were

gaseous

room

vinyl

nitrile

prepared

with

in

the

arene

with

10

employed

fluorides.

temperature,

in

CH 3 COO’ 8 F

displaced

product

need

cleavage

CH 3 COOF

minutes

DMSO

by

elemental

were

as

of

with

for

the

model

short-

for

used

was

use

the

for

F 2 by by

of

at a Me Me CI

I I 3Cr(CO) 3Cr(CO) 3Cr(CO) 3Cr(CO) 4 5 6

3Sn(Bu) HO 20R O/0 —Sn(Bu) // \c) 3 O 33 R’ Sn(Bu) O 30 =HR’=R 3 31 2 =HRMe,R OH 32 2MeR’R oO 0 \\ 34

HO HO

MeO MeO 39 40

iii Table of Contents

Abstract ii

List of Tables vii

List of Figures ix

Acknowledgements x

Dedication xi Chapter

1 GENERAL INThODUCTION 1

1.1 Background 1

1.2 Aspects of Labelling with Short-lived Isotopes 3

1.3 Objectives and Format of this Thesis 9

References 13

2 APPLICATION OF ORGANOCHROMIUM CHEMISTRY TO RADIOLABELLING 16

2.1 Introduction 16

2.2 Preparation of -Arene)tricarbonylchromium Complexes 21

2.2.1 Synthesis 21 2.2.2 Characterization76 30 2.3 Reactions of Organochromium( Compounds with Cyanide 33 2.4 Labelling Studies with 11C-Labelled Cyanide 53 2.5 Summary and Conclusions 65

References 68

iv

Chapter

4

5

3

5.4

5.3 EXPERIMENTAL

5.1

5.2 References

References

3.3

GENERAL 3.4 3.1

3.5 3.2

LABELLING

DEVELOPMENT

Experimental

5.4.1

5.3.5 Experimental

NMR

5.3.4 5.3.3

5.3.2 5.3.1

General Radiofluorination Labelling

Introduction

Summary

Synthesis

Labelling

Sources

Preparation

Substitution

General Sources

Complexes Complexes

Methods

CONCLUSIONS

Methods

of

and

Studies

Vinyl-Tin

for

for

OF

of

Conclusions

of

and

Work

Materials

Materials

Chapter

Chapter

with

METHODS

Work

of

Reactions

Instrumentation

(t 6 -Arene)tricarbonylchromium

with

Precursors

Non-Radioactive

3

2

[ 11 C]Cyanide

V

of

FOR

Organochromium

RAPID

Fluorine

FLUORINE

139

125

135

139 118

116 112

116 115 108

116 104

112

111

101

96

71

85

80 71 Chapter References 5.4.2 5.4.4 5.4.5 5.4.3 Fluorination Radiofluorinations Preparation General of Reactions Vinyl-Tin with vi of Acetyl Substrates Vinyl-Tin [‘ 8 F]Hypofluorite Compounds 156 153 142 148 140 List of Tables

Table

CHAPTER 1

1.1 Characteristics of Radionuclides Used for PET 4

1.2 Physical Properties of Some Radionucides 7

1.3 Positron Emitting Radiopharmaceuticals Used Commonly in PET Imaging Procedures 9

CHAPTER 2

2.1 Summary of Yields Obtained for Complexes Synthesized using Equation 2.9 26

2.2 Summary of Melting Points of Organochromium Complexes 31

2.3 Chemical Yields Obtained for Complex 1 39

2.4 Chemical Yields Obtained for Complex 4 41

2.5 Chemical Yields Obtained for Complex 5 42

2.6 Chemical Yields Obtained for Complex 6 43

2.7 Chemical Yields Obtained for Complex 4 using 18-Crown-6 47

2.8 Chemical Yields Obtained for Equation 2.18 using Acetonitrile as the Solvent 48

2.9 Summary of Chemical Yields 51

2.10 Summary of Radiochemical Yields Obtained for Equation 2.22 55

2.11 Summary of Radiochemical Yields Obtained for

Equation 2.23 . 59

vi’

Table

3.3 3.2

3.4 3.1

with

with

Yields

Summary

of Summary Summary CHAPTER

31

Fluorine

Acetyl

with

of

(E)-Vinylstannanes

of of

of

Acetyl

3

Hypofluorite

Radiochemical

Yields Yields

[ 18 F]Hypofluorite

Obtained Obtained

Yields

for for

.

viii

the

the

Obtained

Reaction

Reaction

for

of of

the

31 31

Reaction

100

89

87 83 List of Figures

Figure

CHAPtER 2

2.1 Changes in arene reactivity when complexed to chromium tricarbonyl 17

2.2 Examples of carbanions which react with -ha1obenzene)tricarbonyl- chromium complexes 18 2.3 Examples of carbanions which react with -benzene)tricarbonyl-(i chromium 6 19 2.4 Principal fragmentation pattern of -arene)tricarbonyl-6 chromium compounds ( 32 2.5 HPLC chromatogram obtained from6 the analysis of the reaction of complex 1 with cyanide at 135°C ( 40 2.6 Radio-HPLC chromatogram obtained from the analysis of the reaction of complex 1 with 11C]cyanide (with 0.37 equiv of carrier KCN added) at 150°C [ 57 2.7 Radio-HPLC chromatogram obtained from the analysis of the reaction of complex 1 with 11Cjcyanide (with no carrier KCN added) at 150°C [ 58 2.8 Radio-HPLC chromatograms of [‘C]cyanide in DMSO 61 CHAPTER 5 t 5.1 Schematic of the fluorine gas handling system used to perform the fluorination reactions 141

x

patience,

thesis

maintenance

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discussions

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invaluable

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( 11 C,

support,

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my

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appreciate

and

helpful

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my

especially

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at

supervisors,

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acknowledge

friends,

NMR,

18 F)

helpful

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including

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thanks

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assistance

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Martin

NMR

advice

Dr.

completed.

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discussions.

the

thank

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to

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service

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work. all

contribution

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their

preparation

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supervisors,

Acknowledgements

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literature particular,

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am

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extend

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and

of

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by

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the of

very

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friends,

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experimental

meetings.

thankful

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this

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in

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thesis.

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his

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for

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times

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grateful

pleasure

family proofreading

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services.

students,

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in

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technical

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production

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their

their

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it

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invaluable

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thesis.

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radio

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work,

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for of Dedication

To my risen Lord

xi

Positron

compounds

volume,

disease, such

protein

tissue

functional

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biochemical

example, radiopharmaceuticals,

impact

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The

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as

pH.

parameters

cancer,

synthesis, on

and

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blood

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it

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Tomography physiological

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quantitative

shown

in

humans

research.’

heart

short-lived

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intended

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of

function

states

glucose-metabolic

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in

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Chapter

stroke,

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INTRODUCTION

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pathology

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viewpoint,

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the

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the

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chemist

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acute

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The

important

significantly, these

lives*, 16

lives

discussed The

*

total

A

are

same

when

most

radionucide and

a13+

SOURcE:

Radionuclide

of

listed

in

properties

synthesis

=positron

properties

using

emit important

the

the

protecting

into

Table

150

‘ 3 N

11 C

‘ 8 F

half-life

in

above

Reference

high

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nudides

the

Table

time,

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1.1:

should

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also

usually

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energy,

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Characteristics

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groups,

beginning

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make

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be

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Half-life

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(mm)

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equivalent 9.96

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to

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manipulative

4

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Radionuclides

%

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99.9 99.8

96.9

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100

radiation.

Decaya

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the

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than

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half-life

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B,

Daughter

minutes.

radionuclide

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the

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distance accelerator

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the

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the

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cyclotron. 21

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the

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of

reactions

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5

facilities.

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site,

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needed

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3.70

specific

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is

product.

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section

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approximately

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generally

x

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the

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for

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1010

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chemical

best

radionuclide

(CF)

that

increases

form

closely

area

same

is

order

the

Bq

is

The

specifying

the

approach,

expressed

the

no

on

state.

(disintegrations

of nuclear

of

issue

element

it

of

no

related.

manipulations

its

form

chemical

study

carrier

the

is

1:3000?

magnitude the

half-life

carrier-added

reported

of

For

6

radioisotope

is

required

is

reaction

whenever

in

synthesis

the specific

(i.e.,

of

inappropriate referred

some

curies,

Specific

composition

the

(see

extent

In

carrier)

that

per

so

radioisotopes,

activity,

for are

used,

same

light

per

time

possible,

Table

that

to

activity

(NCA)

second);

in

is

the

required

mole

as

the

of

is

determined

of

target

some

and

element

target of

radiolabelling

stoichiometry,

for

1.2),

present;

production

this

dilution

is

the

of

state, is

adds

defined

a

carrier

to

compound.

the

and

design,

chemistry.

to

target

problem,

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given

directly

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obtain

maximum

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compound

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only

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the

number

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quantity

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energy

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to

in

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cals

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14 C. 26

or

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to

physiological

Reference

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NCA

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linear

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small

0.1

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Table

which

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109.7

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207

9.96

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12.35

5730

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below

preparation.’ 7

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of

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mg

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present amount

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in

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in

spite

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emitting

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in

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product.

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significance? 4

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the

small

is

radiopharmaceuticals

be

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in

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formation

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various

synthesis,

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comparable

the

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amounts

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solvents,

impurities

by

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can

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difficulties

of

work

much

of

scale,

result

several

of

the

be

the

be

to,

reagent

to

is

and

high

even

results

well.

achieved.’ 7

carrier,

or

reagents,

the

a

progress

desired

great

unwanted

commonly

may

very

orders

have reaction

specific

even

highly

amount

and

8

may

and

care

However,

compete

serious

this

been

exceed,

radiolabelled

has

of

substrate

and

be

challenges

toxic

must

activity

scale.

side-products,

used

will

of

magnitude,

observed.

developed

actually

substrates. 28

impurities

problem

molecules

with

be

lower

the

when

radiopharmaceuticals

radionuclides

are

When

taken

quantity

the

involved

been

product. 27

the

used

Since

the

as

radiolabelling

when

and

present

to

can

a

specific

or

during

concentration

in

made.

exclude labelling

NCA

are

of

be

even

approximately

very

in

the

usually

used

currently

in

a

radiosyntheses

If

activity

the

high

A

to

high

radionuclide

the

carrier

one

reaction

for

reagent

variety

complete

for

reagents

area

leads

specific

specific

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of

of

of

being

from

PET

one

the

the

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of

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in

to is

With

1.3 are

summarized

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continuing

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[ 13 Nlammonia

[ 15 0]water

[ 15 ojcarbon

[1501 [ 11 C]-N-methylspiperone

[ 11 C]glucose [ 11 C]acetate

[ 11 C]-1-butanol

[ 11 C]methionine

[ 11 Cjpalmitate [‘ 1 C]carbon

[ 18 F]-

[ 18 F]-N-methylspiperone

[ 18 F]spiperone [ 18 F]fluorodeoxyglucose

[ 18 F]fluorodopa

Table

Radiopharmaceutical

oxygen

and

16a-fluoro-17fl-estradiol

in

Table

1.3:

Format

development

References

monoxide dioxide

Positron

Commonly

1.3.

of

this

Emitting

7,8,10,29.

of

Thesis

in

PET,

PET

Radiopharmaceuticals

new

9

Myocarclial

Myocardial

Myocardial

Cerebral Cerebral Dopamine

and

Cerebral

Cerebral

Amino

Myocardial

Estrogen

Myocardial Tissue

Cerebral Dopamine

Dopamine

Dopa

Myocardial

Cerebral

Imaging

and metabolism

uptake

pH

acid

innovative

blood

blood

Procedures

glucose blood

oxygen

glucose

receptor

Application

receptor

receptor

receptor

blood

blood

blood

metabolism

metabolism

glucose

metabolism

studies

volume

flow

flow

extraction

metabolism

metabolism

volume

flow

flow

binding

synthetic

metabolism

binding

binding

binding

Used methodologies

extending tin

regioselective

derivatives reaction

form,

in

organometallic

a

electrophilic successfully

of

radiolabelling.

rapidly

incorporation

are

The

(B, 3 °

compounds.

are

partial

Previous

which

Increasingly,

these

reagents

radiolabelled

needed

primary

can

Si, 31 ’ 32

label

reactions

times. the

negative

the

in

with

studies

used

to

was

metal

organic

turn

utility

attack.

manner.

of

objective

Ge, 33

produce

precursors

the

Generally,

radioactive

Therefore,

found

for

positron

is

on

possesses

charge;

in

be

use

the

the

of

the

this

molecules.

Sn, 34 ’ 35

used

to

vinyl-tin

exploitation

the

of

preparation

This

aromatic

of

be

laboratory

emitting

can

their

organometa.llic

as

required

bromine radionuclides

this

for

a

very

potentially

a

partial

Hg, 36

is

prime

reagents

the

result,

study

successful.

important

ring.

The

radionucides—specffically

of

of

radiolabelling

radiopharmaceuticals

( 82 Br)

focussed

positive

TI, 37 )

the

application

radiolabelled

organic

was

an

Boron 3 °

be

to

that

reactivity

10

intermediates

and

organometallic

performed

radiofluorinations

the

have

because

This

charge

on

can

iodine

derivatives

and

exploration

the

has

be

experience

of

of

been

alkyl

silicon 32

and

development

prepared

the

(1231

been

organometallic

under

the

are

the

halides.

polarized

and

for

of

compound

studied

to

electrophilic

derivatives

providing

attached

of

mild

some

11 C

prompted

future

with prepare

1311).38

in

new

and

The

electrophilic

conditions

of

carbon-metal

18 F.

main

and

PET

labelling

methods

The

‘ 8 F—into

carbon

is

precursors,

common

compounds

new

have

our

susceptible

group

utilized

cleavage

applications.

use

avenues

interest

with

also

possesses

vinyl-tin

of

reagent

organic

for

feature

metals

vinyl-

bond,

short

been

in

that

the

for

in

to

of

to a

is

radiolabelling

this

of

chemistry.

some

of arene)tricarbonylchromium withdrawing

chromium

decided which

moieties molecules

of

cyclobutadiene,

interactions for

of

applicable

Chapter

The

The

the

‘ 1 C,

reactivity

reactivity

this

study

introductory

prepared

in

format

organic

the

is

to

the

can

will

the

3

when

complexes

Then,

explore

metal

is

to

could

as

with

the

form

presence

devoted studies

be of

be

vinyl-tin

compared

derivatives

chromium

or

metal

coordinated

this

the

described.

organic

of have

attacked

is

beuzene.

the

background

[“C]cyanide,

thesis

preparation

with

as

bonded

to

centre,

compounds

labelling

of

significant

synthetic

the

to

partly

ligands. 4 °

of

“C-labelled

tricarbonyl

is

compounds

by

those

development

This

transition

to

as

The

the

to

a

transition filled

information

follows.

of

of

wide

onto more

intermediates.

potential

will of

unsaturated

normal

with

aromatic

( 6 -arene)tricarbonylchromium

Transition

the

d

complexes

be

aromatic

cyanide

both

metals,

as

facile

or

range

main

Chapter

of

followed

11

synthetic

f

metals

pattern

for

orbitals.

electrophilic

non-radioactive

rings

is

is

group

of

the

will

however,

presented

organic metals

the

rings.

with

is

2

nucleophiles.

with

of

application

by

intermediates

be

nucleophific

is

changed,

metals. 39

This

reactivity

devoted

non-radioactive

an

presented.

At

are

‘ 1 C

molecules

fluorination exhibit

examination

the

leads

regarding

using

able

fluorine

beginning

whereby

The

of

to

of

to

very

addition. 4 ’

to

(i 1 6 -arene)tricarbonyl-

radiolabelling.

the

for

The

unsaturated

a

fundamental

complexes

form

such

variety

and

methodology

the

evaluation

different

organo

cyanide.

of

the

more

of

radiofluorine.

incorporation

the

complexes

as

the

unsaturated

This

of

chromium

reactivity

ethylene,

electron-

used

chapter,

bonding

patterns

organic

Lastly,

reason

of

It

mode

that

was

for in

The

descriptions with

fluorination

Chapters

This

employed The

In

In

chapter

Chapter

general

will

elemental

Chapter

2

be

for

and

with

for

begins

5,

followed

methods this

4,

the

3

Chapters

fluorine

8 F

will

the

present

experimental

with

of

be

general

by

a

are

an

presented,

and

2 selected

a

study.

and

introduction

presentation

described

acetyl

conclusions

3,

details

Next,

vinyl-tin

respectively.

along

hypofluorite

are

first,

fluorination

to

12

of

with

derivative

given

selective

developed

the

followed

suggestions

for

synthesis

will

the

studies

fluorination

will

from

be

by

work

be

described.

for

of

the

of

presented.

the

performed

the

future

the

specific

of

studies

vinyl-tin

vinyl-tin

organic

work.

Finally,

for

experimental

described

derivatives

molecules.

precursors

this

thesis.

radio- in

12. 9.

11. 8. 7.

10.

6. 5.

4.

3.

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S.

0.

Chapman

J.;

S.;

Toronto,

E.;

S.;

P.;

A.

RadioanaL

L.;

S.;

W.

Pike,

M.;

1982,

S.;

1982,

1984,

Ruth,

Anderson,

Organotransition

Svitra,

Green,

Hegedus,

M.Sc.

Basmadjiam,

Acc.

Garcia,

Seevers,

Coenen,

J.;

V.

19,

19, 21,

T.

1982;

and

Thesis,

Chem.

Science

Zhong-Yum,

Z.

W.,

for

M.

1089-1096.

J.; 767-779.

1171-1188.

Chem.

K.

V.

L.

S.

Hall:

R.

L. Eds.;

Pate, Positron

H.

Chapter

W.;

S.

J.

Res.

R.;

H.;

H.;

The

G.

Books:

Principles

H. Labelled

Metal

London,

1981,

Stone,

Kiuwer

B.

P.;

Friedman,

Powell, Adam,

J.

1984,

University

D.;

Emission

P.;

Labelled

4.

Marchand,

65,

15

Chemistiy:

Mill

W.

Maeda,

Hall,

17,

Compd.

Academic:

and

1979.

P.;

M.

107-113.

E.;

Valley,

215-221.

A.

Applications

Wade,

L.

of

J.;

Compd.

Tomography:

O’Brien,

M.;

M.

A.

D.

British

Radiopharm.

Applications

Ruth,

P.;

CA,

J.

J.

Kojima,

Boston,

K.

Chem.

Chem.

Hinlcle,

Radiophann

H.

Principles

Columbia,

1980.

T.

of

A.,

Methodological

J.

M.

1993.

Organotransition

Soc.,

Soc.,

Jr.

G.

1983,

to

J.

J.

J.

H.;

Organic

of

Labelled

Labelled

Chem.

Chem.

Labelled

Dec.

20,

1984,

Oiganometallic

Earlywine,

619-626.

1985.

Commun.

Commun.

Synthesis;

21,

Aspects;

Compd.

Compd.

Compd.

Metal

1076- A.;

used

which

changes lesser

while

coordinated changes

soluble

2.1

easily The

air-stable,

characterized,

Ofele. 1

w-coordination

The

Introduction

first

for

complexed

purified

degree,

has

most

in

in

in

Since

( 7 6 -arene)tri.carbonylchromium

the

a

diamagnetic,

been

arene

arene

APPLICATION

variety

arene

significant

stereoselective

the

and

by

that

of

most

reactivity

to

reactivity

chromatographic

an

steric

studied

to

of

the

time,

arene

studied

solvents,

undergo

metal

crystalline

effect

change

literally

have

with

are

to

OF

modifications

centre. 2 ’ 3

and

chromium,

of

readily

summarized

nucleophilic

received

respect

ORGANOCHROMRJM

RAIMOLABELLING

in

the

solids,

extensively

hundreds

and

arene

attached

Chapter

characterized

(, 6 -Arene)tricarbonylchromium to

recrystallization

less

generally complex

16

the

its

reactivity

in

of

aromatic

attention

of

reactivity

structure

employed

Figure

2

chromium

the

such

was

yellow

aromatic

by

complexes

2.1.

reported

is

regarding

substitution.

spectroscopic

is

and

techniques.

in

CHEMISTRY

the

to

significantly

tricarbonyl

synthetic

orange

reactivity

increased

side

in

their

have

1957,

chain. 6

in

It

As

chemistry. 5

methods,

potential

colour.

moiety of

altered. 4

been

is

compounds

TO

by

a

ability

the

this

result

Fischer

The

arene

prepared,

has

They

reaction

use

and

of

These

of

other

been To

ring

and

are

the the

are

are

for a

with

substitution. 4

shown

phenoxide,

chromium

investigations

chlorobenzene underwent

Nicholls

synthesis. 8 ’ 9

Of

During

alkoxides,

greater

that

Enhanced

Figure

Cr(CO) 3

I

and

early

also

fluorine

substitution

aniline, 11

interest

2.1:

have

Hinderance

exhibits

Whiting

is

studies

amines,

Acidity

unreactive

Steric

is tricarbonyl.

Changes

shown

more

Enhanced

+

and

for

reactivity

of

of

thiolates,

found

NaOMe

organic

the

Substitution

readily

2-methyl-2-propanethiol.’ 2

chlorine

in

other

toward

reactivity

arene

(Adapted

Nucleophilic

that

toward

displaced

synthesis,

and

nucleophiles

by

HC—C—

reactivity

methoxide

(i 6 -chlorobenzene)tricarbonylchromium

MeOH

65°C

methoxide

cyanide

of

a

17

from

variety

(, 7 6 -arene)tricarbonylchromium

than

is

co

when

the

reference

have

chlorine,

to

of

under

K—OMe

in

reactivity

nucleophiles.

react

complexed

very

been

Cr(CO) 3

I

(, 7 6 -Fluorobenzene)tricarbonyl-

the

7.)

during

high

/1

similarly,

H

reported. 12 ” 3

same

of

Enhanced

Solvolysis

yield. 1 °

to

( 6 -arene)tricarbony1- aromatic

Successful

chromium

conditions.

Enhanced

such

+

Acidity

Uncomplexed

nucleophilic

It

NaC1

compounds,

as

has

reactions

sodium

readily

Later

been (2.1)

are

chlorides

tricarbonylchromium

obtained. 5

shown

excess

(i 7 6 -Benzene)tricarbonylchromium,

also

fluorobenzene;

successfully

chromium

Unfortunately,

Figure

obtained

occur

strong

in

2.2:

fail

Figure

directly

where

complexes

used

upon

acid,

to

Examples

chromium

Cr(CO) 3

see

I

react

X

R

2.3.

to not

=

prior on

=

heating.

Figure

alkylate

Cl

complexes.

C(CH 3 ) 2 CN,

902Me

all

at

the

Furthermore,

or

with

to

F

of

low

synthetically

complexes.

i 6 -arene 2.2

_____

oxidative

carbanions

the

carbanions.

25°C

When

temperatures,

for

chromium

t(CH 3 ) 2 CO 2 Et,

Grignard

examples.

for

ring,

strongly

if

demetallation,

important

example,

.C,

which

the

which

Cr(C0) 3

18

Indeed,

I

reagents,

crude

tricarbonyl

while

basic

Nucleophilic

react

opens

reacts

carbanions

C(CH 3 ) 2 C0 2 ,

reaction

unidentified

anions

a

with

substituted

organocuprates,

variety

up

complexes

with

[01

( 6 -halobenzene)tricarbonyl-

additional

are

substitution

intermediate

a

work

of

used,

number

tH(CO 2 Me) 2 ,

decomposition

1,3-cyclohexadienes

carbanions

/\

of

well

synthetic

such

chlorobenzene

and

for

of

with

is

carbanions

alkylmercuric

as

R

hydrogen

treated

(fl 6 -arene)-

methyl-

have

pathways.

products

been

with

and

are can

or as

if have

final

exposure butyllithium,

A

corresponding tricarbonyl.

excess However,

development

onto

different

An

Figure

number

( 6 -arene)tricarbonylchromium

aromatic

arene

been

important

arene

where

electrophiles,

to

2.3:

this

of

successfully

product

sunlight

Typically,

R

proton

of

approaches

rings

Examples

chromium.

in

arene

can

Cr(C0) 3

=

several

-dH-sph

t(CH 3 ) 2 CN,

feature

a

SPh

be

and

can

and

solvent

complex.

abstraction

a

chromium

used thus

being

methods

be useful

air,

of

have

of

readily

t—CH 3 ,

providing

CH 3

CH

for

being

carbanions

(e.g.,

0°C

(, 7 6 -arene)tricarbonylchromium

R

able

CH 2 CN,

result,

After

been

oxidative

results;

for

hexacarbonyl

the

recovered

to

complexes

1,4-dioxane,

developed

both

the

remove

as

an

tH 2 CO 2 R,

most

CH

the

this which

desired

S

s

additional

Cr(C0) 3

19

demetallation; complexing

common. 5 ’ 6 ” 4

lithiated

produces

by

that

are

to

is

react

mild

di-n-butyl

chemistry

CH(CH 3 )CO 2 R,

either same

C—--

CN

u--complex

to

route

species

oxidation.

the

with

be

the

[01

group

heated

aqueous

for

chromium

This

has

useful

lithiated

ether),

( 6 -benzene)tricarbonyl-

can

chemistry

an ring

,

efficiently

been

is in

-

arene

/\

C(CH 3 ) 2 C0 2 R,

A

a

CH 3

then

modifications. 5

in Ce(IV),

neat

vital

which

variety

, 7 6 -arene

accomplished,

tricarbonyl

synthesis.

be

with

arene,

consideration, has

when

R

treated

affords

iodine,

of

chromium

been

complex.

reagents

desired.

or

group

with

with

The

and

the

the the introduction and subsequent removal of activating groups in organic chemistry presents difficult problems, not easily solved. Classical aromatic nucleophilic substitution suffers from this deficiency, as activating groups like nitro require drastic conditions for nitration, and lack mild and direct methods to remove the riitro group once its activating function is 5completed.’ As a result, classical aromatic nucleophilic substitution has found limited application in complex organic synthesis. -Arene)tricarbonylchromium complexes potentially offer a significant improvement as synthetic intermediates since the chromium tricarbonyl moiety can be readily attached6 in most cases, then decomplexed in high yield once synthetic operations are( done. The synthesis of radiopharmaceuticals labelled with short-lived positron emitting nucides requires special synthetic methods, due to the considerations presented earlier in Chapter 1. Prompted by the unique properties and reactivity of -arene)tricarbonyl- chromium complexes, we decided to explore the potential utility of76these compounds for radiolabelling. There are about five reasons that would commend( these organo chromium compounds for radiolabelling work.

Firstly, most organic pharmaceuticals, either of potential interest for labelling or being currently used in nuclear medicine today, contain arene rings in their structures.

Examples include 6-fluoro-3,4-dihydroxyphenylalanine (6-fluorodopa), the butyro phenone neuroleptics, the estradiol class of steroids, benzodiazepines, and benzamides such as Raclopride (S-(-)-3,5-dichloro-N-[( 1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy-6- methoxybenzamide).’ Therefore, the presence of an aromatic ring provides a possible labelling”67 site for attaching the radionuclide of interest. Secondly, medically useful 20 radioisotopes are generally produced in anionic, nucleophilic 18form. Labelling reactions which can directly use the nucleophilic form of the radionucide are advantageous, because this eliminates additional chemical manipulations and time to modify the reagent form of the radionuclide. Thirdly, -arene)tricarbonylchromium complexes facilitate nucleophffic substitution reactions(ion the aromatic ring. This established reactivity could allow the facile incorporation6 of nucleophilic radioisotopes onto aromatic rings. Fourthly, methods for complexing most arenes to the chromium tricarbonyl moiety, then later removing same, have been well established. This is in contrast to the use of traditional activating groups for nucleophilic aromatic substitution, such as nitro, which cannot be readily removed under mild conditions. Finally, the other modes of reactivity (see pp 1-2)exhibited by -arene)tricarbonylchromium compounds, adds additional synthetic options when designing a radiopharmaceutical synthesis. In this chapter, the synthesis of a number of76(,-arene)tricarbonylchromium complexes will be described. This will be followed by(ijstudies regarding the reactivity of the prepared chromium tricarbonyl compounds with6 cyanide. Lastly, the reactions of “C- labelled cyanide with some chromium tricarbonyl compounds will be presented.

2.2 Preparation of -Arene)tricarbonylchromium Complexes 2.2.1 Synthesis (q The objective for 6this study was to prepare a range of simple 6(i-arene)- tricarbonylchromium complexes in order to study their suitability for radiolabelling. To accomplish this, commercially available arenes were selected to produce the

21 corresponding chromium tricarbonyl complexes using literature methods.

Five general methods have been developed for the synthesis of -arene)tricarbonyl- chromium compounds. The first method, as outlined in equation76(i 2.2, is the direct Arene + 6Cr(CO) snt 63(q-Arene)Cr(CO) + 3 CO (2.2) reaction of arene with 6Cr(CO) under thermolysis conditions. This reaction has been carried out with various solvents ranging from neat arene to non-polar (e.g., decalin) to polar (e.g., diglyme*) solvents. The reaction must be conducted at relatively high temperatures to achieve decarbonylation of the metal carbonyl and obtain ‘7r-complexed product. The majority of -arene)tricarbonylchromium complexes have been prepared by this method. The second(i method involves a two-step process, in which during the first step 6Cr(CO) has three76 carbon monoxide ligands replaced by more thermally labile ligands (L) such as pyridine, 4-methylpyridine, 3CHCN, or ,3NH as shown in equation 2.3. heat 3 L + 6Cr(CO) 3LCr(CO) + 3 CO (step 1) (2.3) heat Arene + Cr(CO) -Arene)Cr(CO) + 3 L (step2) 3L solvent 63(q In the next step, the prepared complex, 3LCr(CO) is allowed to react with excess arene, using significantly lower temperatures,, to obtain the desired product. The milder conditions of this methodology has allowed the preparation of chromium tricarbonyl complexes not obtainable by the first method described above. The third method is the

*Formally named bis(2-methoxyethyl) ether.

22 direct reaction of arene with 6Cr(CO) via photolysis. Irradiation of the reaction mixture at room temperature accomplishes the desired decarbonylation. -Benzene)tricarbonyl- chromium and other complexes have been prepared using equation6(i 2.4. The fourth light Arene + Cr(CO) -Arene)Cr(C0) + 3 CO (2.4) 6 solvent 763(? method is arene exchange, which relies on the observation that 6(fl-arene)- tricarbonylchromium complexes undergo exchange reactions in the presence of another arene at elevated temperatures (ca. 200°C), as outlined in equation 2.5. The use of donor solvents has allowed these exchange reactions to be conducted at lower

6 heat ( 3-AreneA)Cr(CO) + AreneB (q 3-AreneB)Cr(CO) + AreneA (2.5) temperatures (ca. 140°C). However, the synthetic utility of this method has been limited by the high temperatures required, and by the low yields obtained. The final method is the reaction of aikynes with chromium pentacarbonyl carbenes, as illustrated in equation 2.6. A chromium tricarbonyl complex is formed from the condensation of an

2R CR 5Cr(CO) 3 2 R2 + CO (2.6) 3Cr(CO) 3Cr(CO) alkyne with a metal carbene. This novel method requires no arene starting material.

A range of interesting 7r-complexednaphthalene and phenanthrene derivatives have been prepared by this ’419route.’ 23

h.’°

workup

to prepared

(equation of

and

their

by

tricarbonylchromium most

complexes.

When

Although

1

Given

that

adapting

under

tetrahydrofuran

solutions

direct of

‘ji

and

examining

the

in

Nicholls

2.8),

similar

68%

( 6 -arene)tricarbonylchromium

synthetic

The

the

various

isolation,

are

based

method

yield

choice

conditions. 2 °

relatively

+

+

and

these

(THF).

synthetic

2

procedure

on

Cr(CO) 6

Cr(CO)

according

Whiting

were

by

was

the

of

initial

the

Mahaffy

air-sensitive.

made

Mahaffy

amount

6

conducted

options

method

Alternatively,

who

experimental

to to

(n-Bu) 2 OiTHF

to

reflux

reflux

equation

prepare

diglyme

reported

and

prepare

of

and

available,

of

Cr(CO) 6

/17

/48

under

All Pauson, 2 °

Nicholls

Pauson

24

compounds

h

h

the

2.7

preparations

2

results,

(, 7 6 -fluorobenzene)tricarbonylchroniium

a

was

yield

inert

using

desired

it

consumed.

reported

was

and

obtained

and

of

it

an

atmosphere.

desirable

are

Whiting.’°

became

Cr(CO) 3

52%,

Cr(CO) 3

to

(j 6 -arene)tricarbonylchromium

8:1

2

of

1

prepare

a

quite

90%

in

mixture

these

This

after

an

clear

air-stable

to

yield

isolated

result

complexes,

choose

a

( 6 -chlorobenzene)-

+

+

Compound

reaction of

that

for

3

di-n-butyl

3

is

CO

CO

working

in

yield

the

the

comparable

solid

time

including

synthesis

simplest,

of

1

form,

ether

47%

(2.8)

(2.7)

with

of

was

3 1 diglyme was less desirable, since it was very difficult to remove during workup. The butyl ether/THF mixture was readily removed to dryness, making workup much easier.

More importantly, the method of Mahaffy and Pauson exhibited a potential for significantly better yields of chromium complexed product. As a consequence, it was decided to use the Mahaffy and Pauson reaction conditions for the preparation of other

-arene)fficarbonylchromium compounds.

A number of chromium tricarbonyl complexes were successfully synthesized according to6 the general equation 2.9. The results obtained are summarized in Table 2.1. With

( reflux + Arene + Cr(CO) Complex + 3 CO (2.9) 6 2(n-Bu)0/THF j additional work and experience, the preparative yield of 1 was improved to 80% (see

Table 2.1). The reaction (equation 2.9) was found to be very sensitive to any traces of oxygen present in the reaction mixture. Regardless of how carefully the reaction apparatus, reagents, and solvents were handled under inert atmosphere, it was vital to employ freeze-pump-thaw degassing as a final step to ensure an oxygen-free environment for the reaction. The major drawback of the Mahaffy and Pauson procedure was the slowness of the reaction, thus requiring prolonged heating of the reactants (1-2 days) which can cause some decomposition of product complex. Unfortunately, this decomposition could result in further autocatalytic decomposition of any chromium tricarbonyl product formed. Some investigators have recently reported that the prime reason for decomposition of -arene)tricarbonylchromium during the reaction

(equation 2.9) was due to the presence of impurities in the starting materials and (76 25

Me

CVCF

0?—

O

CBr

C—F

,—F

Table

Arene

Me

N

2.1:

/Me

F

e

using

Summary

Equation

Me

Cl

of

Br

Yields

Complex

Cr(CO) 3

I

Cr(CO) 3

Cr(CO) 3

Cr(CO) 3

I

2.9

‘

Cr(CO) 3

Cr(CO) 3

7 6

4 3

5

1

Me

Obtained

26

Me

for

Complexes

Reaction

16.5h

Time

21h 23h

48h

44h 48h

Synthesized

I

70% Yield

85% 89%

80%

12% 19%

fluorobenzene byproduct t

Chemistry yield

withdrawing

overnight made

addition, thereby

toluene, that reactions

However,

condenser mixture.

effectively allowed

of solvents

For

A

Cr(CO) 6

1 This

*The

common

(80-89%).

while

in

our

limiting

and

used,

any

only

would

design

Anticipating

(see

during

results

it

Department,

purposes,

washed

which

could

itself,

electron-donating

was

4-fluorotoluene

groups sublimed

12%

problem

Experimental

and

complex

appear

However,

the

of

found

in

then

the

had

which

yield.

traces

back

this

progressive

reflux

slow

a

synthesis

to

this

paradoxical

be

Cr(CO) 6

with

to

that

U.B.C.,

reaction

1

results

sublimed

be

of

Persistent

the

used

the

result

is

time

problem,

separated

the

atmospheric

for the

were

formed

corresponding

reaction. 22

groups

in

possible—allowing

with

decomposition

of

and

direct

details). to

use

from

vessel

successfully

sublimation

Cr(CO) 6

limitation

be

6,

decomposition

is

a

of

conventional

from

a

using

a

special

reaction

mechanically

described

on

was

di-n-butyl

reductive

significant

oxygen

27

It

4-chlorofluorobemzene,

to

the

column

obtained

complex

was

of

reaction

complexed,

the

of

and

of

the

arene

over

in

the

dehalogenation

found

ether

arenes

reaction

the

glassware

accompanied

the

in

Mahaffy

amount

chromatography.

returned

metal

of

the

from

little

reaction

apparatus

Experimental.

helps

4-chlorofluorobenzene

with

that

with

reaction

producing

mixture.

carbonyl

Dr.

or

of

and

to

10-20%

fluorobenzene,

to

the Cr(CO) 6

no

to

Peter

perform

1

the

was

Pauson

the

process

proceed

product

mixture. 21

was

probably

reaction,

1,

from

reaction

preparation

A

constructed*

of

Legzdins

4,

is

obtained

regular

THF

procedure,

and

the

in

the

the

formed.

longer

which

via

electron-

5

2-fluoro- synthetic

volatility

mixture.

reaction

present,

(6)

in

Liebig

of

some

as

of

than

high

that

was

the

the

In

6,

is a

Toma. 21

fluorobenzene

chromium was

became

at synthesize

tricarbonyl

chromium the very

disappointing

suitable decomposition

and

The

Limited

50°C.

In

desired

(, 7 6 -4-fluoroanisole)tricarbonylchromium

beyond

addition

small

direct

clear

for

They

species

trials

complexes

tricarbonyl

radiolabelling

complexing

( 6 -bemzonitrile)tricarbonylchromium

quantities

the

reaction

that

results,

to

complex

obtained

also

of

6,

scope

F—’—F

a

in

the

other

sustained

accompanied

solution.

that

other

of

complex.’°’

1

preparations

a

arenes

of

(tens

to

Cr(CO) 3

8

benzonitrile

44%

synthetic

studies.

could

time

react

synthetic

study

conversion

with

of

be

Similar

with

available

milligrams)

prepared

methods

would

electron-withdrawing

these

of

approaches

a

However,

with

large

(i 7 6 -l,4-difluorobenzene)tricarbonylchromium

results

28

of

be

reactions.

for

Cr(CO) 6

9

10

in

also

excess

required

were

adequate

this

from

were

have

MeO—F

Mahaffy

were

did

10

attempted.

of

work.

starting does

been

not

cyanide

obtained

to

examined

As

indirectly

quantity

resolve

substituents.

yield

not

and

Cr(CO) 3

reported

9

Therefore,

a

1.

yield

overnight

consequence

In

Pauson

satisfactory

at

this

Semmeihack

were

that

these

by

the

best.

by

problem

settled

would

the

two

corresponding

were

in

allowing

Hudeèek

acetonitrile

results.

cases,

chromium

Extensive

of

be

upon

has

and

able

more

these

only

also

and

this

the

for

to

It 8 reported, in a 1976 review, the successful reaction of cyanide anion with 1 at 25°C, obtaining a 94% 5yield. Unfortunately, the experimental details of this work have never been published to the best of this author’s knowledge. We were able to prepare 10 in

69% yield using different conditions, as outlined in equation 2.10.

25°C123h I + NaCN I + NaF (2.10) 3Cr(CO) DMSO 3Cr(CO) 1 10

Of additional interest was the desire to prepare chromium tricarbonyl complexes in which the attached arene possessed groups of greater mobility toward aromatic nucleophilic substitution than halogen. Prompted by reports of radiolabelling studies using aromatics with dimethylsulfonium and trimethylammonium leaving 2526groups, it was considered whether an analogous chromium tricarbonyl complex could’ be made. Bunnet and Herman successfully methylated -thioanisole)tricarbonylchromium with trimethyloxonium tetrafluoroborate to obtain -phenyldimethy1sulfonium)tricarbonyl- chromium tetrafluoroborate in 89% 27yield. 6 However, they found that (6-N,N- dimethylaniline)tricarbonylchromium 7 could not be methylated by trimethyloxonium tetrafluoroborate. In our efforts, we found (6that complex 7 can be methylated using 27 methyltrifluoromethanesulfonate (commonly called( methyl triflate) according to equation 2.11. -N,N,N-Trimethylanilinium)tricarbonylchromium trifluoromethanesulfonate 11 was produced in 59% yield. In order to compare the behaviour of this new complex 11 with the(, corresponding uncomplexed arene, N,N,N-trimethylanilinium trifluoromethane 6 29 /Me + + 25°C/48 h S0CF (2.11) Cr(CO) CFSOCH C1CH Mel 3 3 2 Cr(CO) 3 L 7 3 J

sulfonate 12 and N,N,N-trimethylanilinium iodide 13 were also synthesized as shown in equation 2.12. Compound 12 was prepared in 83% yield, while 13 was obtained in 56% yield.

C1CFSOCH/CH [N_Me Me +CFSO 25°C/30 mm 3 32 Me 12 /Me (2.12) I3CH 2C1/CH 25°C/24h Me 13

2.2.2 Characterization

All of the -arene)tricarbony1chromium complexes, except for 11, are known compounds. (jTheir melting points were recorded and are presented in Table 2.2. The chromium tricarbonyl6 complexes tended to decompose to some degree during melting point determinations. The degree of decomposition would vary with the heating rate thereby making the melting points difficult to determine in some cases.

30 Table 2.2: Summary of Melting Points of Organochromium Complexes Complex Observed mp Literature mp Reference (°C) (°C) 1 117 116-117 27 2 100-101 101-102 20

3 101-105 120 28 4 71-72 73-74 29

5 59-60 61-62 29

6 61-62 — none found 7 137-138 144 20

11 120-121 — none found

The identification of the chromium tricarbonyl complexes was accomplished by mass spectrometry (MS). The principal fragmentation patterns of simple 6-arene)- tricarbonylchromium compounds using electron impact MS have been well established( and are shown in Figure 2.4.°’’ The fragmentation patterns exhibited by the synthesized chromium tricarbonyl complexes were consistent with the scheme depicted in Figure 2.4. Also, Muller and Göser reported that all -halobenzene)tricarbony1- chromium compounds gave the Cr-halogen ion on fragmentation (i.e., H[(CX)Crj —* [CrX] + + This ion was 65 CH )? observed for each of6 the chromium tricarbonyl 65 complexes with halogen-substituted aromatic rings. These (characteristic features of the mass spectra, exhibited by the chromium tricarbonyl compounds, made product identification rapid and straight forward.

Complex 11 was previously an unknown compound and was characterized by elemental analysis and 1H NMR spectroscopy. Compounds 12 and 13 were identified

31

group by

at

obtained

complexes

Figure

5.77

1 H

protons

(H-3,5),

NMR

for

2.4:

[(Arene)Cr(CO) 2 f

[(Arene)Cr(CO)]

[(Arene)Cr(CO) 3 ]

(11,

11.

[(Arene)Cr]+

spectroscopy.

at

Principal

compounds.

6.07

[Cr]

12,

The

3.56

-Arene

13).

(H-4),

1 H

ppm.

NMR fragmentation

+

A

6.69

The

satisfactory

-Cr(CO)

MS -Cr

spectrum

(H-2,6)

1 H

could

NMR

pattern

ppm,

of

[Arene]

not

elemental

32

spectral

[Arenef’

11

and

exhibited

be

of

employed

a

( 6 -arene)tricarbonylchromium

data

singlet

analysis

the

for

fragmentation

for

aromatic

12

for

Arene

normal

fragmentation

for

and

the

Arene

normal

analysis

C,

trimethylammonium

13

proton

H,

were

N,

of

found

resonances

and

these

S

to

was

salt be the same; the aromatic protons were observed at 7.58-7.68 (H-3,4,5) and 7.97 (H-2,6) ppm, and the trimethylammoriium group protons at 3.61 ppm. These results showed the expected upfield shifts in proton resonances due to complexation with chromium tricarbonyl. This is a characteristic feature of the ‘H NMR spectra of chromium tricarbonyl complexes when compared to the uncomplexed 4arene.

2.3 Reactions of Organochromium Compounds with Cyanide

These studies began with investigating the reactivity of cyanide with -halobemzene)- tricarbonylchromium complexes 1, 2, and 3. All substitution reactions(6were performed

I I I 3Cr(CO) 3Cr(CO) 3Cr(CO) 1 2 3 under an argon or nitrogen atmosphere, using dried solvents. Complex 1 was allowed to react with excess sodium cyanide (ca. 10 equiv) in DMSO at 1500C*for 30 minutes.

During heating, the initial yellow colour of the reaction mixture became dark red. After cooling, the reaction mixture was diluted with water, extracted with diethyl ether, then dried. The dried ether extracts were colourless. The ether extracts were concentrated and analyzed by gas chromatography (GC). GC analysis confirmed the presence of benzonitrile 14 as the only product obtained. This reaction was repeated under slightly different conditions, where complex 1 was treated with about 2 equivalents of sodium

*Reaction temperatures always refer to the oil bath temperature used.

33 cyanide at 155°C in DMSO for 20 minutes. After workup, GC analysis of the ether extracts exhibited two prominent peaks, a major peak due to 14 and a minor peak due to fluorobenzene. For comparison, uncomplexed fluorobeuzene was allowed to react with sodium cyanide under the same conditions. GC analysis showed that only unreacted fluorobenzene was present.

These initial results clearly demonstrated that the fluorobenzene complex 1 underwent successful aromatic nucleophilic substitution with cyanide and that the reaction was rapid under the conditions employed. The control experiment with uncomplexed fluoro benzene confirmed that free fluoroberizene failed to react with cyanide, and that intact chromium tricarbonyl species underwent the substitution reaction.

The reactivity of the chlorobemzene complex 2 was examined next. Complex 2 was treated with sodium cyanide (ca. 0.5 equiv) in DMSO at 160°C for 15 minutes. After workup, the ether extracts were yellow in colour. GC analysis showed only the presence of chlorobenzene. The ether extracts were subsequently treated with iodine to decomplex any intact chromium tricarbonyl components, and the GC analysis was repeated. Chlorobenzene remained the only compound detected. For comparison, the reaction of 1 with sodium cyanide was repeated under the same conditions as used for

2. GC analysis showed two significant peaks, one peak due to 14 and the other due to fluorobenzene. In like manner, the ether extracts were again treated with iodine to decomplex any chromium tricarbonyl components present. GC analysis gave the same results as observed prior to oxidative decomplexation.

Unfortunately, these results showed that 2 is either unreactive toward cyanide or is

34 possibly undergoing significant decomplexation under the reaction conditions used.

However, 1 readily underwent substitution with cyanide using the analogous conditions employed for the reaction trial with 2. Though disappointing, this observation was complimentary to previous studies that have shown that fluorine is more easily displaced during aromatic nucleophilic substitution than 4chlorine. Therefore, these results suggested that chlorine is an inappropriate leaving group to use in future studies, and was thus abandoned.

Lastly, the potential of bromine as a leaving group was investigated using the bromobenzene complex 3. Complex 3 was allowed to react with 0.5 equivalents of potassium cyanide in DMSO at 135°C for 10 minutes. After cooling, high pressure liquid chromatography (HPLC) was employed to directly examine the reaction mixture.

HPLC analysis confirmed the absence of the desired product 14. In contrast, 1 was treated with cyanide under identical conditions, and benzonitrile 14 was produced.

HPLC analysis not only confirmed the presence of 14, but the yield was also determined—these results will be presented and discussed later in this section.

These results also indicated that 3 is either unreactive toward cyanide or is possibly decomplexing under the reaction conditions employed. Bromine, as a consequence, would also appear to be an unsuitable leaving group for aromatic nucleophilic substitution. Therefore, the only useful halogen leaving group for reactions with cyanide was determined to be fluorine.

In order to further characterize the benzonitrile product 14, obtained from the reaction of 1 with cyanide, isolated products from several small scale reactions were

35 combined. This combined product sample (dissolved in diethyl ether) was subjected to

GC analysis, and only one component was observed with almost 99% purity. The ether was evaporated and the product sample was dissolved in deuterated chloroform for

NMR spectroscopy. The room temperature 1H NMR spectrum was recorded at 80

MHz.* In addition, the 1H NMR spectrum of authentic 14 (commercially obtained) was recorded under the same conditions. The spectrum of the product sample exhibited a multiplet centered at 7.57 ppm that was the same as that observed for authentic 14.

Therefore, the 1H NMR spectrum clearly identified the product sample as benzonitrile

14. This is in addition to GC and HPLC studies which readily identified 14 by comparison of its retention time with that of authentic standard. Also, during HPLC studies, an aliquot of reaction mixture was taken and standard 14 was added to see if the assigned product peak would correspondingly increase in size. This was observed, and deemed as further evidence that the chromatographic assignment was correct.

Furthermore, it was noted during the workup of the reactions of 1 with cyanide that the characteristic odour of 14 was present.

A number of general observations were made during the early studies regarding the reaction of 1 with cyanide. Reactions employing approximately 2 or more equivalents of cyanide for 15-30 minutes exhibited essentially a quantitative conversion of 1 to 14, as determined by GC analysis. The temperatures used for these reactions were 150-

155°C. Additional experiments were performed in which the reaction mixtures were

*These spectra were obtained on a departmental Bruker WP-80 spectrometer with tetramethylsilane used as an external standard.

36

be

cyanide

discussed this was

on incorporation undergo

benzonitrile

could

surprising

elevated

decomplexation to heated

at

fold)

1 during and

examining

with

These

GC

using

later

eventually

application.

further

HPLC

of

be

cyanide

and

for

the

substitution

complex

the

assured.

results

temperatures. 32

displacement

earlier

stages

as

as

HPLC

a

confirmed

analyses.

reaction

shortest

14

little

it

product

of

actually

concentration

compatible

has

further

step

With

[ 11 C]cyanide

in

1

of

The

as

analyses.

relative

Chapter

been

reactions

was

reaction

one

this

under

with

excess

Other

half-life

is.

mixture

of

indicated

needed

to

reported

Since

the

additional

discussion.

to

with

three

cyanide

Lastly,

reactions

1.

the

after

into

time

to

cyanide.

of

aromatic

by

Therefore, the

to

10

high

11 C,

just

minutes

conditions

arenes,

treatment

possible.

liberate

that

GC

minutes

intent

decomplexation

and

experimental

however,

how

conducted

specific

Again,

(t 6 -arene)tricarbonylchromium

(after

As

longer

ring

the

37

was

and

facile

the

the

Also,

with

and

a

employed.

studies

in

to

14

benzonitrile

is

workup)

organic

decision

activity reaction

consequence,

to

ultimately

and

20.4 iodine.

was

donor

used

it

experience,

use

is

of

to

rapid

still

minutes,

highly

product.

a

the

cyanide

follow

[“Cjcyanide,

was

solvents,

times,

which

Subsequently,

large

produced,

This

aromatic

the

14

apply

desirable

made

which

was

which

were

excellent

molar

no

substitution

as showed

was

This

this

such

the

obtained,

to

separate

as

designed

nitrile

shall

places

result

demonstrated

excess

chemistry

limit

that

for

limiting

observed

this

as

complexes

reaction

no

be

the

the

pyridine,

observation

was

subsequent

takes

reaction

a

change

(up

presented

according

premium

to

oxidative

reaction

reagent

reasons

not

for

by

model

yields

to

place

GC

can

too

the

17-

by

of

at in (0.5 equiv).

Within these parameters, the reactivity of the chromium tricarbonyl complexes 1, 4,

5, and 6 was examined. The general procedure used is as follows. An aqueous solution

Me—-—F Cl -—F 3Cr(CO) 3Cr(CO) 3Cr(CO) 3Cr(CO) 1 4 5 6 of cyanide, containing a known amount of KCN, was dispensed into a reaction vessel, and was carefully dried under a fast flow of inert gas. (This was done to model the handling necessary in using 1[‘C]cyanide, which is obtained as an aqueous solution after cyclotron production.) The -arene)tricarbonylchromium complex, dissolved in 1 mL of DMSO, was added to the dried cyanide. The mixture was heated for 10 minutes. Upon cooling, the reaction mixture6 was quantitatively transferred to a volumetric flask and diluted to a known volume( with DMSO. This solution was analyzed by HPLC. The extent of product formation was determined using a calibration curve constructed using

HPLC absorbance values of standard solutions of expected aryl nitrile product. The chemical yields were calculated using KCN as the limiting reagent. In order to optimize the results obtained for each of the complexes studied, the reaction temperatures were varied and the corresponding chemical yields were determined.

Complex 1 was treated with cyanide, as shown in equation 2.13, using reaction

0.5 equivKCN 2 K—CN + KF + 1 (2.13) 3Cr(CO) DMSO/10 •

38 temperatures ranging from 105-150°C. The results obtained are summarized in Table

2.3. The optimum temperature found for equation 2.13 was 135°C, giving a best yield of 41%. A representative HPLC chromatogram is shown in Figure 2.5. The chromato gram shows the presence of the desired product 14 (peak A), along with residual starting complex 1 (peak C) and free fluorobenzene (peak B) which is visible only as a shoulder of an unidentified peak. Injection of a solution, consisting of fluorobemzene standard added to an aliquot of reaction mixture, exhibited an increase of this shoulder (peak B) into a distinct peak at the same retention time, thereby confirming the assignment of peak B. Another control experiment was performed with uncomplexed fluorobenzene using 0.5 equivalents of cyanide at 135°C. Once again, only unreacted fluoroberizene was observed in the HPLC chromatogram.

Table 2.3: Chemical Yields Obtained for Complex 1 Temperature Yield no. of Average (°C) runs Yield 150 23-33% 2 28% 135 40-41% 2 41%

120 31% 1 31%

115 32% 1 32%

105 12% 1 12%

Next, the reactions of complexes 4, 5, and 6 with cyanide were investigated. The reactivity of 4 (equation 2.14) was examined over a temperature range of 95-135°C. The results obtained are shown in Table 2.4. The best yields (41-43%) were observed at 105-

115°C. The control reaction done with 2-fluorotoluene (uncomplexed) using 0.5 equiva

39

Figure isocratic

The

The

compounds

HPLC

2.5:

methanol/water,

z

C

40%. HPLC

complex

conditions

are:

chromatogram

1

(A,

with

are:

I

5.4

1:1;

Waters

cyanide

mm),

flow

TIME

14;

rate,

obtained

10

at

(B,

135°C. JLm

2.5

(mm)

40

C-18

10.5

mL/min;

B

from

The

mm),

reverse

the

yield

UV

fluorobenzene;

analysis

phase

of

detection

14

RCM

was

of

set

determined

the

(C,

column;

at

16.8

reaction

280

mm),

nm.

eluent:

to

be

of 1.

present

Table

temperature results were

lents

complex

compound

The

performed

of

2.4).

were

reaction

2i

in

used

cyanide

these

observed

significantly

range

Cr(CO) 3

stoichiometric

aOnly

per

4

of

reactions.

Temperature

using

Table

at

5

reaction

of

with a

135°C

(°C)

135k

143&

115

105

135

125

in

95

tenth

105-150°C.

only

2.4:

better

the

cyanide,

DMSO/lOmin

Yields

1.5

0.5

gave

of

Chemical

HPLC

ratio

trial.

the

mg

equiv

than

no

as

of

of

usual

of

The

This

chromatogram.

those

41-43%

KCN

28-29%

29-36%

summarized

58%

reaction;

5:1,

4,

Yield

58% 41%

58% 26%

Yields

this

chemical

quantity

results

of

were

obtained

41

being

KCN

Obtained

unreacted

obtained

CN

in

in

yields

of

to

about

no.

using

15

equation

runs

a

Two

,Me

4

4.

2 2

4

1

1

1 1

was

five-fold

of

for

obtained

a

at

0.5

reaction

2-fluorotoluene

tenth

used,

Complex

both

equivalents

+

2.15,

Average

of

excess

giving

28.5%

135

Yield

KF

58% 42%

58%

are 26% 41%

32%

trials

was

the

and

4

outlined

usual

+

studied of

a

(equation

of

143°C.

cyanide

was

cyanide

4

quantity

in

the

over

(2.14)

These

Table

being

2.14)

only

(see

the of

unreacted

benzene

togram.

the

These

fluorotoluene

only

26%)

2.5.

The

Cl

reaction

the

The

-—F

results

were

reaction

One

(uncomplexed)

presence

best

4-chlorofluorobenzene

Cr(CO) 3

6

Cr(CO) 3

5

seen

reaction

temperature

are

(0.5

yields

Temperature

Table

of

summarized

of

equiv

at

6

(°C)

(26-29%)

unreacted

105

115

125

150

135

135°C.

trial

with

2.5:

using

DMSO/l0min

of

0.5

DMSO/

0.5

(equation

of

KCN;

cyanide

Chemical

equiv

equiv

115°C.

0.5

The

in

were

4-fluorotoluene.

Table

was

10mm

equivalents

KCN

135°C)

KCN

control

(equation

26-29% 22-26%

2.16)

obtained

the

Yield

21%

21%

11%

Yields

The 2.6.

-

only

exhibited

was

42

experiment

Cl

control

Me<)—CN

The

of

compound Obtained

heated

at

2.16)

cyanide

best 115°C,

no

no.

reaction

runs

was

(115°C)

2

3

yields

1 1

1

performed

reaction.

of

for

at

while

observed

examined

135°C

Complex

(26-34%)

done

+

for

the

+

Average

HPLC

27.5%

KF

Yield

five

exhibited

using

24%

21%

21%

11%

in

next

with

KF

at

the

5

minutes,

were

+

best

115

uncomplexed

analysis

HPLC

4-chiorofluoro-

+

6

no

and

obtained

results

5

reaction;

and

chroma

showed

135°C.

(2.16)

(2.15)

gave

(22-

at 4-

to

nucleophiic behaviour.

there

indicates

complex

sacrifice

6,

only

In

proceed

it

about

would

the

are

studied

in

process

no

Co

that

by

half

chemical

be

However,

“Co

such

substitution

a

a

reaction

interesting

two-step

the

Temperature

exhibits

reaction

Table

of

patterns

yield

examining

(°C)

115k

yield.

135

115

step

inspecting

+Y

2.6:

times

reactions

mechanism

its

observed

time

observable.

1

to

own Chemical

discover

shorter

the

of

OCj

distinct

the

5

KX

of

for

chemical

mm

26-34%

(equation

(, 7 6 -arene)tricarbonylchromium

Yield

results

Cr,

21%

17%

Yields

CO

a

What

than

any

was

pattern

10

“CO

43

minute

trends

emerges yields

used.

presented

10

Obtained

2.17),’

minutes

of

step

reaction

no.

reaction

obtained

or

runs

-x

3

is

1

1

systematic

2

of

for

in

that

analogous

would

Tables

Complex

yields.

time

each

OCj

for

Average

complexes

result

Yield

30%

chromium 21%

(see

17%

patterns

2.3-2.6

Cr,,

to

CO

The

6

systems

classical

“CO

Table

in

mechanism

indicates

a

of

1,

tricarbonyl

2.6).

significant

is

aromatic

chemical

4,

thought

5,

(2.17)

This

that

and for

called

investigated

In

substituent yield

cyanide—yet

similar much best valid,

5

at

fluorobenzene

cyanide exo-substituted,

halide nucleophilic

of substitution,

aromatic

1,

gave

fact,

and

30

the

t The

average

of

degrees

more

SNAr

additional it

may leaving

unexpectedly

the

chemical

42%

more

would

mechanism

ring,

chemical

(relative

lead

surprising.

by

that

this

substitution.*, 34

(see

yield

at

lower

facile,

on

complex group

March.

anionic

105°C.

yields

be

was

to

electron-withdrawing

methyl

the

Tables

for

lower

to

yields

anticipated,

temperature.

low

not

while

side

being

(X),

1

1),

with

5 -cyclobexadienyl

Since

1

was

As

group

observed.

yields,

as

would

substitution

2.4 opposite

obtained

electron-donating

cyanide

giving

a

the

specifically

41%

The

4

result,

and

in

and

baseline

with

be

from

first

obtained

4

the

2.5). the

expected

On

A

by

might

would

5

4

a

best

are

step

yields

groups final

4

essentially

best

chromium

the

comparison

referred

readily

standard,

be

44

Complex simply

average

complex.

hinder

is

at

other

average

substitution

to

during

anticipated

addition

would

groups

135°C,

produce

surpassed

ortho-

to

hand,

equalled

tricarbonyl

the

yield

it

to

the

6,

make

yield

here

The

may

while

would

reaction

of

which

classical

the

the

of

and

short

product.

for

the

second

be

those

of

is

the

30%

the

highest

4

results

both

para-isomers,

expected

hinder

27.5%

nucleophile

addition-elimination,

moiety—this

exhibited

substitution

reaction

bears

with

best

was

of

step

aromatic

complexes.

5

If

chemical

obtained

yield

exhibited

obtained

cyanide,

at

same. 35

an

this

is

that

all

time

expulsion

its

extra

obtained

(Y)

mechanism

temperatures

reaction

results

the

best

respectively,

nucleophilic

used.

yields

relative

by

Using

However,

at

at

presence

onto

chlorine

average

5

115

115°C.

in

of

were

with

with

by

also

The

°C.

the

the

the

the

to

is 1 Unfortunately, circumstances did not permit the opportunity to conduct reactions at temperatures below 115°C. It is possible that higher chemical yields could be obtained for 6 at lower temperatures. Nonetheless, equal or better yields were obtained from 1 and 4 at both 115 and 135°C.

These results may be explained in part by the relative thermal stability of the complexes. Complex 6 was clearly more prone to decomposition in solution; this was particularly evident during its synthesis (see pages 27-28). Due to the presence of the chlorine substituent, in addition to the fluorine, there would be less electron density available on the aromatic ring to complex with the chromium tricarbonyl moiety, and the resulting complex would be anticipated to be less thermally stable relative to 1.

Therefore, the lower chemical yield for 6 at 135°C, compared to that of 1, could stem from greater thermal breakdown of 6 at that temperature. The yields resulting from 1 and 6 at 115°C are quite comparable. As a result, 1 exhibits better yields at 135°C than

6 simply because it is likely the more thermally robust complex, and not from any greater intrinsic reactivity. On the other hand, both 4 and 5 would be expected to be somewhat more thermally stable than 1. Complexes 4 and 5 were both prepared in higher yield than 1, and were found to be as well behaved during storage and handling.

However, as presented earlier, 4 exhibited better yields at lower temperatures as compared to 1, but 5 exhibited significantly lower chemical yields at all reaction temperatures employed when compared to those of 4. Since it would be reasonable to assume that both 4 and 5 would be of equivalent thermal stability, the reason for this marked difference in chemical yields obtained by 4 and 5 is unknown. For each

45

were

procedure

range

2.7.

obtained determined

benefit

As

Therefore,

reagents

1.2 crown-6 investigate

convert that individually

chromium

quite

In

a

equivalents

The

the

result,

order

conducted

sensitive

2

of

on

benzyl

have

nucleophilicity

105-135°C.

(1,4,7,1O,13,16-hexaoxacyclooctadecane)

best

at

was

the

tricarbonyl

by

the

by

to

105-115°C,

Cr(CO) 3

to

18-crown-6

yields

shown

employing

reaction

HPLC

improve

to

achieve

halides 38

followed

use

of

over

reaction

18-crown-6

of

(40-44%)

increased

These

analysis

a

complex

crown

the

of

in

upon

was

temperature

and

of

as

18-Crown-6

a

4

the

temperature,

crown

best

0.5

the

described

with

results

chosen

alkyl

the

as

absence ethers.

were

to

eqv

solubility

cyanide studied,

results

before.

cyanide,

the

ether

chemical

halides 39

did

now

/

KCN

as

reaction

range

10

earlier,

of

The

the

possible.

not

with

and

mm

anion

the

and

observed

The

18-crown-6. as

46

crown

to

yields

surpass presence

of

chemical

hence

shown

potassium

anion

results

except

their

mixture

would

95-135°C

ether

to

has

obtained

must

reactivity

in

the

corresponding

obtained

occur

for

be

of

yields

equation

When

prior

been

cyanide,

previous

to

be

crown

the

enhanced. 36 ’ 37

and

use,

throughout

optimized

thus

obtained

in

to

addition

successfully

the

+

the

are

aprotic

2.18.

to

heating.

ethers

it

best

reaction

far,

KF

chemical

summarized

examine

would

nitriles

The

yields it

were

of for

with

organic

the

+

was

Previously,

be

approximately

The

used each

was

same

in

temperature

its

4

found

yields

many

of anticipated

decided

high

reactions

repeated

potential

in

solvents.

41-43%,

complex

to

general

(2.18)

Table

yield.

to

were

ionic

help

18-

be to

were

yields

mixtures using

concentration

done

2.4)—increases

earlier at

of

In

46%

105°C

addition

using

simply

acetonitrile were

bAt

aAbout

Table

was

reaction

Temperature

using

were

this

obtained.

oil

obtained.

set

to

(°C)

of

105a

105

115

125

95b 135

3

2.7:

80

95

bath

oil

approximately

of

reexamined

these

equiv

2-tolunitrile

aside

yields

as

bath

about

Chemical

temperatures

the

results,

After

of

without

However,

temperature,

30-50%

solvent

that

18-crown-6

chromatographic

by

Yields

15

CH 3 CN

Solvent

DMSO

a

three

were

couple

(see

any

HPLC, with

p

over

the

of

equivalents

Obtained

Table

further

was

the

80

obtained

use

one

earlier

of

and

which

reaction

CH 3 CN

used.

of

47

equivalent

2.8).

40-44%

Yield

manipulations.

35%

46%

40% 41%

42%

18-crown-6

4%

95°C. 3%

average

(HPLC)

for

showed

of

at

These

was

trials

Complex

18-crown-6,

95,

As

of

observed

chemical

analysis,

reaction

(equation

shown

125,

did

18-crown-6

a

no.

runs

significant

4

2

significantly

1 1

1

1

1

1

1

using

The

of

and

a

in

mixtures

these

to yields

slightly

2.18)

Table

be

following

135°C

18-Crown-6

added;

reaction

refluxing.

were

Average

increase

were

Yield

improved

35%

46% 40%

42% 42%

41%

were

2.7,

4%

3%

improve

(see

exhibited.

these

conducted

very

day

again

mixtures

in

Table

these

upon

were

poor

yield

the set

improved

slower the

( 6 -2-to1unitrile)tricarbony1chromium

temperatures DMSO

the

(and concentration

unexpectedly,

increase

aside

obtained

chemical

reaction

decomplexed)

for

rate

as

in

about

yields

the using

at

the

used

yields,

room

reaction

good

mixture

was

Table

concentration

Temperature

two

shown

CH 3 CN

for

yields

during

temperature

observed

(°C)

determined

weeks.

95 80

95 95 80

80

2.8:

the

solvent

in

analyzed

of

reactions

as

using

Table

Chemical

the

15

Then

the

has

of

10

were

with

Acetonitrile

(during

2.8

minute

15

initially,

by

shown

reaction

HPLC

(equation

was

produced

Yields

were

subsequent

Yield

species

HPLC,

21% 50%

46%

21%

4%

3%

observed

reaction

storage),

that

represented

48

due

analysis

Obtained

solvent

only

as

after

2.18)

with

no

to

the

time.

the

decomplexed

reanalyses.

or

initial

further

(see

the

the

done

Time was

Solvent

looked

to

reaction

for

reaction

passage

the

Table

the

What

performed

in

HPLC

—13.5

—13.5

elapsed

Equation

--18h

--16h

total

changes

CH 3 CN,

fact

0

0

wholly

is

2.8).

of

continuing

has

to

that

d

d

not

analysis

Due

nitrile

time.

after

a

been

again

clear

2.18

small

it

Initially,

the

in

unimpressive,

was

to

product

Experience

initially

nitrile

performed

is

extent

and

expected

the

to

whether

the

occur

a

elevated

product

formed

formed

at

further

results

first,

with

at that

and

the

but a then continued to slowly decomplex while being stored.* Unfortunately, this work was not followed up at the time.

The preliminary results obtained using 18-crown-6showspromise for the use of crown ethers in the substitution reactions of chromium tricarbonyl complexes. In fact, other crown ethers and cryptands are available for potential ’°436use. It is anticipated that some experimentation would be needed to find the optimum macrocycle to function in these substitution reactions with cyanide.

The identification of the aryl nitrile products formed from the reactions of complexes

4,5, and 6 with cyanide was accomplished using chromatographic (HPLC) studies. Each of the nitrile products (2-tolunitrile 15, 4-tolunitrile 16, 4-chlorobenzonitrile 17) were readily identified by comparison of their respective retention times with that of authentic standard. To further confirm the identity of the nitrile products 15, 16, and 17, a separate set of reaction trials was conducted to isolate the organic products and analyze these by gas chromatography-mass spectrometry (GC-MS). These reactions were performed as described previously in the general procedure used for the earlier cyanide reactions (see page 38). Upon cooling, however, the reaction mixtures were diluted with water, then extracted with diethyl ether. The ether extracts were cooled to 0°C, then treated with iodine for two hours to oxidatively decomplex any chromium tricarbonyl species present. The treatment was quenched with the addition of aqueous sodium thiosulfate solution. The ether layer was further washed (aqueous 23SONa and saturated

*The reaction mixtures were kept in small, stoppered volumetric flasks, but these mixtures had been exposed to air during HPLC work. As a result, any chromium tricarbonyl species present could gradually undergo oxidative decomposition.

49

values

to

during Table

substitution

Unfortunately,

GC not the

spectrum. products

authentic in first

contained from NaC1

toluene,

16,

In

The

Comparison

oxidative

ether)

17).

analyses

by

completely

presence

addition,

the

solutions),

reported

2.9.

formation

the

GC

4-fluorotoluene,

However,

obtained uncomplexed

and

standards

a

substitution

and

The

with

decomplexation.

third

using

the

were

the

of

of

HPLC,

earlier,

remove

key

then

cyanide

of

the

chemical

minor

chromatographic

above.

a

the

the

14

confirmed

also

feature

mass

small

dried.

as

then

which

starting

reaction

standard

reactions

4-chlorofluoroben.zene)

as product

1

a

analyzed

spectra

side-product

yields

as by

a

quantity

of

were

The

side-reaction,

This

GC-MS.

an

arene

the

mixture

these

mixtures

becomes

for

which

obtained

ether

determined

impurity.

by

purification

further

identity

this

and

results

of

GC-MS

from

solution

Mixtures

containing

was

set

50

for

corresponding

1

decomplexed

from

establishes

affording

of

contaminating

of

identified

is

the

calibration.

without

As

the

reaction

for

of

that

the

(concentrated

and

reaction

of

6,

a

4-chlorofluorobenzene

direct

starting

authentic

reaction

during

none

consequence,

the

benzonitrile

subjecting

that

as

trials

under

aryl

resulting

of

comparison

benzonitrile

These

of

its

all

fluoroaromatics

the

products

6

nitrile

were

the

standards

original

with

the

the

to

the

starting

results

yields

1

nitrile

14.

reaction

estimated

aryl

cyanide

1

product

mL)

reaction

with

preparation,

also

to

14

were

nitrile

surpassed

are

products

was

the

complex

those

and

by

was

underwent

conditions

(dissolved

(2-fluoro-

shown

prepared

mixtures from

analyzed

its

reaction

formed

17

due

of

mass

also

(15,

the

the

did

the

to

in 6.

reported.

(CH 3 CN) 3 Cr(CO) 3

general

with

trifluoromethanesulfonate found

complex However,

and

nitrobenzene)tricarbonylchronfium

to

used.

substitution

examine

aromatic

Other

examine

‘The

trimethylammonium’ 26

arene

that

procedure

11

nitro

leaving

nucleophilic

successful

prompted

we

This

other

for

was

rings

were

as

represents

(i 6 -arene)tricarbony1chromium

allowed

Complex

Starting

leaving

groups

a

bearing

was

able

as

leaving

by 4

5

6

synthesis

substitution. 41

used,

the

to

Table

radiolabelling

groups

apart

to

synthesize

the

a

11.

precursor

group.

react

leaving

as

nitro

2.9:

first

Product

of

from

previously

Nitrile

that

Preliminary

17

15

16

with

Summary

( 6 -2,4,6-trinitrotoluene)tricarbonylchromium,

were

chromium

substituent

Unfortunately,

(, 7 6 -N,N,N-trimethylanilinium)tricarbonylchromium

groups

could

halogen

Hence,

studies

for

cyanide

unsuccessful.

51

described

possess

complexing

Temperature

for

of

using

it

tricarbonyl

have

experiments

systems.

Chemical

have

as

was

nucleophilic

(°C)

115

135 120

shown greater

aromatics

the

been

of

for

been

Chromium

additional

the

attempts

the

An

Yields

complex

successfully

in

mobility

were unknown

obvious

earlier

arene,

equation

substitution

with

—32%

—26%

—24%

Yield

tricarbonyl

made

conducted

interest

of

dimethylsulfonium 24

toward

reactions

has

choice

a

until

used

2.19.

nitroaromatic.

to

been

reactions,

prepare

to

nucleophilic

would

recently.” 42

in

complexes

The

(see

our

in

recently

classical

which

using

same

be

study

page

( 6 -

we to + 3S0CF No Reaction (2.19) L 3Cr(CO) ] 11

38). The reactions were done at 100 and 120°C. Disappointingly, HPLC analysis showed the absence of the desired product 14. The HPLC chromatograms of the reaction mixtures exhibited two new prominent peaks, a large peak and a much smaller peak with a longer retention time; these peaks could not be identified. Complex 11 was then heated in DMSO for 10minutes at 100°C. After cooling, the HPLC chromatogram of this solution showed the presence of a single new peak. The retention time of this peak was very close to that of the large peak observed from the reactions above. These results seem to suggest that 11 is undergoing some kind of transformation or decomposition from the heating in solution. For comparison, a trial reaction was done with uncomplexed N,N,N-trimethylanilinium trifluoromethanesulfonate 12 and cyanide at 100°C (equation 2.20). No reaction was observed, as evidenced by HPLC analysis.

[KMe 3CFSO No Reaction (220)

Unfortunately, the preliminary reactions conducted with 11 failed to produce any 14.

These results suggested some chemical breakdown of complex 11 while being heated.

Additional time to study this problem, and the potential reactivity of 11, was simply unavailable.

52

has

values

0.5

presence

Ci/mmol. 43

some

“C was

The

for

irradiation

radioisotopes

radionuclide 2.4

cyclotron facility

chemistry

In

[ 11 C]cyanide

Although

this

HCO

by

Ci/mmol.

labelling

not

produced

Labelling

H”CN

value

12 C

for

for

section,

been

of

can

is

is

of the

H 11 CN

less

was

the

‘ 2 C

to

use. used

will

determined,

must

Unfortunately,

vary

2)Nicatalyst/450°C

l)H 2

N 2

for

by

Studies

ongoing

be

than

the

maximum

Therefore,

in

trapped

gas

sequential

be

widely

to

performed.

commercial

nature

be

that

substitution

the via

described.

generate

produced

with

PET

the

maximum

in

can

depending

but

specific

invariably

an

the

‘ 1 C-Labelled

nuclear

the

catalytic

program

be

the

aqueous

Fortunately,

positron

sale.

specific

reactions

at

specific

practically

specific

Due

activity

possible

or

on

reaction

dilutes

conversion

at

Carbon-li

very

the

CH

solution

to

activity

emitting

Cyanide

U.B.C.

activity

53

activity

of of

production

the

specific

close

11 C

the

“C

obtained

complexes

14 N(p,a) 11 C

short

of

is

of

is

specific

of

value of

The

2)PtIl000

l)NH 3

to

nucides

was

produced

9.22

the

NaOH

activity.

the

11 C0 2

the

half-life

conditions

small

[‘ 1 C]cyanide are

produced

x

is

H 11 CN

1,

activity

at

site

thought

106

(0.1

4,

according

for

in

15

The

TRIUMF/Nordion

regularly

C

5,

where

Ci/mmol,

the

MeV.

of

M)

PET,

produced

and

used.

of

amount

as

‘ 1 C

to

to

order

used

any

6

the

HCN

be

to

generate

11 C0 2

as

The

at

(20.4

with

Specific

the

“C

no

equation

well

radiolabelling

the

for

of

at

of

[ 11 C]cyanide

lower

radioactive

ubiquitous

reagent

dilution

by

mm),

TRIUMF

this TRIUMF

2

as

Na 11 CN

activity

proton

x

(2.21)

CP-42

work

other

than

2.21.

this

i0

to of

radionuclides. was

of

procedure was

arene)tricarbonylchromium recorded values

dried

added and method

the

and

NMR,

methods standard

[“C]cyanide

can

The

the

best

performed

transferred

possibly

a

its

[“Cjcyanide

radioactivity

to

radiolabeffing

was of

cannot

reaction

radioactivity

was

for

means

the

(e.g.,

chemical

and

this

used

trapped

this

[“C]cyanide

discussed

using

range

designated

HPLC

range).

be

For

with

for

to

purpose

of

mixture

used

and

a

the and

product

example,

detector

different

in

somewhere

HPLC

reaction

measured.

studies

and

aqueous

the

radiolabelling

in

spectroscopic

for

Since

is

as

solution,

was

GC),

mixture

Chapter

instrumentation

HPLC. 4 ’

direct

identification

the

complex,

connected

compounds

began

vessel

amounts

the

subjected

NaOH

start

using

between

The

product quantity

then

was

with

1,

and

of

reactions

For

methods

non-radioactive

dissolved

time

this

solution,

synthesis in

heated

this

of

labelled

dried

investigating

0.5-2000

this

to

series.

54 available.

identification.

added

of

at

that

applies

carrier-added

radio-HPLC

work,

which

actual

for

with

under

of

in

was

a

(SOS).

with

portion

characterization,

10

KCN

Ci/mmol

1

[“Cjcyanide

only

product

equipped

mL

this

minutes.

The

“C-labelled

a

analogues

‘H

the

fast

A

to (i.e.,

of

measurement

can

(CA)

best

of

Therefore,

reactivity

purification,

known

flow

DMSO,

“C

identification

this

(most

be

with

Upon

carrier).

suited

solution

is

and

as

analyzed of

solution

product

amount

as

both

such

inert

standards,

likely

of

was

follows.

cooling,

other

chromatographic

chromatographic

complex

was

of

and

a

as

gas.

added

was

The

by in

UV

of

is

and

[“C]cyanide

‘H

short-lived

taken

‘H

the

KCN

so

the

After

25-50

removed

provides

The

detector

analysis

and

general

NMR. small,*

to

1

lower

peak

with

was

was

the

the

L “C

volume

percentage

The

radiochemical

reflect

obtained

corresponding

eliminate

The

Complex

radiochemical

the

radiochemical

of

are

the

reaction

relative

of

1

summarized

variation

to

aTrace

radioactivity

was

yields

Table

to

Amount

count

used

the

Cr(CO) 3

treated

mixture

efficacy

yield

1

can

product

2.10:

41

43

65

65 [ 11 C]nitrile

65

(mol)

in

yields

of

then

was

of

in

the

time

with

in

for

Summary

was

of

Table

1

the

was

then

Capintec

be

obtained

Equation

the

taken

[ 11 C]cyanide

also

reaction

was

compared

observed,

2.10.

reaction

calculated.

150°C/lOmin

assayed

of

for

collected

KCN

Amount

0.11 0.37

0.35 0.49

well

Radiochemical

have

The

2.22

synthesis

mixture

/

55

DMSO

0

with

equiv equiv

equiv equiv conditions

added

but

counter.

first

as

at

been

and

of

the

outlined

one

its

four

contributed

and

activity

same

assayed

decay

another,

entries

used.

chromatography.

Yields

Radiochemical

in

time,

was

__l

corrected

equation

for

(Table

and

by

Yield

21%

41% 34%

36%

Obtained

thereby

18

radioactivity.

too

the

any

low

[“C]nitrile

2.10)

l4

2.22.

differences

back

determining

Therefore,

represent

The

to

An

product.

SOS

results

would

(2.22)

equal

CA

the

the to ______

reactions, while the last entry represents a no carrier-added (NCA) reaction trial. These initial results demonstrated that some cyanide carrier must be present to achieve successful labelling with 1[‘C]cyanide, under the reaction conditions used. For the CA reactions, the addition of 0.35 equivalents of KCN afforded the highest radiochemical yield (41%). A representative radio-HPLC chromatogram of a CA reaction is shown in

Figure 2.6. The chromatogram exhibits the presence of the product, [“C CN]benzonitrile 18 (peak B), and unreacted 11C]cyanide (peak A). The radio-HPLC chromatogram of the NCA reaction trial is shown[ in Figure 2.7. This chromatogram shows the presence of 18 as only a small peak, indicating a very low radiochemical yield was obtained. The time taken for synthesis and chromatography—the synthesis time—was about 30-60 minutes (measured from SOS) depending on experimental circumstances. Most typically, the synthesis time was 40-45 minutes. Additional CA 1[‘C]cyanide reactions were then performed with complexes 1, 4, 5, and 6. Each of these complexes were treated with [“C]cyanide, using 0.5 equivalents of carrier, as shown in equation 2.23. The results obtained are summarized in Table 2.11.

0.5 equivKCN RF a CN 223 Cr(CO) DMSO/ 135°C/lOmin —11 3 R

The radiochemical yields parallel fairly closely the chemical yields obtained with non radioactive cyanide under similar reaction conditions (see Tables 2.3-2.6for comparison).

Initially, H”CN was trapped in aqueous 0.005 M NaOH solution for the first two reaction trials in order to minimize the amount of hydroxide present in the [“Cjcyanide

56

Figure

25

The The

cm

radio-HPLC

compounds

x

2.6:

9

mm;

Radio-HPLC

complex

150°C.

eluent:

are:

conditions

C

z

C

The

(A,

1

with

isocratic

radiochemical

2.3

chromatogram

are:

mm),

[‘ 1 C}cyariide

A

C-18

methanol/water,

[‘ 1 C]cyanide;

reverse

TIME

yield

obtained

57

(with

phase

of

(mm)

0.37

18

(B,

from

1:1;

Whatman

was

6.5

equiv

flow

determined

mm),

the

of

rate,

analysis

Partisil

[“C-CN]bemzonitrile

carrier

5.0

to

of 10

mL/min.

be

KCN

ODS-3

the

36%.

reaction

added)

column,

18.

of at

Figure

25

The

cm

radio-HPLC

z

C,)

C

2.7:

x

9

mm;

Radio-HPLC

a

complex

0

I

trace

eluent:

conditions

of

1

18

with

isocratic

was

chromatogram

5

I

are:

[ 11 C]cyariide

produced,

/

C-18

methanol/water,

/KZ

TIME

reverse

0 T 65

10

for

(with

I

obtained

58

(mm)

a

phase

radiochemical

no

carrier

from

1:1;

Whatman

15

I

flow

the

KCN

rate,

analysis

yield

Partisil

added)

5.0

of

20

I

10

of

mL/min.

<1%.

at

ODS-3

the

150°C.

reaction

column,

Only of

trapped

reactions.

experiments,

CA

However,

[“C]cyanide

Me’F

[ 1t Cjcyanide

Starting

After

Table

examination

0.1

Cr(CO) 3

Cr(CO) 3

(using

M

Cr(CO) 3

these

Cr(CO) 3

4

6 5

1

Complex

2.11:

NaOH

was

early

0.11

Equation

Summary

of

being

solution

equiv

the

experiments,

radiolabelling

‘ 1 C-Labelled

lost

of

2.23

of

was

KCN)

Radiochemical

during

Product

used

21

20

59

19

18

it

showed

was

1

for ‘CN

the

Nitrile

results

observed

trapping

drying

that

Yields

of

in

1

H’ 1 CN.

procedure.

that

with

these

Obtained

Radio

the

NCA

cases

Yield

34%

31%

19%

chemical

radioactivity

for

[‘ 1 Cjcyanide

the

In

[ 11 C]cyanide

subsequent

of

and the

with

peaks

HPLC

was

HPLC A

for

C.

peak

the to

M

HPLC. was

obtained

tions labelling

solution

underwent

concentration

(containing

second

Next,

this

NaOH,

The

10

addition

obtained.

chromatogram

interfering

(retention

of

observed

minutes.

analysis

chromatogram

[ 1t Cjcyanide

effect

NaOH

the

The

that

from

reaction.

batch

then

nucleophulic

behaviour

trapped

of

chromatograms

efficiently

of

(little

the

of

1

The

in

solution

The

of

time,

dried

mL

with

heating

the

C.

analysis

H 11 CN

As

C,

solution,

extra

colourless

or

11 CN)

of

NCA

These

4.1

as

relative

the

the of a

no

DMSO.

substitution

trapped

to

result,

usual)

resulted

mm),

[“C]cyanide

was

peaks

carrier

of

small

trap

reactivity

[ 11 C]cyanide

was

results

a

radio-HPLC obtained

trapped

to

solution

solution

that

some

H 11 CN,

in

This

were

and

used—this

extra

earlier

used).

in

DMSO.

suggested

are

in

a

retained

solution

experiments

of

significantly

alone

peaks

dramatic

in

low

are

became

of

solution, present.

and

results.

Typically,

0.05

[ 11 C]cyanide

NCA

60

analysis

yield.

shown

introduces

Note

0.025

in

observed

that

of

M

the

DMSO

amber

[ 11 C]cyanide

change

NCA

NaOH

after

With

It

When

the

in

were

[ 11 Clcyanide

M

11 CN

reduced

was

a

was

Figure

volume

NaOH

extra

[‘ 1 C]cyanide

cooling,

in

in

when

50

the

solution

in

repeated

done

thought

solution

chromatogram

(in

A

colour

mol

the

addition

peaks,

have

in

2.8.

low

(originally

was

of

using

11 CN

appearance

size,

exhibited

upon

was

0.5

of

during

that

concentration)

and

become

Chromatogram the

and

apart

was

0H

mL

different

but

of

examined

is

drying.

perhaps

least

dried,

chromatogram

25

heated

heating.

trapped

of

present

not

A

chromatogram

into

from

/Lmol

the

0.1

concentrated

of

is

followed

eliminated.

concentra

the

compared

the

dominant hydroxide

M

the by

at

of

in

may

Radio

in

NaOH

A

radio 150°C

radio

radio-

0.025

KCN

main

was

low

be

by B

from

The

‘ 1 CN’ obtained

chromatogram

[‘ 1 C]cyanide

radio-HPLC

the

was

Figure

from

addition

4.1

that

mm

a

A,

2.8:

solution

was

0

z

and

chromatograms

in

of

Radio-HPLC

each

heated

(iii)

carrier

of

chromatogram

chromatogram.

NCA

B

at

KCN

150°C

[ 11 C]cyanide

11 CN

0

represent

chromatograms

(25

flME

for

mol)

C

61

10

was

(mm)

the

in

mm

to

obtained

DMSO,

following:

in

the

of

DMSO.

[ 11 C]cyanide

C)

[‘ 1 C]cyanide

(ii)

from

(i)

chromatogram

a

The

11 CN

chromatogram

second

in

retention

solution

DMSO.

batch

B

used

time

resulted

of

A

NCA

was

for for

indicated

tolunitrile

These

DMSO.

reaction

of A was

was undergo

glass

CC1 4 /C0 2 reduced.

[ 11 C]cyanide

described

(equation a

different

changing

The

radiochemical

Two

the

second

*Two

trapped

dried

ioop

cooled

two

identification

radiolabelling

vessel

nucleophilic

This

manner

was small

For

into

production

in

2.21),

was

as

(-23°C)

19,

results

in

is

the

reaction

estimated.

usual.

mixture

the

possible

0.025

a

containing

removed

[ 11 C-CN]-4-tolunitrile

crystals

was

general

different

yield

to

first

suggested

cooling

eliminate

M

swept

of

run

substitution.

mixture

Complex

was

trials

trial,

NaOH,

of

of by

the

from procedure.

of

a

KCN

21%.

limiting

heated

chemical

through

mixture bath.

a

were

[ 11 C]nitrile

H 11 CN

that

batch

the

showed

the

followed

6

were

For

presence

some

was

done

for

cooling

the

Any

was

of

the

of

form,

[ 11 C-CN]-4-Chlorobenzonitrile

used,

20,

that

10

the

CA

treated

hydroxide

6,

products,

with

glass by

improvement

ammonia

trapped

minutes

carrier

62

and

bath

21

second

[ 11 C]cyariide

the

in

of

which

6,

was

ioop

hydroxide

the

addition

with

[ 11 C-CN]-4-chlorobenzoriitrile

and

in

KCN

in

quantity

obtained at

[ 11 C-CN]benzonitrile

were

presence

with

trial,

which

gas,

a

the

the

125-130°C.

glass

of

(ca.

was

of

from

not helium

from

H 11 CN

the

CA

radiolabelling

hydroxide

0.11

in

0.4-0.8

in

loop

prepared

weighed,

of

H”CN

the

[ 11 Cjcyanide

29%

the

the

equivalents

transfer

hydroxide,

was

that

reaction

Radio-HPLC

[“C]cyanide

equiv*), conversion

radiochemical

21

concentration

was

slowly

was

thus

using

was

18,

efficiency

gas.

trapped

emersed

mixture.

of

at

and

the

that

[‘ 1 C-CN]-2-

obtained H”CN

added

KCN,

Then

150°C

of

21,

quantity

reagent.

1

analysis

cannot

mL

‘ 1 CH 4

yield.

with

in

to

in

was that

and

was

the

of

as

in

a a a

possibility

hydroxide model

radionudides;

In be

reasons

the

retention

radio-HPLC

demonstrated

was

minutes. nitriles

subjected correspondingly product

gas

14

accomplished

[ 11 C]nitriles

The

this

to

successfully

use

flow,

analyzed

an

instance,

labelling

radiolabelling

(14,

for

identification

of

aliquot

This

time

to

2.0

is

could

high

this

was

15,

that

radio-HPLC

fraction

by

that

mL/min)

was

the

using

as

performed

are 16,

it of

GC

consistent

increase

specific

studies

affect

the

standard

was

aromatic

general

reaction

confirmed

17).

not

(injection

radio-HPLC

was

hydroxide

was

results

thought

clear,

the

For

and

with

activity

in

purification

analyzed

performed

with

reasons

with

14.

mixture

nucleophilic

radiolabelling

the

size.

found

but

by

obtained

non-radioactive

temperature,

that

( 6 -arene)tricarbonylchromium

that

reaction

the

could

NCA

this

Moreover,

studies.

for

by

the

and

18

addition

observed

with

is

and

GC

be

this

to

[ 11 Cjcyanide

presence

not

the

substitution

in

of

63

chemically

be

GC.

the

and

results

phenomenon

an

this

assigned complex

250°C;

of

The

present

another

for

uncommon

peak

cyanide,

the

standard

The

study

of

the

in

chromatographic

peak

hydroxide,

oven

gave

reactions reaction

product

containing

1

changing

three

related

portion

at

with

are

could

(non-radioactive)

due

temperature,

were

a

a

problem

CA

retention

still

disappointing

different

peak

mixture

to

non-radioactive

with

which

of

discussed

be

the

compounds.

[‘ 1 C]cyanide,

18

preliminary,

18

reaction

(RT

CA

the

was

when

[ 11 C]cyanide

exhibited

behaviour

was

of

time ways.

=

90°C;

[‘ 1 C]cyanide

problem.

collected.

8.1

a

in

labelling

absent

reaction

result.

mixture

benzonitrile

mm)

(RT)

Chapter

additional

N 2

However,

The

the

but

aromatic

carrier

of

into

would

in

of

same

with

they

first The

trial

The

The

was

can

the

the

8.1

1. a different form, thereby reducing the already low quantity of 11CN available for reaction. Evidence for this possibility was suggested by the radio-HPLC studies of 1[‘C]cyanide alone in DMSO. It was observed that 11CN underwent change to unidentified radio- pro ducts upon heating. This observation warrants additional study to determine what is actually happening to the 11CN. The second possibility is that the hydroxide is a competing nucleophile with 11CN. Since about 50 mol of hydroxide is present, and the actual quantity of 11CN is about one to three orders of magnitude less, the hydroxide is necessarily in significant excess. Therefore, reaction with hydroxide may become the dominant process, even if hydroxide is less reactive toward chromium tricarbonyl complexes than cyanide. The final possibifity is that hydroxide could be hydrolysing the [“C]nitrile product to the corresponding 11C]amide and [‘Cjcarboxylic acid. Some water would need to be present in the [ reaction mixture1 for hydrolysis to occur. However, given the very small amount of 11C]nitrile product formed, very little water would be necessary. It is quite possible that[ the drying of the trapped [“C]cyanide solution is not totally complete, thereby leaving sufficient moisture to allow hydrolysis to proceed. Standards of the anticipated hydrolysis products, benzarnide and benzoic acid, were subjected to HPLC analysis (using the same HPLC conditions as for the reaction mixtures) and exhibited retention times of 3.2 and 2.2 minutes, respectively.

These retention times are consistent with those of the unidentified radio-peaks observed in the chromatograms presented in Figures 2.6 and 2.7.

64 2.5 Summary and Conclusions

The objective of this study was to explore the potential of -arene)tricarbony1chromium compounds as intermediates for the radiolabelling of arene structures. The results of this investigation have clearly demonstrated that chromium6 tricarbonyl complexes can be used to prepare aryl 11C]nitriles in fair radiochemical( yield. As a result, this study represents an important first[ step in the development of chromium tricarbonyl complexes for radiolabelling.

A range of simple -arene)tricarbonylchromium complexes were prepared in 12-89% yield from the reaction(i of free arene with 6Cr(CO) in a refluxing mixture of di-n-butyl ether and THF. Arenes76 bearing electron-withdrawing groups gave much lower yields of chromium tricarbonyl product in comparison to arenes with electron-donating groups.

The reactivity of -halobenzene)tricarbonylchromium complexes 1, 2, and 3 with cyanide anion was investigated and only 1 was found to undergo aromatic nucleophilic substitution successfully.6 Hence, both chlorine and bromine were determined to be ineffective leaving groups for reactions with cyanide. Therefore, the reactivity of fluorine-substituted, (chromium tricarbonyl complexes 1, 4, 5, and 6 were studied in detail.

Complex 1 was allowed to react with cyanide (0.5 equiv) in DMSO over a temperature range of 105-150°C and gave beuzonitrile 14 in 12-41% yield. The best yield (41%) was obtained at 135°C. Control experiments with uncomplexed fluorobenzene confirmed that no fluorine displacement by cyanide occurred with free fluorobenzene under the reaction conditions used for 1.

65 Complex 4 was treated with cyanide (0.5 equiv) in DMSO over a temperature range of 95-135°C, which afforded 15 in yields of 26-43%; the best yields (41-43%) were produced at 105-115°C. Complex 5 was allowed to react with cyanide (0.5 equiv) in

DMSO over a temperature range of 105-150°C and obtained yields of 11-29% of 16.

The best yields (26-29%) were exhibited at 115°C, while the next best results (22-26%) were observed at 135°C. The reaction of 6 with cyanide (0.5 equiv) in DMSO was studied at temperatures of 115 and 135°C only. The best yields of 17 (26-34%) were obtained at 115°C. The reaction time was kept to 10 minutes for these studies. When the reaction time was reduced to five minutes, the chemical yield was significantly reduced also.

The cyanide substitution reaction of 4 was also studied in the presence of 18-crown-6.

These reactions were conducted over a temperature range of 95-135°C, and improvements in chemical yield, over earlier studies, were observed throughout the temperature range examined. The best yield of 15 (46%) was obtained at 105°C using three equivalents of 18-crown-6. Clearly, the use of crown ethers shows promise toward maximizing the yields obtained from the substitution reactions of cyanide with chromium tricarbonyl complexes. Substitution reactions with 1, 4, 5, and 6 were performed using 11C]cyanide, and the corresponding aryl 11C]nitriles 18, 19, 20, and 21 were obtained. [ Some CA reactions were done (at 150°C)[ with 1 which indicated that 0.35 equivalents of carrier (KCN) was required to afford the best radiochemical yield (41%). Unfortunately, the NCA reaction trial with 1 gave only a trace of 18. These initial results suggest that some carrier must

66 be present to achieve successful radiolabelling with [“C]cyanide, however, continued development of this work could well enable NCA radiolabelling to be accomplished in the future. The aryl 11C]nitriles 19, 20, and 21 were produced in 34%, 31%, and 19% radiochernical yields,[ respectively, using 0.5 equivalents of carrier at 135°C. The synthesis times, as measured from SOS, were typically 40-45 minutes in length, and are acceptable for radiolabelling with ‘1C.

67

17.

16. 7.

15.

9.

5.

14. 6.

13. 8. 3.

4. 2.

11. 10.

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70

new prepared

in

compounds

organic successful In

31

Since

glucocorticoid

the

research

Introduction

early

molecule. 1

the

by

application

of

the

landmark

1950s,

into

potential

Squibb

activity

developing

DEVELOPMENT

the

The

of

Company

work

pioneering

biological

over

selective

fluorosteroid,

0

ways

of

FLUORINE

that

Fried

researchers,

interest,

of

fluorination

work

of

selectively

OF

cortisone

Chapter

and

9a-fluorohydrocortisone

of

71

METHODS

LABELLING

in

Sabo,

Fried

showed

order

3

to

acetate.

introducing

OAc

and

the

modify

to

approximately

FOR

study

modify Sabo

This

the

RAPID

fluorine

led

of

biological

their

report

selectively

to

acetate

the

an

biological

at

stimulated

11-fold

specific

first

activity

22,

fluorinated

significant

that

increase

activity.

sites

much

of

was

an in

486 fluorine pronounced

still

stronger resembles

analogue

substituent. unexpected pharmaceuticals

all

oxygen, molecules focus illness. medicine. 2 ’ 3

important

selective

molecules

compounds

antifungal

The

elements,

kJ/mol,

meet

of

attractiveness

is 3.16

bond

In

fluorination

study

will

hydrogen

role

and

substituted

are

steric

has

addition,

effects

is

Secondly,

electronic

with

while

for

with

usually

continuing

antiparasitic

due These

in

in

resulted

as

requirements

chlorine,

PET

an

carbon on

fluorine

to

anticancer

carbon-hydrogen

(van

pharmaceuticals

methodology. 4 ’ 5

electronegativity

biological

for

the

and

closely

applications

imaging.

fluorine,

effects

der

hydrogen.

to

in

unique

than

utility

agents,

or

chemistry.

increase,

Waals

a

resemble

and

2.96

does

at

in

variety

activity.

with

Perfluorinated

properties

of

general

enzyme

antiviral

a

for

include

radius

hydrogen—the

This

fluorine

its

molecule

bond

along

labelled

(Pauling

bromine.

the

of

Currently,

small

Firstly,

72

allows,

anesthetics,

1.20

receptor

agents,

useful

with

non-fluorinated

energy

of

the

as

van

with

fluorine

A)

scale)

hydrocarbons

after

fluorine

for

the

use

a

It

in

antiinflammatory

carbon-fluorine

der

applications

interest

varies

radioactive

substituent

instance,

sites.

recognition

is

size.

and

the

of

of

Waals

that

this

is

3.98

therapeutic fluorine-containing

introduction

As the

from

Thirdly,

in

molecule

property

can

fluorinated

as

are

a

radius

most

selectively

fluorine

result,

in

in

compared

induce

of

356

no

bond

biologically

the

biochemistry

electronegative

drugs,

fluorine

longer

(1.35

drugs

to

which

in

the

importance

of

profound

energy

( 18 F)

435

analogues

size

fluorinated

fluorinated

A),

antibiotics,

to

a

for

the

produces

forms

kJ/mol. fluorine

3.44

when

play

organic

mental

closely

is

major

active

456-

and

and

for

an

to

of

of

a a Therefore, carbon-fluorine bonds exhibit increased thermal and oxidative stabifity over that of carbon-hydrogen bonds. Lastly, fluorine, when replacing hydrogen in a molecule, usually enhances lipophilicity which increases the rate of absorption and transport of the fluorine-containing compound in vivo. In many cases, this characteristic may be the most important in improving pharmacological 67activity. An additional feature of fluorine is ’the availability of the artificially prepared radionuclide, F,18 which decays by positron emission. Fluorine-18 (half-life, 109.7 mm) is one of the four key radionuclides used in PET. The other conimorily used positron emitting nuclides (C,11 ‘3N, 150) possess very short half-lives (—‘2-20mm) in comparison to ‘8F. The longer half-life of ‘8F allows for more complex or multistep radio- pharmaceutical syntheses to be conducted, and the resulting compounds can be transported over moderate distances for use at different locations. In addition, the study of relatively slow biological processes can be performed with 8F-labelled agents, which would not be feasible with agents using nuclides with shorter‘half-lives. Furthermore, 18F-labelled compounds have the potential to produce PET images of superior resolution due to the relatively low energy positron (maximum 0.635 MeV) emitted by F18 (see

Table 1.2 for comparison)—this factor will be of increasing importance as PET instrumentation 89improves. The utilization’ of 18F-labelled pharmaceuticals with PET imaging has enabled a number of human biochemical and physiological processes to be investigated in vivo, as was presented in Chapter 1. More recently, however, the application of PET is being extended beyond the study and diagnosis of disease to the area of drug discovery,

73

understandably

time.

the

(usually

polyfunctional

compounds Moissan the

challenge biochemistry

where

with

of protocols

active

assessment

3 H-

subjects)

determine drug

development,

Underlying

fluorine

other

ongoing

and

positron

absorption,

In

molecules,

no

nitrogen),

the

in

using

‘ 4 C-labelled

halogens.

can

to

animal

the

to

was

1886,11

into

need

1930s,

of

organic

be

be

the

emitting

and

molecules

therapeutic

PET

discouraged

highly

the

used

carried

organic

distribution,

for

continued

it

models

the

approval

could

Bockemüller

imaging.

18 F-labelled

It

would

new

chemistry.

analogues

to

was

exothermic,

organic

nuclides,

out.

be monitor

at

molecules

and

potential

quickly

exist,

specific

used

of

further

be

development

These

Also,

metabolism,

chemistry

improved

new

possible—in

demonstrated

analogues

such

in

PET

the

for

Although

discovered

and

given

pharmaceuticals.

sites.

studies

research

animals.

or

has biological

selective

as

becomes

often

efficacy

of

11 C

methods

the

74 been

However,

and

via

can

fluorine

and

resulted

elemental

and

principle,

interest

with

that

that

Alternatively,

PET. 1 °

fluorination

application

complement

behaviour

of

and

elimination

a

18 F,

to

fluorine

such

the

unique

fluorine,

the

developed

selectively

in

continues

in

to

Drug

reaction

fluorine

compounds.

explosions.

at

fluorine-containing

mild

provide

of

of

tool

least—to

for

of

when

candidates

information

in

and

drug

established

fluorinated

organic

decades

slowly

of vivo

to

that

introduce

was

information

selective

fluorine

diluted

candidates

be

These

(human

study

still

For

first

in

substrates

of

after

can

comparison

obtained

compounds

with

PET

disease

enables

fluorine

prepared

considerable

with

observations

introduction

the

biologically

be

Moissan’s

or

regarding

in

inert

labelled

imaging

organic

in

vivo

animal

under

states

using

drug

vivo

into

gas

by

to

to is

conditions

temperature reaction

carrier

the has

structurally

books’ 5 ” 6

radiolabelling

available synthetic

in various

based

many

functional

as been

available

controlled

A

Currently,

sources

conventional

seen

different

primary

developed

methods

on

levels,

organofluorine

increasing

solvent,

the

for precursors

today.’ 3 ” 4

and

of

conditions.’ 2

have

groups

diverse

either

limitation

the

use

variables

on

nucleophilic

with

reaction

reviews. 4 ’ 13 ’ 17 ” 8

have

making

range

the synthetic

source of

been

nucleophilic

18 F. 8 ’ 9

application

to

either

substrate

been

that

radiochemical

reagents.

involved

organofluorine

of

of

developed

vessel

possible

of

Since

radiofluorination

can methods

fluorination elemental

developed

chemistry,

‘ 8 F,

molecules.

be

because

material,

However,

that

or

in

These

fluoride

the

electrophilic

produced

optimizing

such

for

time,

yields fluorine,

synthesis

to

are

is

introducing

fluorinating

of

derivatives,

effect

substrate

that

[‘ 8 F]fluoride

75

counterion,

continuing

many

new

Investigators

not

methodology

obtained

in

hydrogen

the

of

a

fluorine.

the

fluorinating

compatible

‘ 8 F-labelled

of

number

the

reaction

transformation

fluorine

concentration, agents

these

and

investigations

many

with

catalyst

anion.’ 9

fluoride,

have

With

is

are

can

methods,

of

[‘FJfluoride. 9 ” 9

conditions

the

organofluorine

with

agents

into

form.

studied

these

be

aliphatic

(e.g.,

catalogued

limited

However,

inorganic

organic

broadly

the

leaving

of

performed

and

fluorinating

crown

The

though

different

requirements

the

for

range

reactions

and

compounds

characterized

only

influence

[‘ 8 F]fluoride

fluorides,

its

in

ethers),

group,

compounds

successful

Reaction

aromatic

of

use

studying

multiple

reagent

organic

agents,

useful

have

with

and

‘ 9 F

of

or

of is compounds have now been successfully radiolabelled with F18 •9,20 As a result, 18F]fluoride has gained increased importance for radiofluorination work. [ In contrast to nucleophilic fluorination, a number of electrophilic fluorinating agents have been produced in 8F-labelled form, using 82[‘F]F as the source of F18 in each case. A list of the various fluorinating‘ agents prepared with F18 is presented below. However, Fluorinating Agents Labelled with ’°92F18 fluorine )2(F chlorine monofluoride (C1F) perchioryl fluoride 3F)(C1O trifluoromethyl hypofluorite 3(CFOF) xenon difluoride )2(XeF trifluoroacetyl hypofluorite (CFCOOF) nitrosyl fluoride (NOF) acetyl hypofluorite (CHCOOF) 3 N-fluoro-2-pyridone N-fluoropyridinium 3trifiates N-fluoro-N-alkylsulfonamides NFR(RSO ‘) N-fluoro-bis(trffluoromethylsulfonyl)imide2 32SONF)((CF most of these reagents have not actually been evaluated) as to their scope and utility for radiolabelling with 19F. In practical experience, the vast majority of electrophilic fluorinations are performed with [218F]F and F.182122CHCOO Acetyl hypofluorite is a relatively new reagent that was originally developed3 by Rozen and co-workers in

1,23 ’ 198 and then was prepared in 8F-labelled form in 1982? Acetyl hypofluorite has been found to be a milder and ‘more selective electrophilic fluorinating agent, in comparison to elemental fluorine, for a variety of substrate 2526molecules. Moreover, the development of a simple on-line gas-solid phase synthesis’ of acetyl 27hypofluorite has significantly increased its utility for radiofluorinations. The other 18F-labelled fluorinating agents listed previously are not trivial to produce on a routine basis, and as

76

yields

These

electrophilic

mercury

70% investigated. 28 ’ 29

silicon, little

electrophilic

derivatives radiofluorine. was

automation.

vity

experimental

available

the much

electrophilic

a

Since

result,

The

PET

of

essential

yield),

study

(2.4-12%),

additional

requirement

studies

main

-germanium,

the

(26-36%

have

program

in

such

reports

tetraphenyltin

‘ 8 F-labelled

had

fluorination.

fluorinating

group

fluorination

manipulations

that

not

It

represent

Also,

Fluorobenzene

as

or

research

was

yield). been

engendered

at

the

of

organometallic

those to

no

-lead,

U.B.C.

Adam

it

develop

known fluorination

detectable

done

form

was

agents.

The

methodology

the

of

needs

(15-56%

-mercury,

be

et

prompted

tin 30

desired

serious

for

other

first

regarding

that

methods

al., 28 ’ 29

as

was

As

to

product and simple

routine

derivatives

reaction

reports

the

successfully

yield),

be

organometaffic

a

and

the

interest

mercury

result,

that

Adam

for

to

done

electrophilic

fluorination

as

the

77

-thallium

use,

prepare

in

radiolabelling.

tetraphenyllead

possible

the

be

of

the

the

in

and

by

reactivity

with

and

rapid,

the

produced

reaction

order

PET

was

case

reactivity

co-workers 28 ’ 29

‘ 8 F-labelled

be

electrophilic

bonds,

derivatives

cleavage

to

of

well

of

the research

halogenation

efficient

perform

to

organometallic

the

of

from conditions

fluorinating develop

established.

with

of

(48%

organothallium carbon-metal

aryl-tin,

of

aromatic

phenyltri-n-butyltin

groups

studied

in

to

elemental

fluorinating

to

aryl-metal

yield),

accommodate

the

the

examine

of

be

(then

incorporation

as

agent

full

compounds

gave

organometallic

However,

compounds

mild

and

yet. 21

fluorine

bonds

potential

later)

derivative.

the

be

agents.

bonds

only

diphenyl

and

Clearly,

readily

reacti

future

poor

aryl

with

very

(48-

was

has

the

for

by

of

of It

understandable

contain

almost

various yield

yields,

compound. from

no1 45

substrates

precursors

derivative silicon

have

chemical dopa 42

lithium 38 ’3 9 been

More

silicon, 33 ’ 34 ’ 35 compounds

The

from

been

the

and

under

significantly,

respectively.

application

by

aromatic

synthetic

exclusively

derivative

yield),

corresponding

reaction

by

4-[ 18 F]fluoro-m-tyrosine 46

using

an

applied

were

and

study

reaction organogermanium, 33

have

organotin

because

respectively. used

Grignard 39 ’ 4 °

rings

options

CH 3 COO 18 F

of

with

by

using

to

the

focussed

6-[ 18 F]fluoroveraldehyde

been

electrophilic

with

the

to

other

in

strategy

CH 3 COO 18 F

precursor

organomercury

prepare

their

to

of

preparation

[ 18 F1F 2

CH 3 COO’ 8 F

radiolabelled

be

researchers

the

on

structures.

reagents

6-[’ 8 F]Fluorodopa

(—40%

available

of

many

fluorination both

(5-10%

introducing

electrophiic

and

using

were

(20%

of

organomercur 6 ’ 37

3-O-methyl-6-[ 18 F]fluorodopa 41

radiochemical

in

organic

have

to

[ 18 F]F 2 ,

derivative. 47

18 F-labelled

as

approximately

Nonetheless,

with

radiochemical

78

radiochemical

successfully

successfully

well.

was

via

fluorine

also

fluorination

compounds

but 18 F

readily

organometallic

has

As

been

interestingly

utilizing

pharmaceuticals

also

a

yield).”

This

other

synthesize

onto

prepared

result,

30%

prepared

yield) 43

yield)

derivatives.

successfully

been

of

case

of

potential

and

organometallic

aromatic

organotin, 29 ’ 32 ’ 33

various

biological

and

prepared

6-[ 18 FjFluorometarami-

intermediates

reaffirms

could 25-30%

in

and

a

from

desired

30%

[ 18 F]F 2

for

and

In

applications

radiofluorinated.

an

not

simple

rings.

organomercury

radiochemical

radiochemical

PET.

addition,

from

6-[’ 8 F]fluoro-

interest

the

aryl-mercury

be

(25%

18 F-labelled

derivatives

obtained

has

need

aromatic

an

Aryl-tin

This

organo

radio-

been

aryl

aryl

also

that

for is

fluorination

suggested use

other

mercury

corresponding reactions

demonstrated

fluorovinyl

organotin fluorination potential

site fluorosilicate

contain reagents,

a

alkyl

anion.

exist.

cyclohexyl

vinyl

Upon

as

for

fluorides

methods

Some

Alternatively,

needed.

function

the

labelling

and

review

of

in

reagents

applications

to

compounds,

fluoride 48

studies. fluorovinyl

aryl-tin

low

alkyl

of

-silicon

in

us

that

acetylenic

of

have

6%

of yield.

in

organometaffic

that

preparation

Vinyl-tin

with

fluorides

they

gave

the

their

reagents

been

radiochemical

derivatives

a

vinyl-tin

and

fluorine.

are

prompted number

Benzyl

fluorination

grouping, 7 ’ 53 ’ 54

the

and

compounds

structures. 50 ’ 51 ’ 52

readily

sufficiently

n-tetradecyl

compounds highest

have

is

are

of

suitable

[ 18 F]fluoride

substrates

of

vinyl-tin

gave

rapid.

been

derivatives

Moreover,

obtained

biologically

interest

yield. 35

chemical

studies

with

good

stable

and

prepared

for

can

Previous

fluoride 49

derivatives

79

tin

The

offered

using

radiofluorinations may

in Generally,

results

was

of

be and

to

some

as

hydride

interesting

extending

be

vinyl

aryl-metal

be

prepared

readily

via

radiochemical

nucleophilic

a

work 55

prepared

important

also.

the

from

of

general

organometallic

are

functionality

reducing

interest

however,

best

prepared

with

also

The

molecules

the

the

from

systems,

in

potential

methodology

available. 58 vinyl-tin

with

substitution

biomolecules

electrophilic

strategy

corresponding

bulk,

for

yields,

potassium

agents. 56 ’5 7

primary

by

provides

18 F-labelling.

18 F.

it

derivatives,

and

exist

reduction

although

compounds

seemed

as

of

then

and

which

These

with

benzylpenta

reagents

electrophilic

fluorination

In

to

a

specifically

secondary

stored

Grignard

potential

addition,

that

prepare

fluoride

organo

contain

such

factors

of

These

have

the

the

for

for as

vinyistannanes

vinyistannylated

mixtures,

methylpropionitrile)),

two ynopyranose

pyranose

of

estratriene

3.11.

in

17a-ethynyl-

commercially

The

acetylenic

3.2

be

a

elemental

vinyl-tin

The

literature

In

the

described.

equivalents

Synthesis

vinyl-tin

this

acetylenic

author’s

chapter,

and

28,

precursors,

fluorine

derivative

25,

1,3,5(10)-estratriene-

procedures. 57

29,

or

was

This

the

derivatives

of

and

M.Sc.

of

7,8-dideoxy-1,2:3,4-di-O-isopropylidene-D-glycero-a-D-galacto-oct-7-yno-

were

products

prepared

compounds,

Vinyl-Tin

the

tri-n-butyltin

chemical

will

characterized

and

7,8-dideoxy-l,2:3,4-di-O-isopropylidene-L-glycero-a-D-galacto-oct-7-

of

preparation

Thesis. 55

hydrostannylated

followed

and

be

a

acetyl

were

followed

steroid

were

using

most

The

Precursors

yields

17a-ethynyl-

hypofluorite.

hydride

by

acetylenic

The

isolated

of

literature

prepared

17i3-ol

by

will

of

the

heating

by

are

the

acetylenic

their

be fluorination

results

and

summarized

(see

vinyl-tin

by

presented.

1,3,5(

80

24,

methods,

precursors

by

physical

the

a

chromatographic

Schemes

Lastly,

catalytic

obtained

hydrostannylation

10)-estratriene-3,

starting

mixture

3,

derivatives

17i3-dimethoxy-

studies

properties

as

the

in

were

3.111

amount

summarized

have

materials

Table

at

successful

of

and

95°C

treated

the

employed

been

workup

of

3.1.

(optical

3.IV)

vinyl-tin

1713-diol

17a-ethynyl-1,3,5(

of

AIBN

overnight.

were

described

with radiofluorination

in

the

Each

by

for

Schemes

of

rotation

either

(2,2

23,

approximately substrates

an

corresponding

this

the

of

3-methoxy-

adaptation

‘-azobis(2-

previously

The

work

the

obtained

reaction

values,

3.1

(E)

(E)

with

10)-

and

will of Scheme 3.!

24 1) KOHIDMSO + 2) Mel

23

25

Scheme 3.11 HO_ // OH 28 -2Cr0 py HCCMgBr 3 + 2C1CH ThF

L-OH (py= pyridine) /

81 _0H

Scheme 3.111

2 20R -Sn(Bu) 3SnH(n-Bu) 3 AIBN/heat R’ 1R O 23 =HR’=R 30 =HR’=R 24 2 =HR’Me,R 31 2=HMe,R 25 2MeR’R 32 21MeR’RR

Scheme 3.W 3Sn(Bu) 3SnH(n-Bu) AIBN/heat

3Sn(Bu) 3SnH(n-Bu) / AIBN/heat 0 o\ 34

82 melting points of crystalline products), elemental analysis, and spectral data (1H NMR, mass spectrometry).

The AIBN catalyzed hydrostannylation reaction was found to be quite successful for all the acetylenic precursors used. However, higher yields of (E)-vinylstannylated

Table 3.1: Yields of (E)-Vinylstannanes Starting Material Product Chemical Yield 23 30 59% 24 31 90% 25 32 94% 28 33 61% 29 34 59% product were obtained from the steroidal acetylenic compounds, 24 and 25, in compar ison with the carbohydrate acetylenic substrates (28, 29). It is known that the hydrostan nylation reaction can produce three different isomers when using terminal 59acetylenes, as shown in equation 3.1. As a consequence, the chemical yield of (E)-vinylstarmane will

— SnH(Bu) (Bu)Sn,,H ÷ H\H + H\,,Sn(Bu) R — H 3 3 R H R 3Sn(Bu) 3R H (3.1) regioisomer Z-isomer E-isomer vary depending on the proportion of (Z)-vinylstamiane and “regioisomer” which are produced. It was observed that the hydrostarinylation reactions of 28 and 29 produced greater proportions of alternative isomeric products, thus giving consistently lower yields of (E)-vinylstannanes. The lower hydrostannylation yield of 17a-(E)-tributylstannylvinyl-

83

from

pylidene-7-C-tributylstannyl-L-glycero-a-D-galacto-oct-7-enopyranose

stannyl-L-glycero-cx-D-galacto-oct-7-enopyranose

been

alternative di-O-isopropylidene-8-C-tributylstannyl-L-glycero-c-D-galacto-oct-7-enopyranose

unprotected product

estratriene-1713-ol

1,3,5(10)-estratriene-17j3-ol

1,3,5(10)-estratriene-3,17fl-diol

During

*A

the

fully

significant

formed

hydrostannylation

a

characterized

isomeric

more

phenolic

during

recent

amount

31,

products,

hydroxyl

the

the

preparation

as

MeO’ 1 ’

of

Sn(Bu) 3

yet.

reaction;*

of

36,

isomeric

17a-vinyl-

30;

(Z)-7,8-dideoxy-

group.

was

30

However,

from

see

also

of

this

product,

Experimental

1,3,5(10)-estratriene-3,

3-methoxy-

23

isolated

was

84

in

was

HO

the

most

due

1,2:3,4-di-O-isopropylidene-8-C-tributyl-

37

3-methoxy-17a-(Z)-tributylstaunylvinyl-

preparation

(—

(Bu) 3 Sn..—

17a-(E)-tributylstamiylvinyl-

to

and

probably

10%

for

significant

Sn(Bu) 3

7,8-dideoxy-

details.

yield).

due

17-diol

of

(E)-7,8-dideoxy-1,2:3,4-

protonolysis

Compound

to

1,2:3,4-di-O-isopro-

38, the

35

were

presence

was

isolated

36 of

recovered

1,3,5(10)-

vinyl-tin

34,

has

of

both

not

the as

lidene-8-C-tributylstannyl-D-glycero-a-D-galacto-oct-7-enopyranose

or pyrine

and elemental lithium

Prior respectively.

electrophiic used

chloromercuricholest-5-en-3j3-ol and stannyl)bicyclo[2.2.ljhepta-2,5-diene) 3.3

difluoride afforded

direct a

17a-(E)-tributylstannylvinyl-1,3,5(10)-estratriene

3:2

The

Our gaseous

19k’

Labelling

Schwartz 62

for

to mixture.

fluorination

study

using

fluorination

NMR

this

the

reagents

in

under

fluorine

CH 3 COOF,

<5%

synthesis

study,

examined

[‘ 8 F]F 2

fluorine.

Compounds

Studies

It

The

prepared

various

was

yield. 6 °

and

there

and

of

of

in

chemical

evident

of

31

with

the

and

18%

a

acetyl

N-tert-butyl-N-fluorobenzenesulfonamide

fluorovinyl

was

were

conditions,

Interestingly,

Since

vinyl-tin

various

37

reactivity

the

Non-Radioactive

radiochenilcal

initially

from

and

yields

hypofluorite.

some

resulting

then,

with

38

simple

TLC

compound

compounds.

but reports

of

of

were

Di

elemental

studied

with

37

the

Flanagan

analysis

Raddo

without

crude

vinyl

85

and

identified

F 2

yield

(E)-vinylstannanes,

of

in

Fluorine

was

reaction

38

vinylmetallated

32,

(1,2,3,4,7,7-hexafluoro-5,6-bis(trimethyl-

fluorine,

and

fluorides

small

that

from

There

success.

were

et

studied,

(E)-7,8-dideoxy-1,2:3,4-di-O-isopropy-

Diksic 6 ’

by

both

al. 5 ’

scale

4-(trimethylsilyl)antipyrine.

was

mixtures

estimated

their

acetyl

in

fluorinating

but

attempted

experiments

an

prepared

71-88%

‘H

early

30,

the

compounds

hypofluorite,

were

NMR

to

31,

desired

as

33,

report

be

yield

3,17(3-dimethoxy-

analyzed

4-[’ 8 Fjfluoroanti-

to

agents

the

spectral

using

15%

and

fluorinate

product

in

having

using

source

and

which

produced

and

34,

excess

by

data.

xenon

vinyl-

been

10%,

TLC

with

Lee

was

the

for

F 2 6- multiple products, but the 17 NMR spectra indicated that the reaction of 31 with 3CHCOOF produced significantly more fluorovinyl product than with .2F It was also observed that neither fluorinating agent consumed all of the starting material. As a result, 31 was fluorinated with 3CHCOOF (Scheme 3.V) on a larger scale in the following manner. Compound 31 was treated with approximately 1.3 equivalents of gaseous 3CHCOOF in 3CFC1 at room temperature. This procedure was conducted with six portions of 31 in order to employ a sufficient amount of starting material for fluorination. The crude reaction mixtures were combined and subjected to column chromatography. The fractions containing 3-methoxy-17a-(E)-fluorovinyl- 1,3,5(10)-estra- triene- 1713-0139and 3-methoxy-l7cx-(Z)-fluorovinyl-1,3,5(10)-estratriene- 1713-ol40 were subjected to additional purification by HPLC, whereby 39 and 40 were isolated in 29.5% and 3.8% yield, respectively. Compounds 39 and 40 were readily characterized by 1H and ‘9F NMR.

Scheme 3.V

HO

HO MeO I T > CHCOOF _J.. L/ 3 + CFCI 3 HO MeO 31 MeO

86

treated

were

fluorinated

products following

This

and evaporated

small

emerged

conditions.

Firstly,

Having

room

solution

observed

excess

with

bRefers

ar.t.

39

31

general

CH 3 OH

to

CH 3 CN

Solvent

temperature.

successfully

CFC1 3

CFC1 3

Table

TIIF

product and

=

CH 3 COOF

and

(ca.

was

A

was

quantitatively

room

(by

number

the

to

40.

1.2-1.4

allowed

analyzed

procedure.

3.2:

HPLC)

the

temperature.

were

reaction

(A

Summary

with

Temperaturea

combined

isolated

equiv)

in

solution

The

of

to

obtained

when

alternative

by

-78°C

Acetyl

r.t. r.t.

r.t. r.t.

react

small

study

mixture

HPLC

results

A

of

the

the

of solution

fluorinating

of

yield

with

Hypofluorite scale

Yields at the

reaction

39

to

fluorovinyl

are

solvents,

was

room

gaseous

determine

was

of

fluorination

reactions

of

summarized

41-42%

26-31%

39 Yieldb

87

dissolved

Obtained

9.3%

24%

14%

used

31

temperature,

was

and

agent

namely

(in

CH 3 COOF

products

performed

as

the

40.

a

with

(F 2

an

in

chosen

for

reactions

combined

in

dried

or

a

external

no.

the

31

known

Table

runs

CH 3 COOF).

although

39

2

2

1

1

1

(Scheme

at

were

solvent)

methanol,

of

Reaction

and

-78°C.

yield

3.2.

of

standard.)

volume

conducted

40,

31

fewer

3.V)

Average was

The

of

Yieldb

Secondly,

of

9.3%

41%

24% 29%

acetonitrile,

14%

under

the

The

both

of

31

treated

at

best

side-products

chloroform.

opportunity

solvent

both

fluorovinyl

using

yields

different

31

with

-78°C

and

was was

the

of a

temperature.

31

to

of

tetrahydrofuran,

these

be

with

the

MeO

MeO

solvents

elemental

best

The

solvent

provided

at

results

room

fluorine

tested

MeO’

are

temperature.

improved

HO 7

for

summarized

(Scheme

F

the

yields

Scheme

fluorination

3M)

The

88

+

+

in

of

0.1%

CFC1 3

Table

yields

fluorinated

3.VI

was

MeO

MeO

reaction

—Sn(Bu) 3

F 2 /Ne

3.3.

are

studied

summarized

It

product.

was

of

31.

at

evident

both

Finally,

Clearly,

HO

in

-78°C

by

Table

both

the

CFC1 3

reaction

and

3.2.

analytical

proved

room

None of

product

for

material formation

dominant

in

30 fluorovinyl

trial

CH 3 COOF. identity

TLC

material

two

comparison estratriene-17/3-ol

The

was

CFC1 3

identification

done

identified

and

reactivity

ar.t.

treated

Temperaturea

of

was

is

was

new

at

with

of HPLC

=

41

-78°C

consumed

Table

product

room

of

r.t.

-78°C.

a

was

observed

component,

17a-vinyl-1,3,5(10)-estratriene-3,173-diol

with

new,

their

F 2

non-fluorinated

of

by

further

that

at

3.3:

temperature.

41.

30

approximately

NMR.

more

respective

-78°C.

(39

The

with

by

with

Summary

The

31

in

F 2 .

Yield

confirmed

and

polar

is

fluorine

as

TLC

the

Fluorine

The

identity

The

However, less

observed

40)

retention

NMR

of

270

component,

4.2%

9.0%

chromatogram

side-products,

of

reaction

reactive

39

0.8

and

Yields

in

of

by

MHz

and

equivalents

spectrum.

by

these

comparison

acetyl

‘H

reaction

times

TLC,

of

40

89

‘H

NMR

Obtained

toward

31

along

compounds

NMR

hypofluorite

was

with

with

24

of

with

spectroscopy

of

Yield

with

Alternatively, F 2

the

isolated

and

spectrum

to

those

F 2

dilute

for

5.4%

F 2 2.2%

than

clearly

reaction

the

other

does

35.

of

the

was 3-methoxy-17a-vinyl-1,3,5

was

of

(0.1%)

24

CH 3 COOF

by

reactions

Reaction

established

authentic

revealed result

minor

No

of

investigated.

gave

column

mixture

a

30

trace

F 2

preliminary

Yield

the

in

components.

was

in

14.5%

of

7.2%

the

performed

that

chromatography

standards.

lowest

as

Ne

of

31

via

exhibited

of

treated

formation

less

the

gas

Compound

fluorovinyl

41

HPLC;

yields

reaction

isolated

mixture

starting

(10)-

with

This

with

The

the

by

of of

fluorine performed

butyldimethylsilyl,

of

functionality

estratriene-3,

due

information

successfully

CH 3 COOF

assigned. mixture

the

of approximately

The

Unfortunately,

the

elemental

formation

to

HOJ5

crude

reactivity

the

at

exhibited

-78°C

in

as

fluorinated

The

presence

due

17i3-diol. reaction

must

which

fluorine

of

fluorinating

1.2

of

an

to

(2

corresponding

no

in

equivalents

be

several

32

its

32.

extremely

trials),

order

fluorovinyl

protected

mixture

of

was

was

extremely

was

as

the

described

to

agents.

allowed

0°C

also weak

investigated

develop

unprotected

-Sn(Bu) 3

complex

indicated

of

(1

studied

with

product

1 H

complex

gaseous

signals

trial),

to

Since

earlier,

NMR

an

react

a

mixture.

synthetic

with

the

and

easily

first.

could

of

the

CH 3 COOF

90

pattern.

phenolic

with

the

total

spectrum

fluorinated

room

fluorine

3-O-methylated

removed

be

difficulty

Four

The

approximately

route

consumption

temperature

obtained hydroxyl

19f?

and

in

small

to

could

CFCI 3

NMR

in

protecting

products

17a-(E)-fluorovinyl-1,3,5(1O)-

acetyl

fluorinating

from

scale

(E)-vinylstannane

not

group. spectrum

0.9

of at

(1

bypofluorite.

-78°C.

30

starting

trial),

which

reaction

equivalents

provide

group,

using

30

Therefore,

in

of

could

TLC

is

material

such

CFC.

the

either

trials

any

most

of

The reaction

analysis

not

31

as

useful

dilute

likely

F 2

were

The

tefl

was

and

this

use

be or

removed.

sumption

temperature.

glacial

ratio

Compound The

42,

new

of

combined isolate

amount

TLC

showed

slower

The

this

and

component

compounds

of

analysis

use

acetic isolated

migrating

the

3,17/3-dimethoxy-17a-(E)-fluorovinyl-1,3,5(10)-estratriene

71:18:11,

the

of

of

and

The

of

32

dominant

32

some

consumption

acetyl

acid

The

of

used

subjected

was

crude

material

was

were

each

plus

component

starting

reaction

and

for

hypofluorite,

added

isolated

reaction

identified

new

reaction

another

all

aninionium

MeO11

to

revealed

of

material

four

to

component

proceeded

column

some

with

a

amongst

mixture

component

trial

trials

slight

as

prepared

continued

that

starting

and

25, chromatography

acetate

exhibited

was

excess

for

was

several

observed

a

the

3,

mixture

recovered

173-dimethoxy-

91

in

about

that

material

formation

analyzed

by

elution.

two

of

similar

other

the

could

CH 3 COOF

15

different

by

of

—Sn(Bu) 3

method

minutes

in

and

TLC,

on

several

by

The

minor

not

results;

of

one

silica

TLC,

a

the

17cr-vinyl-

be

270

forms,

new,

the

portion;

of

before

prepared

components.

identified

compounds

formation

the

gel.

MHz

which

reaction

Rozen

more

was

43

TLC

1,3,5(10)-estratriene

Half

the

1 H

then

in

revealed

investigated

polar

in

et

was

NMR

an

chromatograms

acetic

of

of

mixtures

were

the

a

al? 3

approximate

a

the

In

component present.

solution

dominant,

dominant

spectrum

acid

the order

at

present.

original

room

were

next.

con

was

of to

toward

largely

minor

9 F

The

conversion 32,

to

plus

and

These

Compound

unidentified

NMR

and

9 F

MeO

some

TLC

components.

unreacted

CH 3 COOF

NMR

42,

studies

spectrum

other

chromatogram

of

but

starting

32

spectroscopy.

products,

not

of

minor

was

starting

the

in

showed

fluorovinyl

The

comparison

then

material

reactivity

components.

270

whereas

material

of

treated

MeO

the

The

MHz

the

to

product

presence

of

a

‘ 9 F

to

reaction

the

and

32

1 H with

new,

31.

indicate

NMR

The

1 H

NMR

a

43.

very

excess

slower

of

No

NMR

92

reaction

mixture

spectrum

43.

spectrum

small

fluorovinyl

Me0 7 -

that

gaseous

migrating

spectrum

MeO

this

amount

mixture

exhibited

exhibited

derivative

of

CH 3 COOF

product

the

indicated

component,

of

was

reaction

25

only

a

further

present.

is

43

few

relatively

the

in

a

could

weak

mixture

small

along

CFC1 3

presence

analyzed

However,

be

signals

unreactive

with

degree

at

obtained

revealed

-78°C.

by

of

other

due

the

25,

1 H of

7-enopyranose

45,

This

C-fluoro-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-D-glycero-a-D-galacto-oct-7-enopyranose

TLC, in

dideoxy-

gram

approximately

several

produced with

anticipated fluorination fluorine

some

addition

Next,

and

material

the

was

of

43

(Z)-8-C-fluoro-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-D-glycero-cy-D-galacto-oct-

small

1,2:3,4-di-O-isopropylidene-D-glycero-a-D-galacto-oct-7-enopyranose

the

was

the

which

use

with

isolated

to

separation

reaction

reactivity

the

of

of

a scale

consisted

46,

0.9

gaseous

could

CH 3 COOF

few

32

most

equivalents

in

by

utilizing

experiments.

minor

which

be

mixture

column

effective

of

problems.

CH 3 COOF.

identified

of

33

components.

in

four

44

F 2

toward

chromatography

revealed

acetic

of

was

fluorinating

was

dilute

different

In

in

the

The

acid,

the

a

fluorine

not

mixture

the

fluorine

dominant

reaction

The

first

pursued

whereas

93

compounds

formation

Sn(Bu) 3

agent

dominant

experiment,

and

and

of

in

of

products.

used

component.

CFC1 3

acetyl

only

due

subjected

32

of

with

with

that

new

to

a

a

at

hypofluorite

minute

33

new,

the

elemental

-78°C.

These

32.

were

component,

to

was

low

more However,

1 H

amount

identified

allowed

results

The

NMR

potential

fluorine

polar

was

TLC

as

of

suggested

spectroscopy.

a

to

examined

observed

43

larger

component

as

44,

chromato

react

yield

produced

could

28,

(E)-8-

scale

with

7,8-

that

and

by

be in

major

CH 3 COOF

spectroscopy,

dominant formation

temperature.

Column

acid

CH 3 COOF

In

For

was

the

component.

the

third

removed.

chromatography

new

of

prepared

in

second

which

a

The

experiment,

CFC1 3

component

dominant,

reaction

/°KL

The

HO

revealed

experiment,

in

at

a

crude

-78°C.

solution

28

33

slower

observed

of

was

F

that

was

reaction

the

allowed

Analytical

33

a

treated

migrating

of

reaction

mixture

by

was

glacial

mixture

TLC.

to

with

added

94

proceed

of

TEC

acetic

mixture

component

This

44,

approximately

was

to

of

45,

acid

for

material

HO

analyzed

the

approximately

and

resulted

about

and

plus

reaction

46

44

ammonium

was

was

by

10

a

1.2

o\

in

few

minutes,

TLC,

present

examined

equivalents

mixture

the

minor

0.8

which

isolation

acetate

and

equivalents

then

revealed

components.

by

showed

of

44

the

‘H

gaseous

at

was

of

NMR

acetic

room

the

the

the the of

portions

CH 3 COOF maimer.

fluorination

supply

continued

CH 3 COOF degree

formation

CH 3 COOF largely gel),

dominant

Compound

The

/

and

of

fluorination

a

of

[—OH

of

33—as

mixture

analyzed

new

Compound

Sn(Bu) 3

using

of

conversion

in

in

was

34

work

a

acetic

CFC1 3 34

component,

dominant,

to

the

starting

the

of

was

increase

by

could

most

studies

L-glycero-a-D-galacto

45

acid

at

34

1 H

of

fluorinated

and

CH 3 COOF

room material—was

solution

effective

was

33

CFC1 3

and

not

more

as

46,

of

the

to

observed

treated

temperature.

19 F

be

33,

with

fluorovinyl

poiar

reaction

produced

NMR

fluorinating

conducted.

Scheme

with

though

some

with virtually

component

by

CH 3 COOF

/

spectroscopy.

epimer

95

TLC,

scale.

unidentified

qualitative

44

approximately 3.VII

product

This

[—OH

as

agent

all

was

F

Therefore,

34

the

The consumed

procedure

and

isolated

instead.

used.

(Scheme

main

(45

in

a

impurities

crude

This

few

nature,

and

product.

This

1.3

via

fluorination

+ so

material

was

minor

46).

reaction

3.VII)

equivalents

that

preparative

agent

showed

performed

present.

/

further

Unfortunately,

The

components.

in

was

gave

[—oH

mixtures

the

studies use

that

found

larger

TLC

of

the

following

with

of

gaseous

gaseous

highest

(silica

F 2

to

were

were

scale

The

two

the

be or

will

TRIUMF

3.4

In

measured

to

deoxy-1,2:3,4-di-O-isopropylidene-L-glycero-a-D-galacto-oct-7-enopyranose

collected

7-enopyranose

7-enopyranose

chromatography di-O-isopropylidene-L-glycero-a-D-galacto-oct-7-enopyranose

of

combined

Compound

this

be

47,

be

Radiofluorination

36%

section,

presented.

(Z)-8-C-fluoro-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-L-glycero-a-D-galacto-oct-

which

by

facility.

and

and

‘H

47

the

subjected

10%,

48,

was

49.

NMR

fraction,

was

radiofluorination

and

Fluorine-18

The

found

respectively.

The

readily

7,8-dideoxy-

Work

spectroscopy.

production

to

and

to

ratio

column

contain

characterized

then

can

of

Furthermore,

chromatography.

1,2:3,4-di-O-isopropylidene-L-glycero-c-D-galacto-oct-

components

two

of

be

of

a

The

(E)-vinylstannane

single

18 F,

fractions

produced

96

isolated

by

like

compound,

‘H

an

11 C,

in

were

either and

yields

additional

each

is

(E)-8-C-Fluoro-7,8-dideoxy-1,2:3,4-

‘ 9 F

collected

also

31

identified

using

of

chromatography

oc

NMR.

using

47

routinely

0

47

fraction

the

and

that was

acetyl

as

TRIUMF

48

isolated

contained

(E)-8-C-acetoxy-7-

performed

was

were

[‘ 8 Fjhypofluorite

50

subsequently

by

fraction

determined

in

500

‘H

mixtures

the

NMR.

at

MeV

first

was the

stabifity literature

labeffing radiofluorinated

recoveries

derived

activity

target for

small

cyclotron This

labelled 20 Ne(p,Spall) 18 F

irradiation TRIUMF

cyclotron

the

cyclotron,

Therefore,

Unfortunately,

[ 18 F]F 2

*Natural

2 °Ne(p,2pn) 18 F

process

percentage

gas

of

of

from

F 2 .

reagent

target,

about

target

mixture

production.

the

[ 18 F1F 2

of or

500

of

neon

all

[ 18 F]F 2

creates

more

a

negative

[ 18 F]F 2 ,

gas

MeV

producing

reaction

electrophilic

is

product

and

is

(0.

that

the

consists

in

constructed

mixture

[ 18 Fjfluoride

nuclear

efficiently

1-2.0%)

are

order

provides

a

cyclotron

can

production

fluorine However,

result

thin

obtained. 9

at

must

be

of

high

to

of

500

reaction.

of

layer

fluorinations

90.92%

achieved

significantly

natural

with

in

molecular

a

be

from

ion

MeV.

specific

be

anion. 65

source

if

products

produced

of

of

in

the

the

As

utilized.

nickel-based

nickel

of

the

Ne*

[‘ 8 F]F 2

For

The

a

is

amount

smaller

of

20 Ne,

activity

result,

fluorine

Nonetheless,

reported

gas

97

with

increase

performed

carrier

this

radiofluorine

fluoride

of

in

phase

is

0.26%

Radiofluorine

approximately

high

TRIUMF/Nordion

of

the

low

work,

[ 18 F]F 2 .

necessarily

must

carrier

fluorine

alloy,

to

specific

practical

and

specific

specific

within

of

with be

circumstances

there

be

21 Ne,

attract

it

The

around

is

F 2

present

18 F-labelled

to

must

activity,

obtained

the

is

activity,

upper

has

carrier-added.

was

and

key

be

0.1%

activity. TM

reduced

the

interior

been be

12

present.

in

idea

8.82%

produced

gaseous

limit

F 2

low CP-42

Ci/mmol. 63

passivated

the

the

in

required

present

discussion

F 2 ,

is

too

the

yields

neon

on

surface

only

of

to

Whenever

and

cyclotron

Moreover,

anionic

much

form

the

22 Ne.

exploit

by

Since

target

available

and

using

reagents

that

with

specific

proton

of

of

in

in

poor

‘ 8 F

18 F-

the

the

the

gas

the

the

the

the

via

F 2 .

a a

When

in mixture,

The

18 F yield

yield

source

an such incorporated

yield

produced would

corresponding

expected

electrophilic target,

date, to

The

Ne.

Another

unfortunate

an

production

500

as

continues

possible

at

there

irradiation

electrode,

represent

general

of

The

it

CH 3 COO’ 8 F,

best,

then

MeV

to

would

fluorine-18. 9

would

aspect

are

target

be

rather

fluorination

pure

since

is

radiofluorination

parameters cyclotron

procedure

to

disadvantage

present no

50%.

be

be

a

then

of

regarding

be

gas

Ne true

reports

there

the

than

fluorine-18

a

which

50%

mixture

perform

was

statistical

Due

cyclotron

breakthrough

in

gas

the

is

reaction

because

used

were

a

of

added

contain

to

the

target

only

fluorine-19

18 F-labelled

of

anyone

the

was

an

use

(i.e.,

procedure

for

all

10

improbability

target

a

to

need

irradiated

was

electrochemical

all

mm

radiofluorination

only

proceeded

of

50%

the

dilute

18 F—’ 8 F).

exploiting

18 F-labelled

for

these

filled

was

of

of

radiofluorination

one

atom.

probabffity

F 2

high

98

target

carrier

would

the

stopped,

molecule

reagents

fluorine

with

with

F 2

specific

For

in

that

Therefore,

this

irradiation

be

gas

F 2

the

F 2

100%

the

reactions

oxidation

expected

both

to

approach,

is

of

atom,

the

methods

are

content

desired

(i.e.,

500

that

be

activity

the

time

maximum

prepared

fluorine

reactions

present

MeV

only

the

the

18 F—’ 9 F).

fluorine-18

at

using

to

was

to

to

amount

that

maximum

69

maximum

radiofluorinations.

but

give

one

proton

approximately

generate

A

noted

in

fluorination

from

atoms

utilize

such

chemical

of

50%

fluorine-18

the

of

As

of

31

beam.

atom

beam

and

[ 18 F]F 2 .

a

neon

radiochemical

1%

radiochemical radiochemical

a

in

[ 18 F]F 2

is

[ 18 F]F 2 . 19

development

result,

designated

as

the

F 2 /Ne

becoming

yield,

cyclotron

current.)

reagents

(Typical

0.1%

follows.

atom

This

{ 18 F]F 2

as

if

gas

the

the

To

an

F 2

is is

MeO

was

radiochemical present

corrected

radio-HPLC

assayed gaseous

CFC1 3

evaporation of

dissolution

as

Compound

the

the

collected,

end

target

(20

in

at

acetyl

back

of

the

mL).

the

in

of

purification

bombardment

were

31

reaction

yield

then

some

[‘ 8 F]hypofluorite

to

same

CFC1 3 ),

31

was

The

BOB.

HO

passed

was

assayed

chloroform,

radiofluorinated

time

reaction

mixture.

then

along

and

through

in

(EOB).

for

determined.

the

order

with

mixture

activity.

Based

and

peak

a

a

small

the

After

Scheme

to

was

potassium

with

corresponding

CH 3 COO 18 F

on

determine

was

ammonium

An

target

aliquot

The

added

the

CFC1 3

CH 3 COO’ 8 F,

assayed

equal

3

total

resulting

VIII

irradiation

acetate/acetic

to

of

volume

the

activity

a

acetate/acetic

reaction

for

to

solution

MeO

MeO 3

percentage

radiochemical

‘ 8 F-labelled

radioactivity

as

of

of

was

outlined

reaction

mixture

‘ 8 F

of

acid

completed,

produced

31

of

acid

fluorovinyl

column

(110-120

in

(before

product

yields

was

mixture

Scheme

column.

HO

HO

subjected

the

at

were

to

EOB,

and

mol)

that

was

contents

produce

product

3.VIIL

decay

After

after

also

was

the

to in

parameters

the

experiment, The

triene-

determinations conducted radiofluorination maximize

The

efficiency relative

The

isolated

specific

results

17-o1

identification

to

of

the

at

fluorinating

Table

described

bRefers

chemical ar.t.

of

product

activity

obtained

incorporation

the

51

room

CH 3 COO 18 F

[ 18 FJF 2

chemical

=

was

and

—0.77

—0.50

—0.50

—0.74

room Amount

specific 3.4:

reaction

temperature.

of

to

mixture

of

3-methoxy-

a

yield

are

produced

earlier

Reaction

Summary

this

the

temperature.

the

equiv

equiv

equiv

equiv

agent

mixture

yield,

summarized

of

product

combined

activity

was of

used

[ 18 F]fluorovinyl

of

would

was

radiofluorine.

in

31

determined

but

17a-(Z)-[ 18 F]fluorovinyl-

of

at

of

order

of

determined

The

gave

mixture

EOB. 31

Radiochemical

of

be

3-methoxy-

could

yield

with

Temperaturea

radiolabelled

in

to

of

CH 3 COO’ 8 F

the

100

Table

minimize

quite

-78°C

-78°C

was

of Acetyl

products

produce

from

r.t.

r.t.

highest

Using

51

to

not

17-a-(E)-[ 18 F]fluorovinyl-

low

3.4.

and

be

the

[ 18 FjHypofluorite

Yields

determined.

excess

side-reactions

specific

about

radiochemical

lower

51

product

generated

52;

initial

Compound

and

1,3,5(

the

fluorinating

Obtained

Radiochemical

190

radiochemical

52

activity

activity,

radio-

that

10)-estratrien.e-

Yieldb

was

mCi/mmol.

5.0%

9.7%

19%

19%

However,

using

31

was

and

accomplished

yields

for

was

as

agent

isolated

to

expected.

18 F

the

1,3,5(

kept

maximize

in

yields.

(19%)

production

would

Therefore,

a

17i3-ol

10)-estra-

in

separate

for

excess

using

when

yield

help

The

the 52.

hypofluorite.

most

for fluorovinyl

[‘ 8 F]hypofluorite The

3.5

The from

reaction

Clearly,

thereby

successfully

spectroscopy. that radio-HPLC

radiofluorinations

allowed

addition,

The

In

radiofluorinations

Summary

purpose

observed

additional

of

EOB

this

vinyl-tin

the

confirming

the

is

to

the

study,

essentially

compounds

to

vinyl-tin

decay

synthesis

extended

studies.

In

leftover

of

the

for

and

substrates

The

addition,

time

this

in

the

isolation

to

the

done

Conclusions

respectable

the

substrates

19J

fluorination

study

instantaneous

zero

required

reaction

with

time

The

related

from

to

successful

NMR

at

one

were

accomplish

chromatographic

activity.

‘ 8 F.

of

is

was

vinyl-tin

room

quite

of

crude

studied

non-radioactive

mixtures

readily

spectra

thereafter

This

radiochemical

to

the

reaction

radiofluorination

temperature

develop

short

vinyl-tin upon

reaction

These

intermediates,

objective

were

the

obtained

readily

(after

and

addition

101

was

18 F-labelling

of

successfully

a

mixtures

behaviour

derivatives

mixture

well

general

31

radio-HPLC

was

yield.

fluorovinyl

for

confirmed

from

(first

with

of

suited

indeed

the

and

of

fluorinating

was

were

the

methodology

two

gaseous

31.

of

was

to radio-HPLC

fluorinated

of

AIBN

for

in

51

utffize

fulfilled

compounds

the

entries

then

analysis),

31.

radiofluorinated

the

and

radiolabelling

presence

acetyl

catalyzed

order

this

analyzed

The

agent.

52

to

of

using

to was

synthetic

purification

obtained

a

of

Table

radiofluorination

hypofluorite

(39

directly

large

The

consistent

15-17

gaseous

of

hydrostamiyl

by

and

with

39

with

time

degree,

3.4),

‘ 9 F

approach

from

minutes.

prepare

and

40).

‘ 8 F.

acetyl

acetyl

NMR

work.

taken

were

with

was

the

40,

as In

be product,

yield.

with

mixture produced

all CH 3 COOF protecting

result from isomeric

employing toward hypofluorite,

an

elemental ation

(Z)-fluorovinyl

Compound

The

Compound

performed.

consumed,

analogous

elemental

the

of

is

The

most

fluorination

of

the

most

but

mixture

reaction

only

fluorine

this

products.

elemental

reactivities

(prepared

corresponding

gave

at

33

effective

likely

30

manner

so

Therefore,

group,

40

fluorine

a

room

was

that could

(yields

44

trace

of

were

and

due

readily

as

31

as

temperature,

further it

F 2

in

to

fluorinating

not

of

acetyl

the

with

would

of

prepared

gave

compared

determined

to

as

31.

acetic

fluorination

(E)-vinylstannanes

(E)-fluorovinyl

acetylenic

the

be

main

fluorinated

some

CH 3 COOF.

larger 9.0%

hypofluorite

Alternatively,

be

directly

presence

acid

product.

anticipated

and

43

which

to yield

via

scale

agent

precursors,

solution)

could

studies

isolated

31.

fluorinated

using

HPLC

of

at

102

afforded

reactions

However,

under

product

used

the

best.

Reaction

be

32

gaseous

were

30,

that

analysis).

in

unprotected

or

obtained

was

to

with

varied

31,

29.5%

Furthermore,

30

using

with

yields

continued

with

43.

fluorinate

found

the

32,

CH 3 COOF.

can

of tri-n-butyltin

F 2

conditions.

either

gaseous

Better

stock

and

33,

In

of

32

be

as

also

to

4

contrast,

phenol

successfully

and

a

with

with

1-42%

3.8%

be

of

minor

F 2

31

results

(E)-fluorovinyl

generated

CH 3 COOF

34

33

Treatment

L-glycero-a-D-galacto

relatively

or

gaseous

was

yields,

hydride,

function

of

had

were

CH 3 COOF.

fluorination

component

39

were

gaseous

been

fluorinated

and

studied

respectively,

fluorinated

CH 3 COOF

unreactive

in

of

of

could

observed

virtually

40

59-94%

33

30.

39

acetyl

as

of

with

This

with

in

and

not

By

31

an

in a

were

radiochemical room

radiolabelling

and epimer

[‘ 8 F]fluorovinyl

Compound

10%

of

temperature)

34

the

yield,

instead.

order

with

31

51

yield.

respectively.

was

and

18 F.

of

and

Compound

radiofluorinated

(Z)-[ 18 Fjfluorovinyl

15-17

(E)-fluorovinyl

The

minutes

radiolabelled

34

was

(measured

47

using

allowed

103

52

and

product

of

gaseous

(Z)-fluorovinyl

low

to

from

specific

react

consists

acetyl

EOB)

with

activity.

[ 18 F]hypofluorite

48

which

of

gaseous

were

a

The

is

mixture

obtained

well

CH 3 COOF

reaction

suited

of

in

in

times

36%

19%

(E)

for (at References

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Phelps,

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30,

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Sastry,

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1886-1889.

Massin,

D.

E.

Barrio,

C.;

P.;

v.;

N.

L.

E.;

J.

43-46.

K. Isot.

R.

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Grafton,

Phelps,

Herscheid,

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Nucl.

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A.

F.;

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1994,

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C.

Brinlcman,

J.

Labelled

1983,

Theriault,

R.

Fox,

C.;

R.

Med.

J.

M.

S.

34,

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Med.

mt.

34,

J.

T.;

E.

J.

J.

565-570.

1984,

613-615.

J.

J.

Compd.

Huang,

.1.

D.

Y.

G.

Chem.

K.

Appi.

Nuci.

Med. 1989,

1988,

M.;

X.;

A.;

25, C.;

65. 63.

64. 62. 59.

61. 58. 57. 55.

56.

60. 54.

53.

52.

Bioorganic

pp van

See Di Banks,

See Lee,

596-598. Poller,

See Jung, Ailmendinger,

Buescher,

Omae, Balatoni, and Bey,

Franke,

Chemical Chemical

Raddo,

112-113.

Bioorganic

reference

reference

reference

der

P.;

S.

M.

R.

R.

I.

H.;

Kerk,

L.

McCarthy,

J.

J.

E.;

Society:

Society:

C.

E.;

R.

P.;

A.;

Chemistry;

Schwartz,

Organomet.

A.,

The

R.;

Light,

Haszeldine,

9;

9;

9;

Diksic,

G.

T.;

Hanson,

Chemistiy;

M.Sc.

p

pp

p

Lee,

Chemzstiy

J.

Felder,

Washington, Washington,

37

5.

3.

M.;

22-24.

L.

J.

R.;

Thesis,

and

M.

K.

Welch,

Chem.

J.

A.

R.

Noltes,

.1.

mt.

E.;

McDonald,

Welch,

Am.

R.

43.

N.

Tetrahedron

Org.

of

Hungerbuehler,

N.;

J.

The

J.

J.

Organotin

Libr.

Chem.

App!.

DC, DC,

J.

Nucl.

Chem.

T.,

Prodgers,

J.

University

C.

T.,

1989,

1991; 1991;

Ed.;

107

J.

I.

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Med.

Soc.

Ed.;

App!.

1982,

A.

Left.

Compounds;

ACS

21,

Chapter Chapter

In

1986,

A.

ACS

1984,

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of

Isot.

47,

Chem.

1982,

Selective

1-341.

J.

Symposium

In

British

Chem.

108,

Symposium

404-408.

25,

1985,

Selective

8.

13.

23,

1959,

1116-1121.

2445-2447.

Academic:

Fluorination

Columbia,

385

Soc.,

36,

9,

Fluorination

1-3854;

Series

953-956.

Series

Perkin

106-113.

New

Dec.

456;

in

Ensley,

456;

Trans.

Organic

York,

in

1985.

American American

Organic

1

H.

1970;

1973,

and E.;

with

a

and

to

drying

nucleophilic

an

to be

organotransition represents The

addition short-lived

attached

chromium

study

The

improve

investigation

the

the

the

additional

investigation

of

application

first

metal

of

use

of

the

arene

alternative

complexes

the

radiochemical

nucides.

various

step

of

forms

[“C]cyanide

centre.’

first

smaller

studies.

ring

of

to

metal

application

of

presented

various

of

nucleophiles

a

with

ways

From

can

chromium

range

medically

volumes

A

complexes.

This

“C

be

solution

yields,

further

of

crown

a

of

used

via

GENERAL

pattern

trapping

broader

of in

new

of

useful

nucleophilic

particularly

chromium

tricarbonyl

exploration

onto

Chapter

as

and ether

reaction

A

radiolabelling

synthetic

of

perspective,

microwave

number

H 11 CN

unsaturated

Chapter

radioisotopes, 2

and

reactivity

CONCLUSIONS

108

2

tricarbonyl

solvent

with

complexes

other

of

substitution

demonstrated

intermediates

in

of

reaction

4

the

NCA

heating

transition

catalysts,

however,

methods

needs

organic

to

absence

such

concentrate

complexes

[“Cjcyanide.

could

conditions

with

of

to

molecules

as

metal

for

based

the

employment that

this

of

be

be

‘ 8 F,

[ 11 C]cyanide.

the

hydroxide

radiolabeffing

accomplishment

explored

significantly

for

( 6 -arene)tricarbony1-

systems

75 Br,

the on

should

radiolabelling

radiolabelling

This

the

while

reactants.

77 Br,

of

could

be

may

utilization

facilitate

further

microwave

complexed

This

conducted

and

advanced

reaction,

result

include

of

123 j

result

could

Also,

with

with

the

the

in of significantly improved labelling yields. Furthermore, other potentially effective leaving groups should be explored to complement or supersede fluorine. Lastly, the substitution reactions of F-, Br, and 1 with chromium tricarbonyl complexes warrant study because of the importance of radiohalogens in nuclear 2medicine. The investigation described in Chapter 3 revealed that vinyl-tin derivatives can be directly fluorinated with gaseous acetyl hypofluorite, in most cases, to produce stable and 8F-labelled vinyl fluorides. This result represents another extension of the use of organotin‘ compounds for electrophilic fluorinations, including radiofluorinations with ‘8F. Very recently, other researchers have reported using vinyl-tin compounds to prepare vinylfluorides. Tius and 3Kawakami fluorinated a number of simple vinyl-tin derivatives with 2XeF (in the presence of )6AgPF in 24-52% yield, however, reaction times ranged from 3-18 hours. Hodson and 4co-workers used cesium fluoroxysulfate to fluorinate some vinyl-tin compounds which produced vinyl fluorides in 25-56% yield, and in some cases, a-fluoroketones were unexpectedly made in 47-75% yield (reactions were run overnight). Matthews et 5al. reported the electrophilic fluorination of several (fluorovinyl)stannanes with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2joctane bis(tetrafluoroborate) affording difluoro olefins in 35-74% yield (30 mm reaction time at 80°C). Each of these reports provides new methods for fluorinating vinyl-tin compounds which is very positive, however, each of these methods, for various reasons, would appear to be incompatible for radiolabelling with ‘8F. What is gratifying is that several years after choosing vinyl-tin intermediates for our fluorination studies, other research groups are also selecting tin reagents for the preparation of vinyl fluorides.

109 Undoubtedly, the application of organotin compounds will continue to be extended as interest in selectively fluorinated organic molecules remains.

Nonetheless, the following suggestions for future work can be made. The exploration of alternative fluorinating agents for use with vinyl-tin substrates would be very prudent.

Also, the reactivity of fluorine and acetyl hypofluorite should be further examined with a wider range of structurally diverse vinylstannylated derivatives. Moreover, the fluorination of vinyl-silicon and -mercury derivatives warrant some additional study.

In retrospect, it is pleasing to see that although a few years have unfortunately elapsed since the experimental work was performed and the writing of this thesis completed, the results obtained are still new and currently relevant, and have not been duplicated in the literature. Even though various aspects of the specific experimental studies could have been done differently, the studies pursued for this thesis were well worthwhile and exhibit significant future potential. The application of organometallic compounds as synthetic intermediates for radiolabelling is only in the early stages of development still, but will continue to expand with future research.

110

5. 3.

4.

2.

References

1.

Lett.

Hodson,

Tius,

Nozaki, Davies,

Matthews,

2, Pergamon:

Chapter

1993,

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T.

S.

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D.

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34,

3.

Toronto,

F.;

Kawakami,

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P.;

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3057-3060.

Madge,

Miller,

1982;

D.

S.

J.

C.;

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Production;

3.;

Chapter

Synth.

Widdowson,

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Metal

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111

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Helus,

T.;

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F.,

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Applications

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1461-1471.

BocaRaton,

to

831-832.

Organic

J.

R.

Tetrahedron

1983;

Synthesis; Vol.

were

pressure was

methoxide

solvents

acetonitrile

pressure

acetonitrile

sodium

using

on

determined

capillaries

except

Solutions

5.1

Tetrahydrofuran

a

General

Fisher-Johns

distilled

filtered

a

for

benzophenone

used

high

from

liquid

were

prepared solutions

(in

were

and

using

were Methods

vacuum,

(0.45

air)

from

calcium

methanol,

concentrated

chromatography

distilled

a

melting

using

of

m

(THF)

Perkin-Elmer

in of

sodium

spectro

rotary

ketyl.’

situ

hydride,

organochromium

Millipore

a

from

Büchi

point

and

by

and

or

under

vacuum

under

reaction

Dimethyl

reagent

calcium

reagent

then

apparatus,

diethyl 510

(HPLC)

brand

model

EXPERIMENTAL

reduced

oil

carefully

nitrogen,

grade

Chapter

pump

hydride.

of

grade,

bath

ether

sulfoxide

Durapore

complexes,

141

methanol

112

and

work,

hexanes

melting

assembly.

pressure

polarimeter.

and

were

stored

are

5

Methanol

while

(DMSO)

singly

were

uncorrected.

with

membrane)

distilled

which

and

point

under

with

hexane,

used

magnesium

Melting

distilled

diethyl

was

apparatus,

were

was

a

nitrogen.

without

from

distified

Büchi

distilled

before

dichioromethane,

ether

Optical

concentrated

points

water,

calcium

turnings.

rotary

further

or

were

from

Di-n-butyl

use.

under

were were

rotations

HPLC

used,

magnesium

evaporator,

hydride

treatment.

All

obtained

For

in

taken

reduced

which

vacuo

grade

other

ether

were

high

and

or in

mm,

water/acetoriitrile,

also hexanes/diethyl

(85:15)

solvent

Phenomenex

series

(column of

performed

operated system,

performed

column

compounds). short-wavelength

effected

x

(Baker-flex

HPLC

Thin-layer

9

the

mm,

used

and

(column

following

was

a

mixtures

chromatography

either

A),

a

was

Rheodyne

equipped

at

for

constant

using

using

used,

254-280

Silica

(b)

Ultremex

done

chromatography

HPLC:

The

B),

by

ether,

columns,

Silica

two

followed

Silica

UV

were

(a)

gel

(c)

with

with

TLC

1:1

7126

composition

nm,

Waters

spraying

a

light,

(i)

1B2-F

4:1

gel

(solvent

5

a

C-18

gel

used

a

solvent

injector,

and

system

of

Silica

from

either

Waters

(solvent

by

60

60

or

the

reverse

or

a

a

10

(E.

for

with

(c)

(TLC)

(E.

Spectro-Physics

0

systematic

column,

B),

E.

individual

consisting

(a)

systems

of

m

an

to

Merck,

C-18

HPLC: by

D).

Merck,

Merck

100%

30%

a

(iii) ISCO

10 phase

C-18

visual

Waters

was

guard

The

mm,

25

used

sulfuric

water/acetonitrile,

113

230-400

methanol

(model

of

increase

Silica

reverse

(i)

70-230 compounds.

Whatman

performed

cm

inspection

following

a

an

column

10

were

methanol/water,

Spectro-Physics

SP

x

Lm

acid

gel

isocratic

mesh)

V 4 )

10

mesh).

phase 4270

to

was

very

60,

C-18

mm

in

(column Partisil

variable

100%

gradient

(for

on

maintained

ethanol,

integrator

No.

by

similar

Column

RCM

reverse

(column

mixture

pre-coated

Flash

coloured,

the

methanol

3:2

5534).

10

wavelength

C),

SP

solvent

method

columns

ODS-3

to

(solvent

1:1

then

chromatography

chromatography

8700

phase

or

recorder,

of

D).

those

from

Visualization

(d)

(solvent

organochromium

methanol/water

heating,

silica

during

solvent

programs

column,

of

The

RCM

normal

connected

listed

12

C),

UV

Still

to

gel

using

following

and

10

detector

A),

delivery

(b)

column

20

et

for

25

phase

plates

to

were

mm

al. 2 with

one

(iv)

was was

was

(ii)

the

cm

12 in (solvent program A), and (ii) from 0 to 18 mm, an isocratic mixture of methanol/water

(75:25) was used, followed by a systematic increase to 100% methanol during 18 to 21 mm, and a constant composition of 100% of methanol was maintained from 21 to 30 mm

(solvent program B). Radio-HPLC analysis and purification was performed with the same HPLC system fitted with a NaI(Tl) scintillation detector system and a dual channel strip chart recorder. Radioactive samples were assayed with either a Capintec well counter (model CRC-543X) or a Beckman 8000 scintillation counter.

Analytical gas chromatography (GC) was performed with a Hewlett-Packard model

5840A GC, equipped with an FID detector, using a 30 m x 0.75 mm i.d. wide bore

(Supelco SPB-1) capillary column. Unless otherwise stated, GC analyses were performed isothermally using the following conditions: injection temperature, 200°C; oven temperature, 120°C; 2N carrier gas flow, 2.0 mt/mm.

Low resolution electron impact mass spectra were recorded with either a Kratos/AEI

MS902 or a Kratos/AEI MS5Omass spectrometer. An ionization potential of 70 eV was used for the mass spectra obtained. Spectra are quoted as m/z values, while selected ion fragmentations are reported as percentages of the base peak. High resolution mass measurements were determined using the Kratos/AEI MS5Omass spectrometer. Gas chromatography-mass spectrometry (GC-MS) was performed using a Delsi Nermag RiO

1OCquadruple mass spectrometer interfaced with a Varian 6000 GC or a Kratos MS8O coupled to a Carlo Erba 4160 GC.

All microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory,

University of British Columbia.

114 5.2 NMR Methods and Instrumentation

1H NMR spectra were measured at room temperature at 270 and 400 MHz. The 270

MHz spectra were obtained with a home-built spectrometer based on a Bruker WP-60 console, a Nicolet 1180 computer (32K), a Nicolet 293B pulse programmer, a one

Megabyte Diablo disk drive (model 31), and an Oxford Instruments Superconducting solenoid magnet. In addition to this spectrometer, a separate data processing system, consisting of another Nicolet 1180 computer (32K), one Megabyte Diablo disk drive

(model 31) and a digital plotter, was available for processing and plotting of NMR data.

Standard NTCFTB software was used on the spectrometer and data station.

Furthermore, some of the 270 MHz data was transferred from the Nicolet 1180 data station to a newer Nicolet 1280 computer, for processing with increased computer memory and digital plotting.

The 400 MHz spectra were obtained with a Bruker WH-400 high-resolution spectrometer equipped with an Aspect 3000 computer. Along with this spectrometer, a separate Bruker data processing system, comprised of an Aspect 3000 computer, digital plotter and dot matrix printer, was available for data processing and plotting. Factory

Bruker software was used on the spectrometer and data station. ‘9F NMR spectra were measured at 188 and 254 MHz, also at room temperature. The 188 MHz spectra were obtained with a Bruker AC-200E spectrometer. The NMR data from this spectrometer was transferred to and processed on the Bruker data station, described above. The 254 MHz spectra were obtained using the previously described home-built spectrometer (controlled by the Nicolet 1180 computer) with a home-built,

115

were

nitrogen

Chemistry

manipulation All

atmosphere

fluorotoluene,

chromium 5.3.2 Scientific Co. hexacarbonyl

the

sulfonate,

5.3.1

Chemicals 5.3

19 F-tuned

The

The

manipulations 2-tolunitrile.

supplied

Experimental

prepared

General

Sources

( 6 -arene)tHcarbonylchromium

inlet,

probe

Ltd.,

probe.*

and

Department,

complexes

and

of

the

of

was

a

of

18-crown-6

construction

or

4-chiorofluorobeuzene,

either

nitrogen

magnetic

air-sensitive

reagents

benzonitrile

Materials

BDH

HPLC

for

obtained

for

Chapter

using

were

the

U.B.C.).

Chemicals.

or

grade

stir

were

were

preparation

and

from

argon

a

compounds. 3

performed

bar,

and

2

200-mL,

purchased

electronics

methanol

purchased

and

4-tolunitrile,

Pressure

using

a

complexes,

4-chlorobenzonitrile,

condenser

and

round-bottom,

so

116

conventional

from

and

was

Chemical

as

from

purification

acetonitrile

done

and

Aldrich

to

that

equipped

suppliers

maintain

ICN

by

were

Co.

Tom

Chemical

three-neck bench-top

Pharmaceuticals

of

were

synthesized

Fluorobenzene,

with

Markus

the

as

all

methyltrifluoromethane

obtained

( 6 -arene)tricarbonyl-

follows.

a

chemicals

Co.

mineral

techniques

flask

(Electronics

Eastman

from

fitted

Inc.

from

oil-bubbler

Chromium

under

2-

Cr(CO) 6 ,

supplied

for

with

and

Kodak

Fisher

shop,

the

an

4- a (glassware A), or a specially constructed reaction apparatus (glassware B) that consists of a 250-mL, round-bottom flask fused to a 3 in. long condenser which is joined to an additional 3 in. long glass tube (1 in. o.d.) equipped with a central ST*24 ground glass joint and two angled ST 19 ground glass joints. This glassware is fitted with a glass rod that is placed through the central ST 24 joint and reaches to a dimple at the bottom of the flask and has a small paddle near the bottom of the flask (to stir the reaction mixture) plus a 3 in. long screw paddle which closely fits the interior wall of the condenser region (to scrap and return sublimed 6Cr(CO) to the reaction mixture). The glass rod is rotated by a variable speed, overhead stirrer motor. The assembled glassware is also equipped with a nitrogen inlet and mineral oil bubbler. With either set-up, the glassware was wrapped with aluminum foil to protect the reaction from light.

Silica gel 60 (E. Merck, 70-230 mesh) was used for the filtration of organochromium solutions to remove any decomposition.

All substitution reactions were carried out in oven-dried Pierce Reactivials®

(Rockford, IL) equipped with magnetic stir bars and screw caps that were fitted with Teflon-lined, silicone tsepta. H”CN was produced via the catalytic conversion of .2“CO The 2“CO was produced on the TRIUMF/Nordion CP-42 cyclotron using the 4C11N(p,a) reaction at 15 MeV. The 2“CO in the 2N target gas was converted to 4“CH‘ by mixing the target gas with

*sT denotes standard taper. 1These septa provided an excellent seal to maintain the exclusion of air and moisture, and to prevent the loss of volatile components.

117

initially, warmed

obtained

{lit. 5 crystallization. reduced washings

in

Schlenk was

The

and reintroducing were

reaction

Preparation

5.3.3 H’ 1 CN

H 2 (g)

combined

Chromium

diethyl

filtered

bright heated

mp

dissolved

then

Preparation

was

pressure

tube.

then

from

116-117°C}.

gently mixture

were

ether,

yellow

with

passing

trapped

through to

of

under

a

hexacarbonyl

the

likewise

reflux

The

nitrogen

in (i 6 -fluorobenzene)tricarbonylchromium

Bright

NH 3 (g)

until

and

until

was

filtrate

mother

a

of

the

undissolved

in

a

a

mixture

for

the

(, 6 -Arene)tricarbonylchromium

short

degassed

all

an

high

yellow

Mass

added

mixture

yellow

atmosphere

and

was

48

resulting

aqueous

liquor,

crystals

pad

vacuum

h. (1.0

spectrum,

passed

evaporated

of

crystals

to

crystals

The

of

over

residue by

(n-Bu) 2 0/THF

g,

the

affording

silica

solution

solution

redissolved,

4.54

performing

reaction

overnight.

into

ether

over

a

began

Ni

m/z:

were

gel

was

mmol)

to

the

118

cata]yst

Pt

solution.

a

of

to

dryness

was

to

reaction

232

then

total

mixture

at

isolated

NaOH

remove

appear.

three

and

Two

then

(80

transferred

1000°C,

(M,

washed

yield

at

in

fluorobenzene

mL/10

Solvent

450°C.

vessel,

(1

additional

was

vacuo.

freeze-pump-thaw

any

Complexes

was

and

38),

of

mL,

The

1.

thus

greyish-green

with

0.84

cooled

placed

dried

204

the

mL)

0.1

was by

ether/hexane

The

Thereafter,

obtaining

g

some

canula stirred

(M-CO,

M)

crops

(80%)

slowly

in

to

under

residue

in

to

(5.0

glassware

room

hexane

produce

reaction

the

of

filtration

of

removed

decomposition.

mL,

a

cycles.

H”CN. 4

the

was

crystals

3),

1,

temperature

mixture

flow

freezer

mp

and

53

11 CH 4

176

dissolved

A.

Na”CN.

mixture

mmol)

of

117°C

into

under

Upon

(M

these

were

The

was

The

was

N 2 ,

for a 2(CO), 9), 148 (M-3(CO), 54), 96 3(M-Cr(CO) 21), 71(33), 52 (100).

Preparation of -ch1orobenzene)tricarbony1chromium, 2.

Chromium hexacarbonyl (1.86 g, 8.45 mmol) and chlorobenzene (25 mL, 0.25 mol) were added to diglyme(, (30 mL) in glassware B. The stirred reaction mixture was heated to reflux for 16.56h. The reaction mixture was cooled to room temperature, then filtered through a short pad of Celite using some diethyl ether to rinse and facilitate the transfer of the reaction vessel contents. The yellow filtrate was concentrated via distillation under reduced pressure, then some petroleum ether was added to induce crystallization.

Even with cooling, no crystals had formed. Therefore, some ethyl acetate was added to this solution and was then evaporated in vacuo. This process was repeated several times and the volume of diglyme was successfully reduced. Once again, petroleum ether was added to the concentrated solution till a small amount of precipitation occurred, then was placed in a fridge for cooling. A single large, yellow crystal was obtained, which was removed and washed with cold petroleum ether, then dried under a flow of argon. The filtrate was heated and filtered hot, to remove some greenish decomposition, then was placed back in the fridge for crystallization. Yellow crystals (400 mg) were isolated and dried in vacuo. The large single crystal, obtained initially, was recrystallized from hot petroleum ether. This afforded 265 mg of additional yellow crystals, which gave a total yield of 47% (665 mg) of 2 (based on 6Cr(CO) consumed*), mp 100-101°C 6{lit. mp

*Unreacted Cr(CO) remaining in the reaction vessel was recovered by sublimation under high vacuum;6 this gave 0.60 g of recovered 6Cr(CO) 119 .

were

72°C

2(CO),

Compound

subsequent Preparation 3(CO),

Cr(CO) 3 ,

Mass to were

as gel reintroducing

( 79 Br: reaction Preparation

101-102°C}.

Chromium

Chromium

reflux

dark

and

{lit. 8

dissolved

spectrum,

added

MtCO,

4),

the

26),

yellow

for

mixture

4),

mp

162

4

yellow

44

steps

of

of

to

208

133

hexacarbonyl

was

hexacarbonyl

an

73-74°C}.

(Mt3(CO),

h.

3),

(i 6 -2-fluorotoluene)tricarbonylchromium

crystals,

in

( 6 -bromobenzene)tricarbony1chromium

m/z:

a

N 2

( 81 Br:

was

( 79 Br:

obtained

mixture

The

a

filtrate

were 238

atmosphere

mixture

294

degassed

cooled

5),

( 81 Br:

in

Mt3(CO),

Mass

essentially

( 81 Br:

was

131

of

a

(4.00

(1.0

as

25),

yield

of

M-2(CO),

reaction

(n-Bu) 2 0/THF

reduced

yellow

spectrum,

e 9 Br:

by

M,

g,

(n-Bu) 2 0/THF

g,

110

over

performing

4.54

of

18.2

31),

28),

(M-Cr(CO) 3 ,

7),

identical

992

crystals,

the

mixture

to

mmol)

rninol)

52

292

m/z:

120

6),

reaction

dryness

158

mg

(100).

236

( 79 Br:

(19%),

(100

and

in

( 81 Br:

246

a

and

was

to

(80

single

a

in

( 79 Br:

bromobenzene

mixture,

(M,

the

total

filtered

2-fluorotoluene

26),

M,

mL/10

vacuo.

mL/10

M-Cr(CO) 3 ,

mp

freeze-pump-thaw

preparation

M-2(CO),

109 34),

3.

15),

yield

4.

101-105°C

through

it

mL)

Compound

(44),

218

mL)

266

was

of

(M-CO,

( 81 Br:

in

0.99

71(12),

in

(10.0

heated,

5),

a

(5.8

glassware

6),

glassware

of

short

{lit. 7

g

M-CO,

mL,

156

210

3

(89%),

mL,

compound

was

with

cycle.

52

1),

mp

pad

95.2

( 79 Br:

( 81 Br:

53

(100).

190

obtained

B.

120°C}.

A.

stirring,

of

mp

3),

mmol)

mmol)

Upon

(M

silica

M

M

The

264

All

71- 1.

pressure

showed removed

mesh)

nimol)

stirred Preparation

temperature,

concentrated

71(16), further

3.79 silica were

reintroducing

to

(M-CO, reaction Preparation

Chromium

Chromium

reflux

g

gel

added

with

(85%),

were

drying

reaction

the

52

and

mixture

in

and

for

1),

hexane

presence

(100).

vacuo.

added

of

of

a

to

190

reaction

16.5

hexacarbonyl

the

hexacarbonyl

the

an

mp

in

plug

(q’-4-chlorofluorobenzene)tricarbonylchromium

(i 7 6 -4-fluorotoluene)tricarbonylchromium

a

vacuo,

mixture

(M-2(CO),

N 2

was

yellow

reaction

59-60°C h.

mixture

as

to

of

TLC

atmosphere

of

the

The

a

degassed

mixture

sublimed

mixture

two

compound

filtrate

eluent.

analysis,

was

cooled

(4.00

mixture

{lit. 8 of

(4.00

components.

3),

was

(n-Bu) 2 0/THF

heated

of

by

Cr(CO) 6

was

mp

g,

over

g,

A

162

reaction

(n-Bu) 2 0/THF

chromatographed

18.2

performing

on 5

single

18.2

was

61-62°C}.

reduced

was

(M-3(CO),

the

alumina

mmol)

to

mmol)

concentrated

(1.1

obtained

yellow

Column

121

reaction

reflux mixture

g)

to

and

(100

a

and

was

(eluent:

Mass

dryness

band

single

(100

for

23),

4-chlorofluorobenzene

chromatography

as

mixture,

was

4-fluorotoluene

recovered

mL/10

on

bright

spectrum,

was

23

to

mL/10

110

freeze-pump-thaw

neutral

filtered

under

hexane),

5.

about

h.

collected

(M-Cr(CO) 3 ,

yellow it

mL)

was

from

mL)

Upon

reduced

alumina

m/z:

through

6.

10

in

of

heated,

crystals,

was

in

the

(10.0

mL

and

glassware

the

246

glassware

cooling

condenser.

repeated

pressure.

the under

(Fisher,

yellow

a

mL,

(10.0

(M,

17),

with cycle.

short

in

solvent

91

a

to

109

mL,

B.

reduced

11),

stirring,

A.

yield

residue

80-200

pad mmol)

on

Upon

room After

(31),

The

The

93.9

The

was

218

the

of of two-component mixture using silica gel with hexane/ether (5:1). The first fraction, after solvent removal, afforded 0.42 g of 6 as yellow crystals, mp 61-62°C {lit. mp: none found}. TLC analysis on silica gel (eluent: hexane/ether, 1:1), indicated the presence of only one component. Mass spectrum, m/z: 268 (37C1: M, 6), 266 (35C1: M, 17), 240 (37C1: M-CO, 2), 238 (35C1: M-CO, 3), 212 (37C1: M-2(CO), 2), 210 (35C1: M-2(CO), 5), 184 (37C1: M-3(CO), 9), 182 (35C1: M-3(CO), 25), 132 (37C1: 3M-Cr(CO) 10), 130 (35C1: 3M-Cr(CO) 29), 95 (22), 89 (37C1: 3), 87 (35C1: 9), 71 (14), 52 (100). A second fraction (0.12 g) was collected, , 1 which contained a mixture of and 6, with

6 , being the dominant component as determined by ThC analysis (silica gel; eluent: hexane/ether, 1:1). This material unfortunately underwent partial decomposition and was discarded.

A final fraction was collected, and after the eluate was evaporated to dryness in vacuo,

0.11 g of yellow crystals were isolated, mp 97-100°C. TLC analysis (silica gel; eluent: hexane/ether, 1:1) showed this material to be a mixture of 1 and 6, with 1 being the major component present. Mass spectrometric analysis of this mixture gave the following results; mass spectrum, m/z: compound 1, 232 (M, 22), 204 (M-CO, 3), 176 (M 2(CO), 5), 148 (Mt3(CO), 27), 96 (M-Cr(CO) 40); compound 6, 268 (37C1: M, 0.6), 266 C1: M, 2.0), 240 MtCO,3 0.1), 238 (35 (37C1: (35Cl: M-CO, 0.3), 212 (37C1: M-2(CO), 0.2), 210 35C1: M-2(CO), 0.4), 184 37C1:, M-3(CO), 1.1), 182 C1: M-3(CO), 3.7), 132 ( ( (35 (37Cl: 3MtCr(CO) 1.8), 130 (35C1: 3M-Cr(CO) 6.9). The, isolated yield of 6 (obtained from the first fraction) was 12%, based on the amount of , 6Cr(CO) consumed.

122

were

gel

isolated

magnesium

yellow washed

stirred

0.437

Preparation

(20 pressure

then Preparation

temperature,

mol)

stirred

DMSO

Chromium

and

mL)

canula

washed

were

minol)

for

crystals,

reaction

repeatedly

the

as

and

and

(2

23

dissolved

yellow

sulfate.

solvent

transferred

mL)

of

of

with

subsequently

contained

h

a

hexacarbonyl

the

large

at

for

((-benzonitri1e)tricarbony1chromium

(q 6 -N,N-dimethylaniline)tricarbonylchromium

mixture

was

aqueous,

ambient

crystals,

volume

with

a

wasjaken

The

in

crop

yield

added

a

in

to

cold

mixture

dried

of

was

a

extracted

another

temperature.

of

in

of

saturated

(4.00

5-mL

to

yellow

hexane,

3.30

a

the

to

ether

compound

yield

heated

of

g,

dryness

Reactivia1®

g

reaction

flask.

(n-Bu) 2 0/THF

crystals

with

(70%),

18.2

sodium

extracts

of

then

to

32

The

diethyl mmol)

The

123

under

1 dried

mg

reflux

mp

deposited.

(44.8

mixture

chloride

were

reaction

crystals

(69%).

under

137-138°C

in

ether

reduced

and

mg,

for

filtered

vacuo.

(60

was

N,N-dimethylaniline

solution

0.193

argon.

10.

were

(3 mixture

21

The mL/5

pressure. x

concentrated

h.

Compound

through

{lit. 6

mmol)

collected

15

remaining

The

mL)

and

7.

was

mL).

After

mp

reaction

dried

and

in

then

a

Compound

144°C}.

The

short

on

glassware

cooling

7

supernatant

NaCN

over

under

was

added

a

ether

glass

(20

pad

mixture

isolated

anhydrous

(21.4

mL,

to

to

reduced

of

extracts

A.

frit

10

water

room

silica

0.16

The

was

was

was

and

mg, as

N(CH 3 ) 3 ),

C total

sequential

initially, batch

until

121°C crop

overnight.

resulting

of

overnight.

temperature

and Preparation

added

sulfonate

The

Compound

37.40,

CH 3 CN

*Performed

the

of

yield

the

of

previous

(dec.).*

by

yellow

supernatant

then

crystals.

solution

H

syringe

solution

5.77

11.

recrystallizations

was

of

The

353,

until

of

under

0.97

7

crystals.

Anal.

reduced

(t,

in

solution,

yellow

(1.00

( 6 -N,N,N-trimethy1aniIinium)tricarbony1chromium

and

was

2H,

Both

capillaries

N

dissolved.

became

g

high

was

calcd.

3.49,

(59%).

g,

the

transferred

H-3,5),

crystals

by

These

batches

3.89

in

canula

vacuum.

mixture

a

which

S

for

slightly

of

third

rnmol)

that

Methyltrifluoromethanesulfonate

7.44.

6.07

were

An

a

C, 3 H, 4 CrF 3 NO 6 S:

were

of

transferred

portion

the

under

were

by

was

analytical

crystals

(t,

Compound

isolated

cloudy.

was

‘H

dried

reaction

canula

1H,

stirred

packed

reduced

NMR

of

added

124

H-4),

in

were

11

filtration

to

and

vacuo,

sample

was

This

overnight.

from

another

(270

and

11

to

6.69

isolated,

recrystallized

C

pressure,

allowed

was

CH 2 C1 2

37.06,

mixture

sealed

acetonitrile/diethyl

then

MHz,

was

(d,

into

obtained

flask.

2H,

Yellow

dissolved

H

and

obtained

to

a

then

(25

under

DMSO-d 6 )

was

3.35,

Schienk

continue,

H-2,6).

dried

This

mL)

as

(1.1

diethyl

as

placed

crystals

nitrogen. N described

in

yellow

and

solution

by

mL,

3.32,

under

tube.

trifluoromethane

acetonitrile.

afforded

ether

performing

&

stirred

ether,

in

9.7

had

S

3.56

crystals,

a

7.61;

The

for

the

rnmol)

was

was

flow

deposited

mp

the at

another

(s, volume

freezer

found:

stirred

added

of

room

120-

first

in

The

9H,

two

was

N 2 a

were

Substitution &

5.3.4 Compound

which

deposited allowed Preparation

After

(d, dried nitrogen

1 H

mL,

Preparation

consumed.

General

N,N-Dimethylaniline

3.61 N,N-Dimethylaniline

NMR

2H,

9.7

added

in

Substitution

30

afforded

(s,

H-2,6).

to

vacuo.

mmol)

atmosphere.

(270

mm,

were

9H,

Procedure:

stir

13

to

The

of

reactions

of

MHz,

was

N(CH 3 ) 3 ),

CH 2 C1 2

overnight

N,N,N-trimethylanilinium

TLC

N,N,N-trimethylanilinium

collected,

a

were

These

copious

total

obtained

Reactions

DMSO-d 6 )

analysis

added

(25

with

yield

An

crystals

The

(1.00

(1.00

7.58-7.68

quantities

at

washed

mL)

aliquot

reaction

room

stable

in

of

sequentially

mL,

mL,

of

indicated

a

were

under

1.87

&:

yield

Organochromium

7.89

with

temperature.

3.61

7.89

(200

cyanide.

(m,

of

g

recrystallized

mixture

a

of

(83%)

white

mmol)

(s,

3H,

diethyl

mmol)

nitrogen

L,

that

1.16

by

125

9H,

iodide

trifluoromethanesulfonate

H-3,4,5),

10

crystals

syringe

was

of

g

all

N(CH 3 ) 3 ), and

mg/mL)

ether

and

(56%).

12,

atmosphere.

The

13. the

allowed

methyltrifluoromethanesulfonate

from

Complexes

iodomethane

mp

and

that

to

7.97

resulting

N,N-dimethylaniline

1 H

of

CH 2 C1 2

82-83°C

dichloromethane/diethyl

7.58-7.67

dried

deposited,

(d,

aqueous

to

NMR

2H,

stir

The

white

under

(25

{lit.

(270

(0.54

at

H-2,6).

(m,

reaction

KCN

mL)

room

were

crystals

mp:

reduced

12.

3H,

MHz,

mL,

(32

while

H-3,4,5),

collected

none

temperature.

present

mixture

8.67

DMSO-d 6 )

mo1)

which

pressure.

under

found}.

mmol)

ether,

7.97

was

was

had

was

and

(1.1 a

analyzed

concentrated

sodium

and

sodium

stirred

complete

conducted these

solution KCN by volumetric

ether bath)

to

temperature

arene)tricarbonylchromium

added to injected

A

determine

HPLC,

dryness,

was

separate

by

as

extracts

to

by

ether

thiosulfate

thiosulfate

dried

(3

the

into

GC-MS,

initially

room

decomplexation.

syringe

which

as

mL),

flask

using

limiting

in

solution

the

under

set a

follows.

over

were

a

5-mL

temperature,

and

and

was

of

extent

thermostated

by

a

therefore,

to

solution

anhydrous

solution

reactions

washed

reduced

block

GC

diluted

extracted

reagent.

standardized

the

Reacti-vial

was

The

of

and

Reacti-vial®.

product

treated

heater,

(4

The

reaction

(5

to

with

complex

were

the

HPLC, pressure

magnesium

the

mL,

with

a

mL,

silicone

known

treatment

workup

water

reaction

with

performed

with

formation.

under

0.1M),

under

diethyl

0.

mixture

then

1M)

(65

to

oil

iodine

known

volume

The

or

inert

of

sulfate.

a

then

1

126

mol)

bath

by

and

was

ether

mixture

saturated

mL. rapid

these

stirred

was

to

GC-MS.

The

(146

with

solutions

atmosphere.

the

for

with

quenched

isolate

was

(1

The

diluted

The

flow

reaction

chemical

10

ether

saturated mo1)

was

x

DMSO. mixture

taken

NaC1

minutes.

6

dried

concentrated

the

of

mL,

of

quantitatively

layer

with

with

nitrogen

at

organic

expected

mixtures,

solution

up

yields

ether

2

The

was

0°C

This

NaC1

water

was

x

the

After

in

3

heated water

for

layer

solution

were

DMSO

products

mL).

washed

addition

solution

or

aryl

ether

(2

or

cooling

after

2

argon.

transferred

was

hours

calculated

was

saturated

x

nitrile

The

at

(1

was

3

solution

cooling,

further

filtered and

(2

the

of

evaporated

mL).

(ice/water

mL),

combined

to

analyzed

x

The

aqueous

product,

identify

desired

ensure

4

NaC1

using

mL)

with

then

to

The

was

and

was

(,- a

reaction

30.7

was

of general

solvent Reaction

of was

1.62

that

general

eluent:

Reaction

Two

Other

A

Other A

26,

12,

1 These

‘RT

mol),

allowed

mg

typical

allowed

1.34 typical

41,

32,

reaction

solvent

denotes C; procedure.

procedure

of

trial

reaction

reaction

of

mg

of

29,

31,

flow

results

2-tolunitrile

at

reaction

reaction

4

1

to

was

of

to

and

and

with

with

135

A;

rate,

trials

benzonitrile

react

retention

react

performed.

trials

trials

36%,

33%,

flow

and

represent

above.

cyanide.

cyanide.

The

trial

trial

2.5

were

with

with

143

rate,

were

were

respectively.

15

respectively.

final

mL/min;

was

was

time.

°C,

The

performed

(RT=

KCN

KCN

2.5

the

14

conducted

DMSO

conducted

performed

performed

using

final

mL/min;

(RT*

12.1

best

(2.10

(2.10

UV

the DMSO

=

mixture

mm)

chemical

5.4

using

mg,

detection,

mg,

general

at

at

as

as

UV

127

mm)

was

105,

95,

follows.

follows.

32.2

mixture

32.2

1.5

was

detection,

115,

present,

was

yields

mg 115,

procedure.

jmol),

mol),

analyzed

270

(6.1

present,

125,

was

120,

Compound

Compound

obtained

rim)

for

1 Lmol)

280

and

analyzed

at

at

and

by

a and

105°C,

135°C,

In

for

nm)

135°C,

yield

HPLC

150°C,

of

each

where

it

a

4

1

and

4

by

yield

was

(16.2

(15.6

with

of

as

as

case,

which

(column

HPLC

which

it

43%.

described

described

more

determined

was

of

KCN

mg,

mg,

0.41

40%.

gave

gave

determined

(column

65.8

67.2

than

B;

(2.00

mg

eluent:

yields t

yields t

in

mol)

in

1 Lmol)

of

that

one

mg,

the

the

15 A;

was

solvent general

Reaction

1.11

spectra identity

(M-H, solution

270

117 comparison

analyzed fluorotoluene was

(RT

GC

Compound

described

A

A

(M,

allowed

rng

obtained,

typical

nm)

and

separate

16.2

C;

procedure.

(acquired

of

of

100),

of

by

of

100),

and

only

in

the

flow

nun).

4-toluriitrile

authentic

reaction

5

of

4

HPLC

to

the

with

108

products

(RT= 3 . 2

(16.2

for

found

the

reaction

116

rate,

two

react

general

under

(M-2H,

a

GC

cyanide.

Identification

The

(column

(M 4 -H,

yield

mg,

trial

2.5 significant

that

samples.

with

and

mm)

was

16

final

very

trial

mL/min;

65.8

procedure.

was

of

15

(RT=

HPLC

KCN

further

15),

85),

A;

and

58%

DMSO

similar

performed was

eluted mol)

eluent:

Mass

89

12.2

peaks

2-tolunitrile

115

(2.10

based

retention

of

done

UV

confirmed

(3),

instrumental

mixture

(M 4 -2H,

mm)

was

first

The

the

spectra,

solvent

mg,

detection,

83

were

on

to

as

128

allowed

was

above concentrated

(RT=7.3

(15),

4

follows.

32.2

times

identify

was

15

by

as

observed,

m/z:

13),

C;

present,

(RT=5.7

74

GC-MS, the

/Lmol),

analyzed

flow

products

conditions)

with

270

to

90

(12),

2-fluorotoluene,

mm),

limiting

Compound the

react

(44),

nm)

rate,

those

for

ether

at

59

mm).

which

organic

using

by

followed

a

and

89

115°C,

2.5 with

was

(15),

reagent.

of

yield

HPLC

obtained

solution

(47),

for

mL/min;

This

authentic

it

were

5

accomplished cyanide,

57

products

was

(16.1

comparison

of

as

63

by

sample

(column

(6);

110

29%.

described

identified

determined

was

from

(16).

2-fluorotoluene

mg,

compound

UV

(M,

samples.

at

by

analyzed

was

65.4

a

B;

detection,

120°C,

premade

the

48),

GC-MS.

eluent: by

further

in

ILmol)

as

mass

that

The

109

the

the

15,

by

as 2-

was

reaction

Reaction

of

(30), the

of fluorotoluene

270

(acquired (RT=

analyzed

Compound

100), GC described

of

A

A

Other

the

authentic

11,

‘These

products

allowed

mm)

typical

and

63

separate

15.9

89

21,

GC

(7).

trial

(2),

reaction

by

of

and

under

mm).

26,

only

in

and

results

reaction

6

5

HPLC

samples.

83

the

to

was

was

and

with

(RT= 3 . 2

(16.5

found

reaction

HPLC

two

(21),

react

very

Identification

general

further

performed.

trials

21%,

represent

cyanide.

(column

mg,

trial

prominent

similar

57

that

with

retention

mm)

Mass

were

respectively.

trial

(3);

67.0

procedure.

was

confirmed

16

KCN

A;

and

instrumental

compound

the

conducted

spectra,

was

performed

mo1)

eluted

of

eluent:

times

4-tolunitrile

peaks

best

the

(2.10

done

by

was

above

first

The

m/z:

chemical

with

solvent

GC-MS,

mg,

were

at

16,

to

as

conditions)

129

allowed

concentrated

(RT= 7 . 7

105,

4-fluorotoluene, those

follows.

117

products

identify

32.2

16

observed,

C;

yields

125,

(M,

(RT=6.3

using

Mmol),

of

flow

to

mm),

authentic

135,

the

Compound

was

obtained

100),

react

obtained

for

rate,

ether

at

mm).

which

organic

and

performed

comparison

followed

116

115°C, 2.5 with

110

150°C,

solution

samples.

from

mL/min;

This

(M-H,

where

were

6

(M,

cyanide,

products

(18.2

as

a

by

sample

by

which

premade

described

the

66),

identified

more was

52),

4-fluorotoluene

the

mg,

The

UV

at

mass

109

by

analyzed

comparison gave

was

90

68.3

identity

than

detection,

135

GC-MS.

solution

(38),

(M-H,

spectra

further

yields*

in °C,

1 mol)

as

one

the

89

by

as

of 4- general procedure. The final DMSO mixture was analyzed by HPLC (column B; eluent: solvent C; flow rate, 2.5 mL/min; UV detection, 270 urn) and it was determined that

1.53 mg of 4-chlorobenzonitrile 17 (RT= 12.5 mm) was present, for a yield of 34%.

A reaction trial was also conducted at 135°C, which gave a yield of 21%.

An additional reaction trial was performed at 115°C that was heated only for 5 mm

(instead of 10 mm) and gave a chemical yield of 17%.

A separate reaction trial was done to identify the organic products by GC-MS.

Compound 6 (17.7 mg, 66.3 mo1) was allowed to react with cyanide, at 115°C, as described in the general procedure. The concentrated ether solution was analyzed by

GC and two major peaks were observed, which were identified as 4-chlorofluorobenzene

(RT = 3.5 mm) and 4-chlorobenzonitrile 17 (RT= 7.1 mm), and also a smaller unknown peak was observed that was identified eventually (by GC-MS) as benzonitrile 14 (RT 4.5 mm). This sample was further analyzed by HPLC (column A; eluent: solvent A; flow rate, 2.5 niL/mill; UV detection, 270 nni) and found that 14 eluted first (RT= 4.6 mm), followed by 17 (RT= 7.6 mm) and an unidentified peak (RT= 10.1 mm), then finally 4- chlorofluorobenzene (RT= 18.3 mm) appeared last. Identification of the principal products was performed by the comparison of the GC and HPLC retention times with those of authentic samples. The identification of the products was completed by GC

MS, using for comparison the mass spectra (acquired under very similar instrumental conditions) obtained from a premade solution of authentic samples in the case of the principal products, and by inspection of the mass spectrum obtained for 14. Mass spectra, m/z: 4-chlorofluorobenzene, 132 (37C1: M, 32), 130 (35C1: M, 100), 95 (M.-Cl,

130

Reaction

1 Lmol) by

was

(26

(2.10 35, a

general

and added

Reaction

M,

Cl, 58),

102

yield

Two

An

Other A

HPLC

36),

40,

mg,

it

(M-H,

94

31),

allowed

typical

mg,

additional

was

was

to

42,

of

reaction

(M-HCl,

procedure

76

98

reaction

137

of

of

the

32.2

(column

44%.

allowed

and

determined

(14),

1 Lmol)

reaction

4

4

2),

to

( 35 C1:

reaction

with

with

mol),

41%,

77

react

75

trials

reaction

trials

and

11),

except

B;

to

cyanide (M-CN,

M,

cyanide

(25),

trial

respectively.

react

eluent:

at with

mixture 69

were

afforded

were

that

100),

74

105°C,

that

(13),

trial was

with

in

KCN

in

(11),

1.65

performed

conducted

8),

solvent

112

performed

about

was

the

the

68

before

a

KCN 76

which

mg

68

(2.10

chemical

(13),

( 37 C1:

presence

presence

performed

(M-HCN,

1.2

(4),

of

C;

(2.10

heating.

used

65

2-tolunitrile

mg,

equivalents

at M-HCN,

as

flow

51(19),

as

131

(8),

95,

follows.

yield

mg,

of

of

follows.

32.2

approximately

rate,

using

115,

51(11),

18-crown-6

18-crown-6

40),

The

32.2

of

50

1 Lmol),

2.5

1),

125,

of

63

46%.

16.2

15

(35);

Mmol), final

In

Compound

110

mL/min;

18-crown-6

50

(4), and

(RT=

the

mg

at

DMSO

compound

(36);

( 35 C1:

and

and

52

3

at

first

135°C,

105°C,

(65.8

14.3

equivalents

(9),

80°C,

CH 3 CN.

DMSO.

compound

UV

M-HCN,

4

trial,

mm)

mixture

(9.8

1 .mol)

51

(16.0

which

as

detection,

as

14,

(21),

mg,

4

described

was

described

mg,

(16.2

of

103

of

gave

was

37

17,

3),

50

4

present,

18-crown-6

65.0

(M,

1 .mol)

with

102

139

(26).

mg,

analyzed

yields

270

in

1 Lmol)

in

KCN

( 37 C1:

(M

100),

65.8

nm)

was

the

the

for of

was

Attempted

exhibited was

solvent general

which

analysis. to

refluxing). present,

oil

days mm)

mixture

detection, general

to

approximately

Two

The

21%.

the

bath

stored,

allowed

after

was

reaction

represents

second

reaction

procedure.

C;

procedure

was

for

This

temperature

The

a

the

270

reaction

present,

A

and

flow

large

a

analyzed

to

mixture

chemical

final

initial

final

reaction

18

nm)

mixture

upon

react

trials

rate,

hours

a

peak

except

yield

The yield

yield

of

and

for

HPLC

reanalysis

by

were

was

with

of

2.5

11

yield

trial

and

later

final

(RT= 7 . 9

HPLC

it

a

of

of

of

95°C

with

stored

that

mL/min;

was

performed

KCN

yield

50%.

CH 3 CN

21%.

analysis.

15

was

of

by

DMSO

cyanide.

1

was

4%

was

(column

about

determined

HPLC;

performed

equivalent

again,

mm)

(2.10

of

The

was

found

was

used

mixture

3%.

UV

At

16

as

and

obtained,

then

mg,

it

mixture

B;

used

hours

this

follows.

was

132

(it

detection,

to

eluent:

of

This

that

32.2 in

a

reanalyzed

be

was

was

time,

as

found

much

the

18-crown-6

later,

was

46%.

the

0.094

mo1),

as

analyzed

mixture

noted

In

solvent

same

1.90

determined

that reaction

the

stored

smaller

the

270

mg

mg

13.5

yield

way

that

at 0.81

first

nm)

C;

(8.5

by

was

of

again,

of

100°C,

days

flow

peak solvent.

as

mg

HPLC

trial,

was

the

2-tolunitrile

15

mg,

and

stored

the

by

of

after

was

rate,

reaction

found

then

HPLC.

11

(RT=

32

as

15

first,

the

(column

The

determined

(27

1 mol)

was

described

the

2.5

and

reanalyzed

to

chromatogram

18.2

except

mg,

mL/min;

initial

final

now

be 15

mixture

The

reanalyzed

was

A;

mm),

increased

(RT=

64

present,

mixture

CH 3 CN

that

eluent:

HPLC

in

mo1)

added

to

13.5

13.8

was

UV

but

the

be an

2.8

fluorobenzene.

by

and Attempted

at

identified.

the HPLC

in

and

Heating

reported reaction

of neither

exhibiting

Fluorobenzene

135°C, Compound

the

The

HPLC

any

mm,

chromatogram

the

its

same

(column

desired

associated

second

peak

chromatogram

thereby

of

temperature

in

as

(column

a

reaction

11

fashion

the

retention

described

could

11

in

reaction 14

A;

Under

first

confirming

DMSO

(27

(5.7

drying in

A;

eluent:

as

exhibited

of

be

trial

the

mg,

eluent:

time

1 .L,

in

described

used

fluorobenzene

these

identified.

exhibited

trial

the

product

was

without

64 above.

60

solvent

of

was

the

general

mo1)

mol)

HPLC

solvent

not was 4.4

a

absence

in

single

120°C.

mm.

mixture.

done.

cyanide

a

C;

performed

the

was

Under

was

single

conditions,

procedure.

flow

B;

with

Therefore,

general

large

allowed

heated

flow

The

of

133

The

rate,

present.

peak

cyanide.

these

14

rate,

resulting

peak

in

same

procedure;

2.5

in

in

benzouitrile

to

(RT

The

HPLC

the

the

HPLC

mL/min;

2.5 react DMSO

(RT=8.1

=

essential

same

final

product

4.2

mL/min;

DMSO

with

conditions,

analysis

mm)

DMSO

the

(1

way

UV

KCN

14

mm)

mL)

mixture.

addition

results

solution

which

had

UV

as

detection,

confirmed

mixture

for

(2.00

which

the

benzonitrile

a

detection,

were

was

retention

10

of

was

first,

mg,

mm

aqueous

could

was

identified

270

analyzed

obtained

the

30.7

except

at

analyzed

270

nm)

absence

time

not

!mo1),

100°C,

14

KCN

urn)

and

was

the

be

by

as

of as

was was

30.7 Attempted

detection,

270

identified Attempted

retention

,Lmol), identified

analyzed retention

Attempted

270

mol),

analyzed

4-Chlorofluorobenzene

4-Fluorotoluene

2-Fluorotoluene

mol),

analyzed mn)

nm)

identified

at

at

by

by

time

time

and

135°C,

and

135°C,

270

as

as

reaction

reaction

reaction

at

HPLC

HPLC

4-fluorotoluene.

2-fluorotoluene.

by

mm)

135°C,

the

of

of the

as

as

4.1

as

3.9

HPLC

chromatogram

and

chromatogram

(column

(column

(6.6

(6.6

of

of

described

of

described

4-chlorofluorobenzene.

mm,

miii,

as

4-chiorofluorobeuzene

4-fluorotoluene

2-fluorotoluene

the

L,

L,

described

(column

thereby

(6.4

thereby

chromatogram

A;

A;

60

60

in

in

L,

eluent:

eluent:

Under

Under

mo1)

mol)

the

the

confirming

confirming

A;

in

60

exhibited

exhibited

general

general

the

mol)

eluent:

with

was

was

with

solvent

solvent

these

these

general

134

exhibited

allowed

allowed

cyanide.

cyanide.

was

procedure.

procedure.

a

HPLC

a

HPLC

with

the

the

solvent

B;

B;

single

single

Under

allowed

procedure. flow

flow

absence

absence

cyanide.

to

to

a

conditions,

conditions,

rate,

rate,

B;

single

peak

peak

react

react

these

The

The

to

flow

of

of

2.5

2.5

react (RT

(RT

peak with

16

15

with

The

final

final

mL/min;

niL/mm;

rate,

HPLC

in in =

=

4-tolunitrile

2-tolunitrile

7.3

final 7.2

KCN

KCN

with

the

the

(RT=7.6

DMSO

DMSO

2.5

mm)

product

mm)

product

DMSO

KCN

conditions,

(2.00

(2.00

UV

UV

mL/min;

mixture

mixture

miii)

which

which

detection,

detection,

(2.00

16

15

mg,

mg,

mixture.

mixture.

mixture

which

had

had

30.7

30.7

UV was

was

was

was

mg,

4-

a a

vial®

syringe solution

non-radioactive

evaporated

solution

solution

Substitution 5.3.5 by

time

detection Attempted

and

at

chlorobenzonitrile

of

General

Compound

100°C,

HPLC

17

This

no

of

(which

in

Labelling

to

product

4.1

of

was

the

(1

point

as

at

the

(colunm

(, 6 -arene)tricarbonylchromium

Procedure:

reaction

to

mm,

mL,

product

described

270

reactions

counted

contained

Reacti-vial®.

12

dryness

in

KCN

peaks

Work

0.1 thereby

mu). (18

time

A;

17

of

M),

mg,

mixture.

(carrier)

were

at

eluent:

had

(using

with

in

with

12

was

Under

After

an

this

confirming

the 63

0.5-1.0

with

a

inert

designated

observed

[“C]

The

.4mol)

[“C]

retention

general

a

stage

the

solvent

was

these

block

cyanide.

Cyanide

stirred

mL

cyanide.

atmosphere).

H 11 CN

was

added,

and

the

HPLC

procedure.

heater)

of

in

C;

time

allowed

as

mixture

the

the

this

flow

absence

was

135

then

the

(40-65

chromatogram

of

conditions,

time

radioactive

under

generated

rate,

start

this

4.6

to

was

The

The

mol) of

was

react

mm,

2.5

mixture

of

a

14

heated

final

synthesis

[“C]cyanide

fast

notedD

mL/min;

in

with

benzonitrile

thereby

in and

stock

flow the

DMSO

DMSO

was

(12

at

trapped

KCN

product

and

(SOS).

the

of is

solution

added

confirming

UV

not

nitrogen

mixture

(1 (2.10

solution

desired

a

detection,

14

in

mL)

known

observable

to

mixture.

aqueous

had

was mg,

a

was

5-mL

was

temperature

or

was

the

32.2

a

taken

amount

argon.

added

retention

analyzed

270

absence

Reacti

rapidly

NaOH

by

pmol),

(the

am)

UV

by

of A

no

Reaction

respectively.

carrier

KCN procedure.

to

of

detection,

mol)

of

Reaction

in

HPLC

and

ambient

Compound An

Other

A

SOS)

36%.

carrier

a

carrier

counted

thermostated

representative

additional

(0.11,

was

purification

KCN,

of

reaction

temperature,

of

of

KCN

KCN

254

treated

[ 11 C-CN]benzonitrile

1

HPLC

1

0.35,

to

and

with

1

with

mn)

(15

determine

(0.98

added),

reaction

trials

afforded

with

0.49

silicone

no

mg,

and

[“C]cyanide.

of

analysis

reaction

mg,

carrier-added

the

a

were

a

65

the

equiv)

then

small

mixture

trial

reaction

15

mol)

the

oil

a

peak

(column

conducted

trial

radiochemical

mol),

heated

was

bath

portion

decay

and

18

corresponding

was

of

was

(RT

performed

mixture

27.8

for

gave

then

[ 11 Cj

C;

corrected

treated

at performed

=

of

at

10

6.5

mCi

eluent:

150°C,

136

cyanide.

heated

the

21%,

150°C

minutes.

mm)

determined

yield

with

(SOS)

at

reaction

radiochemical

to

as

solvent

41%,

was

135

which

at

of

as

22.8

the

described

of

150°C,

35%. °C,

follows.

produced

Upon

[ 11 C]cyanide [ 11 C]nitrile

mCi and

mixture

used

that

A;

which

flow

cooling

34%

(SOS)

as

varying

9.93

in

Compound

yield.

for

described

used

was

the

rate,

mCi

product

radiochemical

a

of

and

radiochemical

(ice/water

general

subjected

0.51

amounts

[“Cjcyariide

5.0

(decay

0.37

equivalents

in

mL/min;

was

1

the

(9.5

equivalents

procedure.

corrected

of

collected

to

bath)

general

mg,

carrier

yields,

radio

(with

yield

UV

41

of to

produced

B;

that

Reaction produced

135 [‘ 1 C]cyanide

B;

that

be

Reaction

[“Cjcyanide

nm) HPLC

135

(RT

Compound

Compound

flow

flow

counted

°C,

°C,

=

2.39

2.93

of

6.5

as

analysis

as

rate,

rate,

the

mm)

mCi

mCi

of

described of

for

for described

with

5

reaction

4

and

and

2.5

2.5

a

a

with

5

4 with

(decay

was

(decay

radiochemical

radiochemical

(column

(14.8

(14.8

mE/mm;

0.51

the

mL/min;

0.51

present—the

[“C]cyanide.

[“C]

in

in

Capintec

mixture

corrected

mg,

corrected

equivalents

mg,

equivalents

the

the

cyanide.

C;

general

60.1

general

60.1

UV

UV

eluent:

determined

yield

yield

well

mol)

mol)

detection,

detection,

to

to

activity

procedure.

of

procedure.

of

SOS)

SOS)

solvent

counter.

of

of

carrier

carrier

was

was

31%.

34%.

of

of

of

137

270

treated

270

that

treated

the

A;

[‘ 1 C-CN]-4-tolunitrile

[ 11 C-CN]-2-tolunitrile

KCN

KCN

HPLC

flow

HPLC

mu)

collected

urn)

only

with

(2.00

with

(2.00

rate,

of

of

a

analysis

analysis

the

the

trace

a

a

mg,

5.0

mg,

product

mixture

mixture

reaction

reaction

mL/min;

30.7

30.7

of

(column

(column

[“C-CN]benzonitrile

fraction

mol),

mol),

20

of

of

19

mixture

mixture

7.84

8.50

(RT= 4 .l

(RT

UV

A;

A;

then

eluent:

then

was

=

eluent:

mCi

mCi

detection,

4.0

determined

determined

too

heated

mm) heated

mm)

(SOS)

(SOS)

solvent

solvent

low

was

was

254

of

18

at

of

to at

vial®

indicated

mol*),

complete, ioop passed

trapped hydroxide) Reaction

produced

KCN,

mL/min;

the

equivalents Reaction

(decay [‘ 1 C]cyariide

Another

An

Compound

Two

general

was

which

and

experiment

through

corrected

and

out

removed of

small of

was

UV

for

the

afforded

reaction

from

contained

of

6

6

the

procedure.

(in

DMSO

a

with

6

with

estimated.

detection,

carrier

radioactive

a

radiochemical

crystals

(12.3

H 11 CN,

this

glass

the

to

was

from

[‘ 1 C]

[“C]cyanide.

trial

a

case

labelling

(1

mg,

SOS)

radiochemical

KCN

loop,

a

done

of

while

cyanide

mixture

was

mL)

the

HPLC

254

the

46.1

KCN

mixture

which

(0.33

of

cooling

performed

H 11 CN

to

under

mn)

sweeping

yield

mol)

[ 11 C]cyauide

[ 11 C-CN]-4-chlorobenzonitrile

were

in

of

analysis

eliminate

mg,

was

of

the

6

was

of

bath

yield

was

N 2

was

(10.0

used,

5.0

the

emersed

21%.

absence

at

away

counted

atmosphere.

trapped

(column

treated

138

mol),

and

of

reaction

135°C,

mg,

the

reagent.

which

19%.

the

H’ 1 CN

37.5

in

presence

of

then

with

(3.87

NH 3

a

which

in

base.

were

C;

CC1 4 /C0 2

mixture

mo1),

0.025

The

was

eluent:

heated

a

with

When

mCi,

used

not

mixture

of

slowly

H 11 CN/NH 3

M

carrier

helium

weighed,

determined

base

SOS).

0.51

NaOH

at

solvent

(-23°C)

the

21

150°C,

of

purged

equivalents (both

(RT

H 11 CN

KCN

gas

16.73

solution)

This

A;

thus cooling

=

flow.

gas

as

12.0

(1-2

that

ammonia

into

mCi

flow

transfer

mixture

the

described

stream

mg,

mm)

The

a

bath, 3.54

of

(SOS)

and

rate,

quantity

Reacti

carrier

15-31

glass

mCi

0.11

was

was

was and

was

and

3.0

of in

diethyl

A

DMSO, hydrostarinylation

and

hydroxide

of

method

17fl-ol

was

and

Co. methylpropionitrile),

5.4.1

5.4 solvent

heated

l7cr-Ethynylestradiol (RT= determined

The

mixture

the

3,

25

purchased

Experimental

14.9

17fl-dimethoxy-

Sources

crude

41

O-methylated

ether in

for

and

of

A;

was

67%

in

mm)

Johnstone

of

10

flow

that

then

product

DMSO,

(1:1)

also

23

minutes

of

and

from

was

1.11

rate,

with

Materials

and

of

prepared

gave

for

31%

produced

23

the

mixture

17a-ethynyl-

23

commonly

mCi

followed

estradiols,

and

iodomethane.

17a-vinyl-1,3,5(10)-estratriene-3,17f3-diol

Chapter

3.0

at

(see

pure

yields,

was

Aldrich

125-130°C.

Rose. 9

(decay

mL/min;

by

Subsection

obtained

41

on

for

by

an

respectively.

3

referred

in

3-methoxy-

silica

Chemical

corrected

1,3,5(

the

a

Compound

adaptation

52%

radiochemical

UV

Flash

addition

from

After

gel

10)-estratriene

5.4.3),

yield

to

139

detection,

with

Co.

to

chromatography

as

l7cr-ethynyl-

Sigma

cooling,

3-Methoxy-l7cr-vinyl-1,3,5(10)-estratriene-

of

23

(based

SOS)

AIBN,

was

of

hexanes/diethyl

and

the

was

iodomethane.

Chemical

yield

treated

procedure

Alfa

of

HPLC

254

was

on

treated

25,

[“C-CN]-4-chlorobenzonitrile

1,3,5(

of

the

were Products,

nm)

supplied

with

29%.

analysis

on

amount

Co.

with

10)-estratriene-

prepared

of

of

silica

potassium

ether

35,

Flash

Johnstone

Tri-n-butyltin

the

powdered

by

and

obtained

(column

of

gel

Aldrich

(2:1)

reaction

chromatography

35

2,2

by

with

hydroxide

used). adapting

‘-azobis-

afforded

and

17f3-ol

potassium

C;

hexanes/

Chemical

from

mixture

hydride

eluent:

Rose. 9

the

24

the

(2-

24

21 in

used

shown Fluorine

handling

5.4.2

purity

or hexanes/diethyl

mixture

bromide

obtained

according galactopyranose

chromium published

hexodialdo-

dipyridine

7-ynopyranose

Freon-li

Research

The

Canadian

to

General

(suitable

in

acetylenic

perform

was

gas

Figure

with

according

(85%

to

trioxide-pyridine

procedures

complex

1,5-pyranose

(CFC1 3 ) grade

separated

is

Liquid

Garegg

great

toxic, 28

yield)

for

5.1.

ether

all

26

sugars,

Ne

and

18 F

to

studies

Air

was

care.’ 3 ” 4

(in

(Koch-Light

highly

This

and

and

in

using

(6:2:1). the

production)

its

in

Ltd.

27

52%

a

purchased

7,8-dideoxy-

L-glycero-a-D-galacto

1%

Samuelsson.”

gas

procedure

ratio

was

two

involving

column

corrosive,

complex

(Vancouver,

F 2

yield)

handling

Hence,

prepared

steps.

of

in

Laboratories

Ne 62:38

by

chromatography

from

l,2:3,4-di-O-isopropylidene-D-glycero-a-D-galacto-oct-

in

as

elemental

of

and

either

gas

a

the

system

described

Hems

by

First,

specialized

(determined

Matheson

140 Then

BC).

mixture

generally

oxidation

presence

Matheson

was

et

epimer

27

1,2:3,4-di-O-isopropylidene-a-D-galacto-

fluorine

Ltd.)

al. 12

were

by

was

constructed

Gas

on

dangerous,

of

fluorine

of

using

Arrick

by

and

1,2:3,4-di-O-isopropylidene-a-D-

29,

silica

treated

acetic

Gas

specially

and

Products.

‘H

were

a

either

Products

NMR),

gel

acetyl

mixture

gas

and

anhydride

with

from

with

and

prepared

prepared

handling

co-workers,’°

hypofluorite,

chromium

ethynylmagnesium

therefore

respectively.

dichloromethane/

components,

of

(Edmonton,

28

(in

in

according

system

and

68%

ultra-high

requires

trioxide

29

or

and

yield)

such

AB)

This

was

was

the

to is

based

TRIUMF with

the tubes

cylinders, tank

as

Figure

stainless

reaction

radionucides.

and

to

alloy

the

gas

5.1:

fabricated

500

steel

(for

gas

vessel

handling

Schematic

fluorination

MeV

the

targets

and

transducer

pressure

with

The

500

Teflon,

from

cyclotron.

system

CYCLOTRON

used

SHIELDING

MeV

gas

Teflon

of

nickel

reactions.

that

handling

the

on

are

cyclotron).’ 6

the

fluorine

are

tubing

stationed

(for

The

TRIUMF/Nordion

compatible

system

the

cyclotron

(1/16

gas

141

CP-42

transducer

in

pressure

The

is

handling

a

or

connected

fume

with

gas

cyclotron)’ 5

gas

1/8

handling

reactive

hood

in.

targets

system

CP-42

vent

o.d.)

via

(

specifically

fluorine

or

1/8 used

system

are

cyclotron

using

Inconel

in.

essentially

to

metering

o.d.

valve

was

Swagelok

gas.

perform

designed

and

600,

stainless

reaction

connected

The

the

a

gas-tight

the

fluorine

fittings

for

nickel-

larger

steel

use to (Crawford Fitting Co., Salon, OH) and Teflon ferrules. Gaseous 3CHCOOF was produced by passing a dilute mixture of 2F (—0.1%) in Ne through a column containing a solid mixture of potassium acetate/acetic acid in a molar ratio of 2:3. The CHCOOHCOOK/CH mixture was prepared according to the method of Jewett et al.17 3 The quantification of the amount of 2F or 3CHCOOF used for fluorination experiments was accomplished by iodometric ”918titration. Prior to performing actual fluorination reactions with vinyl-tin substrates, one or two “dummy”trials would be done in which the fluorinating agent was added to an aqueous solution of excess KI, and the liberated 12was then titrated with standardized 0.1 M sodium thiosulfate solution. 82[‘F1F was produced by the 20Ne(p,Spall)’ reaction with a target gas mixture of 0.1% F in natural neon that wasFirradiated with 500 MeV protons from the TRIUMF 2 8 16cyclotron. Gaseous 38FCHCOO’ was prepared by venting the 82[‘F]F produced after target irradiation through the solid 3CHCOOHCOOK/CH 17column that was described earlier. 5.4.3 Preparation of Vinyl-Tin Substrates

General procedures for hydrostannylation of acetylenic compounds.

Procedure A: Under an 2N atmosphere, a solution of acetylenic compound in 1,4- dioxane was prepared. To this stirred solution, five equivalents of tri-n-butyltin hydride was added by syringe, then the mixture was refluxed overnight. The solvent was removed and the crude mixture was chromatographed on a silica gel column to obtain

142

purified

to in unidentified

was

ether

vinyl-1,3,5(10)-estratriene-3,17j3-diol

stannylated

Preparation

result

Vinyl-tin

open

isolate

thoroughly

cooling,

stirred amount

the

Method

be a

General:

Procedure

stannylated

performed

ratio

present

under

in

(6:2:1).

the

mixture

of

by

the

gradual

compounds

of

A:

AIBN,

dried

stannylated

as

byproducts,

column

In

29:71

of

normal

entire

B:

in

Compound

described

l7cr-(E)

all

on

The

product.

Under

was

the

under

decomposition.

and

as

silica

cases,

reaction

second

chromatography

conditions,

heated

first

determined

are

two

-tributylstannylvinyl-

high

product.

an

while

gel

in

sufficiently

23 the

N 2

fraction

equivalents

procedure

vacuum,

fraction

(3.5

overnight

mixture

(1986

atmosphere,

vinyl-tin

further

however,

cm

by

Proper

mg,

contained

‘H

for

then

air-stable

35.

x

was

elution

on

A.

of

products

(thermostated

NMR.

6.70

15

a

storage,

143

tri-n-butyltin

stored

silica

yield

a

chromatographed

prolonged

Flash

cm)

1,3,5(10)

mixture

mmol)

isolated

30

so

Therefore,

with

of

gel

in

after

chromatography

that

therefore,

as

38%.

vacuo

in

of

(150

-estratriene-3,1713-diol

dichloromethane/hexanes/diethyl

the

exposure

a

they

silicone

chromatographic

1,4-dioxane hydride

acetylenic

mixture

over

The

mg)

dominant

774

can

is

on

sodium

first

very

were

mg

with

be

oil

to

of

a

compound,

of

23 easily

the

silica

fraction

of

bath,

(10

important.

combined,

dichloromethane/

product

the

and

35

hydroxide

atmosphere

mL)

was

handled

isolation

gel

crude

95°C).

35

30

was

was

(1090

column

estimated

a

plus

and

catalytic

mixture

and

further

pellets.

hydro

in

After

were

l 7 a-

mg)

two

will

the

the to

mL/min)

onto

35 rate, benzene/hexanes,

separation

fractions

in

hexanes/ether

eluted

a

H-21),

Anal.

m,

viscous

CH 2 MHz,

hexanes

dichioromethane/hexanes/ether

analytical

=

portion

the

In

8.8

(R.=5.0

26H,

of

column

6.0

an

early

Hz,

CDC1 3 )

calcd.

with

6.20

steroid

syrup,

attempt

mL/min;

/ether

that

17-OH,

of

employed

1H,

was

fractions.

sample

all

mm)

(d,

the

for

C

contained

&

and

H-2),

carried

nucleus),

(6:4:1).

fractions

3 JSn,H

and

(6:4:1)

mixture

0.81-0.97

to

C 32 H 52 O 2 Sn:

Sn(CH 2 CH 2 CH 2 CH 3 ) 3 ,

of

UV then

upon

separate

for eluting

7.13

was

19:81

=

Therefore,

out

which

detection,

analyzed

66

HPLC

Unfortunately,

the

of

drying

5.30

containing

(d,

(m,

by

Hz,

obtained

was

23

lowest

35

35

1H,

injecting

afforded

(s,

18H,

C

and

using

analysis.

1H,

present.

from

overnight

65.43,

by

1H,

a

H-i).

(6:4:1),

280

35

percentage

sample

18-CH 3

H-20),

HPLC

35,

the

3-011),

23

was

by

nm)

this

780

H

complete

with

for

Mass

The

CH

same

As

mp

performed

in

flash

8.92;

144

sample

mg

was

and

6.57

and

(column

characterization,

vacuo,

a

6.07

86-87.5°C,

the

and

peaks

spectrum,

of

of

result,

conditions

obtained

Sn(CH 2 CH 2 CH 2 CH 3 ) 3 ),

found

found:

(d,

23.

30

chromatography

largest

separation

(d,

CH 2

(dissolved

24

crystallized

C; (20%

corresponding

This

on

J 2021

that

to

eluent:

of

=

C

silica

[a] 4

by

m/z:

percentage

effectively

2.9

sample

65.60,

steroid

overall

(flow

=

a

combining

ratio

19.4

in

was

Hz,

column

+

gel

531

methanol/water,

THF) 19.00

as

rate

H

with

was

isolated

Hz,

not

nucleus),

1H,

of

an

( 120 Sn:

to

8.78.

on

isolate

23

of

was

(c

off-white

chromatography

recrystallized

2 JSn,H

achieved

in

35

H-4),

dichloromethane/

several

1.20-2.37

23

(RT= 3 . 6

1.7,

silica

several

were

M-C 4 H 9 ,

changed

yield)

1 H

being

35

2.80

1,4-dioxane).

6.62

NMR

70

of

an

collected,

solid.

gel

as

3:1;

portions

as

Hz,

(several

(m,

mm)

the

present

(dd,

HPLC

23

to

a

from

100).

flow

(270

with

very

late

2H,

1H,

3.0

co

J 1 , 2

An

to of

in was

B. Preparation

procedure

TLC

m/z:

hexanes/diethyl

spectral

298.1934.

but

Hz,

purification

CH 3 ),

CH 2

crystals, additional

80.50,

=

Compound

Method

2.8

the

Column

due

not

1H,

of

298

analysis

Hz,

1.24-2.37

H

first

steroid

eluted (‘H

H-21a),

mp

to

8.78;

(M,

1H,

B:

B.

chromatography a

HPLC

fraction

NMR)

169.5-170°C,

of

was

minute

of

24

Compound

H-4),

found:

51),

nucleus),

off

3-methoxy-17o&(E)-tributyIstanny1vinyI-1,3,5(10)-estratriene-173-o1

Column

(several

ether

the

5.20

(492

recrystallized

the

280

properties

purification.

6.62

reaction

114

amount

(dd,

C

mg,

(6:4:1)

column.

(M-H 2 O,

80.54,

m,

chromatography

mg

(dd, 4.68

2 O, 2 lb

23

[a1 5

1.59

14H,

on

of

(1.00

J 12

mixture

afforded

of

(hr

of

H

silica mmol) +

=

crude

from

23 this

=

17-OH,

58.5°

8.72.

s,

15).

17.3

g,

The

8.2

still

1H,

material

gel

3.37

confirmed

3-methoxy-17a-(Z)-tributylstannylvinyl-1,3,5(10)-

benzene/hexanes,

was

in Hz,

Hz,

Exact

(c

‘H

present,

3-OH),

(100

material

CH

one

on

145

1,

mmol)

NMR

1H,

1H,

bydrostannylated

1,4-dioxane).

g)

silica

mass

and

were

portion

H-2),

H-21b),

with

5.15

the

the

was

(270

CH 2

obtained

calcd.

identical

gel

hexanes/diethyl

presence

isolated

7.14

(dd,

1.17 hydrostannylated

of

MHz,

(100

6.11

for

steroid

J 2021 a

which

(d,

g

Anal.

with

(dd,

C 20 H 26 0 2 :

(59%)

g)

from

as

CDC1 3 )

1H,

material

of

with

described

afforded

those nucleus),

35,

1H,

calcd.

H-i).

10.8

the

of

but

ether

dichloromethane/

H-20),

ô:

30.

was

298.1934;

reported

Hz,

for

Mass

0.95

as

second

the

in

2.80

(5:1) Physical

35 described

‘21a,21b

subjected

C 20 H 26 0 2 :

6.56

compound (s,

procedure

spectrum,

as

(m,

3H,

yielded

earlier.

found:

HPLC

(d,

white

31.

2H,

and

J 24

18-

1.2

in

to C

M,

75

6.75 nucleus),

Sn(CH 2 CH 2 CH 2 CH 3 ) 3 ,

0 The

CHC1 3 ).

in was

the

94% Preparation

Column spectrum,

1.01

calcd. estratriene-17fl-ol

Compound

5.35.

the

Hz,

second

isolated

(dd,

1),

material

(m,

as

first

for

1H,

an

601

chromatography

‘H

J,, 2

6H, Anal.

3.23

C 33 H 54 O 2 Sn:

m/z:

oil, fraction

fraction

H-21),

NMR

( 120 Sn: of

=

as

Sn(CH 2 CH 2 CH 2 CH 3 ) 3 ),

25

from

(s,

and

8.6

3,173-dimethoxy-17o-(E)-tributy1stanny1viny1-1,3,5(1O)-estratriene

calcd.

602

a

(1.00

3H,

colourless

36,

(270

6.37

Hz,

M-CH 3 ,

after

0.23

1.56

the

(‘ 20 Sn:

17-OCH 3 ),

for

and

g,

CH

C

1H,

MHz,

(d,

g

second

g

drying

3.08

on

65.90,

C 34 H 56 O 2 Sn:

of

of

and

in M,

3 Sn,H

H-2),

32

silica

5),

oil

pure

the

minol)

C 6 D 6 )

CH 2

in

plus

0.2),

fraction

H

559

in 3.39

=

following

—7.16

vacuo

32.

gel

9.05,

90%

69

of

a

(‘ 20 Sn:

ô:

was

545

(s,

1.12

minute

(200

steroid

C

Hz,

Compound

0.93

yield,

0

(d,

for

3H,

66.35,

exhibited

hydrostannylated

(‘ 20 Sn:

146

(s,

1H,

5.32;

g)

two

M-C 4 H 9 , 1H,

(t,

15-30

3-OCH 3 ),

nucleus),

with

amount

3H, J

[Qf]4

H-20),

H

fractions,

M-C 4 H 9 ,

H-i).

found:

9.17, minutes,

32

18-CH 3 ), hexanes/diethyl

mp 7.3

+

was

66).

17.1°

of

6.68

Mass

6.23 Hz,

2.63-2.86

50-52.5°C,

0

C

unidentified

860

isolated

5.20;

65.83,

100).

as

crystallized

9H,

(d,

(d,

(c

1.21-2.29

spectrum,

described

mg

J 2 , 4

J 2021

1.2,

found:

Sn(CH 2 CH 2 CH 2 CH 3 ) 3 ),

(m,

H

of in

=

[a] 4

1,4-dioxane).

ether 9.00,

=

2H,

31.

an

2.6

byproduct,

(several

C

19.7

m/z:

as

in

overall

+44.1°

CH 2

Hz,

Compound

0

66.37,

(20:1)

a

procedure

Hz,

white

5.28.

616

1H,

of

m, yield

2 JSn,H

H

yielded

steroid

(c

and

( 120 Sn:

H-4),

Anal.

solid.

Mass

25H,

9.18,

32.

1.2,

31

B.

in of =

fraction nimol)

tributylstanny1-L-glycero-c-D-galacto-oct-7-enopyranose chromatography B

m/z:

ro-oc-D-galacto-oct-7-enopyranose

Preparation

4.45 2.81

(dd, Sn(CH 2 CH 2 CH 2 CH 3 ) 3 ), as

B. 8.41;

ro-a-D-galacto-oct-7-enopyranose

19.2 ether

Preparation

Compound

except

Compound

a

Column

J 1 , 2

colourless

Hz,

(dd,

(d,

561

found:

(6:6:1) was J 6 ,OH =

3 Sn,H

444

J 3 , 4

that

( 120 Sn:

5.0

chromatography

added

of

afforded of =

=

C

Hz,

29

after

28 mg

=

syrup,

8.0 7.0

(E)-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-8-C-tributylstannyl-L-glyce-

(E)-7,8-dideoxy-

54.21,

on M-CH 3 ,

64

(898

(884

J 23

Hz,

of

Hz,

silica

19

and Hz,

[a] 3

=

in

mg,

mg,

hours

a

H

1H,

1H,

2.3

1.21-1.55

1H,

one

heating

gel

mixture

3),

8.52.

3.16

3.11

-36.1°

Hz,

H-4),

6-011),

on

(200

H-7),

fraction

of

519

mmol)

mmol)

1H,

silica

heating,

1,2:3,4-di-O-isopropylidene-8-C-tributylstannyl-n-glyce-

1 H

34.

4.61 (c

(2

g)

33.

was

( 120 Sn:

6.38

of

3.68

H-2),

with

1,

m,

NMR

gel

1093

CHC1 3 ).

(dd,

was

(Z)-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-8-C-

continued

was

24H,

(dd,

(dd,

M-C 4 H 9 ,

0.50

(200

hexanes/diethyl

147

4.34

mg

hydrostannylated

1H,

hydrostannylated (270

2 Sn,H

J 5 , 6

2

mL

g)

(m,

(6

H-3),

Anal.

x with

=

1%)

MHz,

of

for

J 6 , 7

=

C(CH 3 ) 2

6.5

100).

70

tri-n-butyltin

dichioromethane/hexanes/diethyl

5.59

of calcd.

=

another

Hz,

37

Hz,

33.

4.4

CDC1 3 )

ether

and

(d,

J 4 , 5

and

Hz,

for

1H,

Compound

as

as

1H, 7,8-dideoxy-

=

three

(4:1)

J 6 , 8

described C 26 H 48 O 6 Sn:

Sn(CH 2 CH 2 CH 2 CH 3 ) 3 ),

described

H-8).

&

1.7

H-i), hydride

=

0.81-0.97

Hz,

yielded

hours.

1.4

Mass

33

6.18

1H,

Hz,

in

in

(0.54

1,2:3,4-di-O-

was

C

in

procedure

procedure

(dd,

H-5),

spectrum,

1H,

(m,

54.28,

Column

the

isolated

g,

J 78

H-6),

15H,

first

4.32

1.86 H =

pure

the

perform

via

under

either

a

at controlled

Fluorination

(different

spectrum, for

5.4.4

Compound isopropylidene-7-C-tributylstannyl-L-glycero-cr-D-galacto-oct-7-enopyranose

of

estimated

C0 2 /2-propanol

The

General

Further

0

3:2

a

vinyl-tin

C 26 H 48 O 6 Sn:

or

Ne

1/16 Fluorination

the

inert

as

desired

-78°C,

fluorinations

was

determined

CP-42

solvents

to

m/z:

by

elution

Procedure:

in.

34

atmosphere.

be

solution

the

of

added

was

the

o.d.

quantity

present

561

vinyl-tin

or

fluorine

C

vinyl-tin

isolated

(-78°C)

were

500

afforded

Reactions

Teflon

54.28,

( 120 Sn:

to

with

after

by

A

MeV

dilute

in

of

employed)

A

substrates

gas

1 H

solution

the

F 2 , H

M-CH 3 ,

as

cooling

tube,

solution

stream

1%

the

NMR.

gas handling

1076

a

8.41,

mixture,

the

the

of

colourless

F 2 /Ne

inert

Vinyl-Tin

target

positioned

diluted

F 2

of

of

bath.

mg

0

was

with

and

2),

As

concentration

inert

vinyl-tin

gas

system

16.68;

for

gas

using

of

519

cooled

a

placed

elemental

F 2 /Ne

148

syrup,

flow

chemical

34

result,

gas

Compounds

mixture

( 120 Sn:

at

the

found:

(see

in

was

compound

was

the

with

in

[a] 4

gas

fluorine

a

266

Figure

passed

a

yields

M-C 4 H 9 ,

bottom

F 2

to

second

turned

(60-230

mixture

C

either

glass

-37.0°

mg

or

approximately

54.57,

5.1).

gas

gaseous

of

through

(60-200

of

reaction

off.

an

of

fraction,

(c

15%

mol

was

37

handling

100).

H

To

1.3,

ice/water

the

and

then

However,

and

8.47,

conduct

CH 3 COOF.

CHC1 3 ).

1 mol)

F 2 )

the

solution,

vessel

178

for

10%,

0.1%

added

vinyl-tin

system,

was

0

(0°C)

was

mg

a

16.55.

fluorinations

(oven

38

respectively.

loaded

Anal.

to

in

59%

which

directly

of

in

prepared

and

perform

Ne.

solution

bath

38

a

dried)

calcd.

yield.

Mass

then

ratio

into

was

was

To

to or

the

39

fraction

continued

graphy

(column

same

general glass

approximately

methoxy-17a-(Z)-fluorovinyl-1,3,5(10)-estratriene-173-ol

Preparation

the

appropriate. removed

mL/min

fluorinations

solution. through

The

Compound

(RT=

isolated

reaction

reaction

manner,

reaction

on

procedure.

17.8

(55

a

D;

to

in

Both

elution,

solid

silica

the

chromatography

vacuo.

eluent:

mg)

mm)

with

of

mixture

31

vessel

employing

1.3

vinyl-tin

fluorinating

mixtures

CH 3 COOK/CH 3 COOH

3-methoxy-17a-(E)-fluorovinyl-1,3,5(1O)

gel

collected

(92.7

gaseous

and

a

equivalents

Five

solvent

second

The

(100

(2.0

was

40

mg,

solution.

additional

obtained

residue

(RT=26.2

a

g)

CH 3 COOF,

cm

contained

transferred

fraction

154

total

agents

D;

with

fractions

of

o.d.

flow

mol)

of

After

was

CH 3 COOF,

hexanes/diethyl

were

(F 2

fluorinations

x

mm)

554.6

(66

rate,

39

analyzed

were

or

was

10 the

the

to

mg)

combined,

column

in

in

CH 3 COOF)

149

cm

mg

3.5

diluted

addition

a

dissolved

subjected

96%

a

was

round-bottom

ratio

at

of

length).

mL/min;

by

room

31

of

obtained

and

purity

F 2 /Ne

TLC,

ether

then

of

compound

of

(922

in

the

79:21

to

were

fluorinating

temperature,

This

CFC1 3

UV

as

subjected

further

-estratriene-1713-ol

then

mol). gas

(4:1)

40.

effluent

which

indicated

added

by

flask

detection,

mixture

solution

worked

31

as

HPLC

(20

purification

contained

were

the

added

to

and

at

agent

mL)

as

was

by

column

a

eluent.

analysis.

was

up

conducted

flow

described

the

280

and

HPLC

was

to

instead

as

treated

a

the

solvent

nm).

rate

via

added

39 completed,

considered

mixture

chromato

The

vinyl-tin

Both

analysis

HPLC.

and

of

passed

in

in

With

with

first to

-

was

the

the

50

of

of

3- a

by with

required

Compound mm)

external flow

general

of glass

approximately

whereby

Quantification

respectively.

another portions

employed Each

Compound

Additional

Compound

CHC1 3 .

HPLC

approximately

rate,

was

reaction

fraction

procedure.

standard.

batch

all

present,

about

onto

analysis

6.0

for

The

31

of

31

fluorination

mL/min;

31

HPLC

(74.1

was

vessel

1.3

product

of

the

(11.5

39

0.5

(80.7

(76.4

yields

for

that

equivalents

It

was

dissolved

1.3

After

HPLC

mg,

was

mL

mg).

analysis.

(2.0

a

equivalents

mg, 5.59

mg,

isolated

mixture

yield

UV

123

for

solvent

determined

of

cm

trials

127

silica

134

mg

The

the

mo1)

detection,

in

of

CHC1 3

of

o.d.

The

of

mol)

mol)

was

a

41%

reaction

in

were

isolated

CH 3 COOF,

removal,

gel

minimum

39

of

was

one

x

analyzed

peaks

CH 3 COOF

based

and

that

to

column

was

10

was

conducted

280

dissolved

batch

of

150

help

cm

yields

40

the

17.0

dissolved

corresponding

dissolved

urn)

31

on

of

was

at

by

length).

residue

(90.0

with

and

mg

the

ether,

solubilize

room

as

HPLC

using

of

in

obtained,

using

of

described

amount

39

dried

eluted

gaseous

mg)

in

in

39

was

and

temperature,

a

and

This

CFC1 3

(column

dried

and

standard

alternative

and

CH 3 OH

to

dissolved

31,

then

using

for

of

40

CH 3 COOF.

solution

40

39

above.

all

31

CH 3 CN

(20

and

a

were

was

(both

and

C;

yield

used.

of

the

solution

(20 mL)

solvent

as

in

was

40

injected

40

It

reaction

29.5%

was

co-elute,

mL)

same

a

of described

was

(20

and

was

were

known

treated

14%.

treated

mL),

program

and

determined

of

added

isolated

and

conditions

in

collected,

39

solvents.

RT=S.O

volume

treated

several

which

in

3.8%,

as

with

with

to

the

A;

an

in a

41

use

CFC1 3

side-products procedure.

mm)

estratriene-173-ol flow

external

ethynyl- with

CHC1 3 . glass by

approximately

HPLC

Quantification

approximately

An

Compound

Compound

were

HPLC

as

approximately

rate,

was

reaction

additional

(20

external

analysis

1,3,5

present,

standard.

The

present,

analysis

6.0

mL),

(

After

10)-estratriene-

product

that

31

mL/min;

31

vessel

1.25

1.2

of

standards.

that

which

fluorination

for

(103.2

(71

were

41

yields

for

equivalents

that

It

solvent

equivalents

1.4

10.4

yields

(RT was

mg,

a

(2.0

mixture

was

equivalents

present

3.62

yield

mg,

UV for

=

mg

determined

118

5.70

cm

removal,

HPLC

treated

of

mg

the

172

173-ol

detection,

of

of

experiment

5.4%

mo1)

was

of

o.d.

mm).

in

9.0% of

39

of

reaction

mol)

CH 3 COOF

significant

F 2 ,

analysis

39

of

and

with

analyzed

24

x

and

the

was

based

CH 3 COOF

Standard

that

at

(RT

and

10

was

40

280

approximately

7.2%,

room

residue

of was

=

151

dissolved

cm

5.10

was

40

indicated

4.39

on dissolved

31

nm)

amounts

by

as

was

length).

done

temperature,

mg

respectively.

obtained,

with

the

solutions

mm)

HPLC

described

using

as

was

obtained,

of

amount

described

in

using

elemental

and

that

39

were

in

dissolved

dried

a

(column

1.35

This

and

CFC1 3

of

3-methoxy-

for

standard

2.89

95.9

above.

identified

24

of

equivalents

for

as

40

THF

a

solution

above.

31

and

mg

F 2 . yield

mg

described

(20

(both

a

in

C;

used.

yield

It

of

41

(20

solution

(159

mL)

a

solvent

17a-vinyl-

of

was

24

as

were

known

It

co-elute,

was

mL)

24%.

of

In

was

3-.methoxy-

and

and

ILmol)

of

determined

in

9.3%.

addition,

prepared

treated

F 2

program

of

and

determined

the

3.85

added

volume

1,3,5(10)-

at 39

RT= 4 . 97

of

general

treated

-78°C,

mg

as

31

l 7 a- with

to

two

for

A;

an

by

in

of

of a as described above. It was determined by HPLC analysis that 2.23 mg of 39 and 40 was obtained, for a yield of 4.2%. Furthermore, the side-products 24 and 41 were obtained in 2.2% (1.11 mg) and 14.5% (7.23 mg) yields, respectively.

Preparation of (E)-8-C-fluoro-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-L-glycero-a-D- galacto-oct-7-enopyranose 47 and (Z)-8-C-fluoro-7,8-dideoxy-1,2:3,4-di-O-isopropyli- dene-L-glycero-a-D-galacto-oct-7-enopyranose 48. Compound 34 (83.6 mg, 145 mol) was dissolved in 3CFC1 (20 mL) and added to a glass reaction vessel (2.0 cm o.d. x 10 cm length). This solution was treated with approximately 1.3 equivalents of 3CHCOOF, at room temperature, as described in the general procedure. A second fluorination of compound 34 (80.9 mg, 141 mol) was performed as outlined above. The reaction mixtures obtained were combined, then subjected to column chromatography on silica gel (60 g) with dichloromethane/hexanes/ diethyl ether (6:2:1) as the eluent.

The first fraction (29.5 mg) collected contained 47 in —98%purity as indicated by ‘H

NMR. The second fraction (4.0 mg) contained a mixture of 47, 48, and 7,8-dideoxy-

1,2:3,4-di-O-isopropylidene-L-glycero-a-D-galacto-oct-7-enopyranose 49 in a ratio of

43:36:21 as determined by ‘H NMR. The third fraction (9.0 mg) contained a mixture of 47, 48, and 49 in a ratio of 6:83:11. The final fraction (5.4 mg) contained a single compound that was identified as (E)-8-C-acetoxy-7-deoxy-1,2:3,4-di-O-isopropylidene-L- glycero-a-D-galacto-oct-7-enopyranose 50.

The chemical yield of 47, as contained in the first three chromatography fractions, was

152

rate production

end

through

the

then

MeV

a

General

5.4.5

subjected

/diethyl additional mg,

a fractions,

of cm

determined

glass

A

total

A

CH 3 COOF,

irradiation

o.d.

of

of

142

solution

larger

pure

gas

Radiofluorinations

bombardment

—50 reaction

of

x

mol)

a

procedure ether

target

to

was

solid

fluorinations

10

326.5

Ne

run,

scale

mL/min.

to

column

of

cm

determined

(6:2:1)

of

was be

was

at

vessel

CH 3 COOK/CH 3 COOH

vinyl-tin

was

the

length).

synthesis

mg

the

36%

room

dissolved

for

target

chromatography

added

filled

(EOB).

of

target

With

as

(2.0

radiofluorination

(32

of

34

the

temperature,

compound

with

This

compound

with

of

to

gas

cm

the

mg).

until

(567

gas

eluent.

in

47

be

After

o.d.

mixture

Acetyl

addition solution

4

CFC1 3

was

and

10%

mol).

The

or

100

x

irradiation,

stopped,

(110-120

6

48

on

34

12.5

(9

[ 18 F]Hypofluorite

yield

psi

psi (20

as

was

was

was

of

were

silica

column mg).

with

The

153

described

(0.27

mL)

cm

CH 3 COO 18 F

(6.8

irradiated

of

treated

carried

this

performed

gel

mol)

length)

gaseous

48,

reaction

and

atm)

or

the

and

(140

time

as

0.41

with

added

out

radioactive

in

in

contained

was

into

under

g)

for

was

CH 3 COO’ 8 F.

CFC1 3

completed,

atm)

the

as

mixtures

with

in

approximately

reached.

the 10

to

follows.

the

noted

general

inert

a

of

minutes

dichioromethane/hexanes

(20

reaction

same

glass

gas in

1%

and

were

atmosphere.

mL)

the

the

Compound

mixture

F 2 /Ne

reaction

manner,

procedure.

For

designated

at

second

reaction

was

vessel

combined, 1.35

69

a

gas

prepared

1 A.

was

equivalents

typical

vessel

employing

at

and

mixture,

The

34

mixture

passed

a

When

as Three

(81.9 third

flow

then

(2.0

500

the

‘ 8 F in was transferred to a round-bottom flask, then assayed for radioactivity. The 3CHCOOK/ 3CHCOOH column was also assayed for activity. The reaction mixture was evaporated to dryness in vacuo and reassayed for activity, then dissolved in a small amount of .3CHC1 An aliquot of this mixture was subjected to radio-HPLC purification and the peak corresponding to the 18F-labelled product was collected, then counted to determine the percentage of product present in the reaction mixture. The decay corrected radiochemical yield was calculated by dividing the total activity due to product (in the reaction mixture) with the total activity of F18 produced in the cyclotron target at EOB.

Reaction of 31 with 3F18CHCOO at room temperature. Compound 31 (72.1 mg, 120 mol) was radiofluorinated using approximately 0.74 equivalents of 38FCHCOO’ (produced with 6 psi of 21%F/Ne), at room temperature, as described in the general procedure. HPLC analysis (column C; solvent program A; flow rate, 6.0 mL/min; UV detection, 254 mn) of the reaction mixture determined that 3.68 mCi (decay corrected to EOB) of 3-methoxy-l7cy-(E)-[’F]fluorovinyl- 1,3,5(10)-estra- triene- 173-o1 51 and 3-methoxy-Fjfluorovinyl- 1,3,5 10)-estratriene- 17i3-ol52 17a-(Z)-[’ 8 ( (both co-elute, RT=5.5 mm) was8produced for a radiochemical yield of 19%. An additional radiofluorination trial was conducted using a greater excess of vinyl-tin 31. Compound 31 (71.0 mg, 118 1Lmol) was radiofluorinated using approximately 0.5 equivalents of 38FCHCOO’ (produced with 4 psi of 1% 2F/Ne), at room temperature, as described in the general procedure. HPLC analysis (column C; solvent program B; flow rate, 6.0 mL/min; UV detection, 254 mu) of the reaction mixture determined that

154 3.79 mCi (decay corrected to EOB) of 51 and 52 (both co-elute, RT 11.0 mm) was produced for a radiochemical yield of 19%.

Reaction of 31 with 3F18CHCOO at -78°C. Compound 31 (69.0 mg, 115 1mol) was radiofluorinated using approximately 0.77 equivalents of 38FCHCOO’ (produced with 6 psi of 1% 2F/Ne), at -78°C, as described in the general procedure. HPLC analysis (column C; solvent program A; flow rate, 6.0 mL/min; UV detection, 254 am) of the reaction mixture determined that 1.72 mCi (decay corrected to EOB) of 51 and 52 (both co-elute, 4RT=S. mm) was produced for a radiochemical yield of 9.7%.

An additional radiofluorination trial was conducted using a greater excess of vinyl-tin

31. Compound 31 (71.7 mg, 119 mo1) was radiofluorinated using approximately 0.5 equivalents of 3F18CHCOO (produced with 4 psi of 1% 2F/Ne), at -78°C, as described in the general procedure. HPLC analysis (column C; solvent program B; flow rate, 6.0 mL/min; UV detection, 254 nm) of the reaction mixture determined that 1.65 mCi

(decay corrected to EOB) of 51 and 52 (both co-elute, RT= 10.7 mm) was produced for a radiochemical yield of 5.0%.

155

17.

18.

9. 7.

16.

15.

5. 4.

8.

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