Polymer=Bound Ketenes and Allenes:

Preparation and Applications

Adel Rafai Far

A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy

Department of Chemistry University of Toronto

O Copyright by Adel Rafai Far (2000)

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Abstract

The main scope of the research presented in this thesis is the investigation of the

viabilit y of polymer- bound ketenes and allenes, and of their reactions. These studies

represent a continuation both of the current developments in polyrner-bound synthesis.

and of the recent progresses in cumulene chemisuy.

Attempts were made to use 1,3-dioxin4ones as preçursors of polyrner-bound

acylketenes. Usùig both insoluble and soluble polymeric supports, three different

polymer-bound clioxùiones were prepared. These were thermally converted to the parent

ketenes. but attempts to trap these showed that the main products came from competing

hydration. This was countered by reversing the procedure, namely by adding the ketene

to the support. Soluble poly(ethy1ene glycol) (MPEGOH) of average MW of 5000 g

mol-' was reacted with 2.2.6-trimethyl-1.3-dioxin-Cone. an acetylketene precursor, to

give a po Iymer- bound acetoacetate. Condensation of this with primary amines under

dehydrating conditions gave polymer-bound enamines, These were then treated with the

acetyketene precursor again. and gave 4-pyridones, which were Liberated from the

support by methano lysis.

Using MPEGOH. the Wang min. and a spacer modified Wang resin. stable

polymer-bound silyl ketenes were prepared by the reaction of the hydroxy groups on

these polyrners with 2.3-bis(trimethylsily1)- 1 -3-butadien- 1.4-dione. a persistent and stable

bisketene. The soluble polymer-bound silyl ketene was converted to amides via reaction

with amines. Folio wing fluorodesil ylation. the amides were cleaved from the support

either via methanolysis. to give succinimides o r mixed ester amides of succinic acid. or

via reaction with butylamine to give unsymmeuîal succinamides. The solid supponed

silyl ketenes were subjected to the same process, with the exception that hydrolysis was

used for the cleavage. to forrn succinamic acids and esters. The Wang rein supported

ketene was also converted to its parent esters under catalysis with base. yielding succinic

acid mo noesters. after cleavage.

Using MPEGOH. polymer-supporied allenecarboxylates and an aiienylketene

were prepared. The alienecarboxylates were treated with amines to give enamines and.

fo llo wing treatment with acet yiketene and methanolysis, 4-pyridones were O btained fiom

these allenes. The sarne enamines were treated with acryloyl imidazole, to give, afier

mathano lysis. glactams. The treatment of the aiienylketene with amines. foilowed by

the same reac t ion with acrylo y1 imidazo le and methano lysis. also gave Glactarns.

iii

Acknowledgements

Carrying on my doctoral studies in Professor Thomas T. TidweIl's group has been

a true privilege. Professor Tidweil is an example of what a supenisor should be: patient.

enthusiastic. willing to discuss aii the different aspects of chemistry, and open to new

avenues to explore. And 1 would like to thank him above aii for letting me carry on this

unusual research in the realrn of ketenes.

1 am also indebted to ail the rnembers past and present of the Tidweiî group,

pmicularly Anne tte Allen. Mike FenwicL, Hu& Henry-Riyad. Wenwei Huang. Ronghua

Liu and Patrick Moore. It was wondehl to be assoçiated with them.

Most of this work wouldn't be b i b l e without the skiiis of the support staff at the

department of Chemistry: Dan Mathers (ANALEST). Aiex Young (Mass Specuometry).

T h Burrow (Solution state NMR). Patricia Aroca-Ouektte and Hiltrud Grondey (Solid

state NMR). 1 &O would like to thank Professors McCleiland. Kresge. McMillan. Still

and Yudin from the University of Toronto and Professor Lemoff frorn York University

for useful suggestions.

Above aU. 1 owe aU of this to my family. through their help. support and

encouragements. None of this would be possible without my father Afram, my mother

Leila. my grandmother Violet, Sherry. Dina and DaMd (Au téléphone: -Alors David. qu*

est-cc que tu fais de beau? -Rien, -Tu ne fais rien de beau? -Non...). Thank you for this

gift.

Table of Contents

Abstract

Acknowledgments

Table of Contents

Abbreviations

Supports for Combinatoriai Chemistry

A few defmitions

Chapter one: Polymer-bound cumulenes

il Reactivity in po lymer-bound synt hesis

Polymer-bound carbodiimides

IlIJ Polymer-bound diazoaikanes

N] Polymer- bound isocyanates and thioisocyanates

VI Polymer-bound ketenes

VI] Conclusion

VIII] Reîèrences

Chapter two: Polymer-bound acyl ketenes: Preparation and attempted use

a Applications of ketenes to polymer-bound synthesis

a) Dehydro halogenation

. . 11

iv

v

ix

xii

1

b) Acyl Meldrum's acid

c) Diazoketones

d) Chromium carbene complexes

ïlJ Acyl ketenes from 4H- 1.3-dioxin-4-ones

ïïlJ Acyl ketenes bound on a solid support

IV] Soluble polymer-supported 1,3-dioxin4one

VI Soluble polyrner-bund synthesis of 4-pyridones

a) Preparation of 2.6-dimethyl-4-pyridones

b) Atternpted use of alternative acyl ketenes

VI] Conclusion

Va Experimental

1) Preparation of polymer-bound dioxinone 54

2) freparation of polymer-bound dioxinone 58

3) Soluble polymer-supported dioxinone 64

4) Preparation of 2.6-dimethyl pyridones

5) Preparation of 2.2-dimethyl-6-phenyl- 1.3-dioxin-4-one

6) Preparation of 6-alkyl su bstiuted dioxinones via Meldrurn's acid 7 1

7) Preparation of 5-ethyl-6-trifluoromethyl-2.2-dimethyl- 1.3-dioxin-

4-one (79) 75

8) Preparation of 2,2,5.6-tetramethyl- 1.3-dioxin-&one (80) 76

V W References 77

Appendix A: Selected 'H-NMR spectra 83

Appendix B: Selected IR spectra

Appendix C: CP-MAS ' 3 ~ - ~ ~ ~ spectrurn for 54

Chapter three: Stable polymer-bund silylated ketenes 97

r] Introduction 97

LI] Preparation and nucleophilic reactions of a soluble polymer bound silyl

ketene 99

Uïj Solid-supported silyl ketenes 104

a) Preparation 104

b) Reaction with amines 105

C) Reaction with alcohok 107

N] Conclusion L 11

V] Experimental 112

1) Soluble polymer-bound ketene 113

2) Solid supponed ketenes 122

VT] References 128

Appendix A: selected ' H-NMR spectra 13 1

Appendix B: selected IR spectra 159

Chapter four: Po lymer- bound allenecarboxylates

Tj Introduction

II] Soluble polymer-bound allenecarboxylates

a) Preparation

b) Reactions with amines. Preparation of pyridones and Glactarns L67

III] Soluble po lymer- bound stable dien y1 ketene 170

IV] Atternpts towards the preparation of allenes on a solid support 174

V] Conclusion 179

V u Experimental 180

1 ) Polymer-bund allei-aarboxylates 181

2) Polyrner- bound allen y1 ketene 191

3) Solid supported reagents L93

Va) References 196

Appendix A: selected 'H-NMR spectra 200

Appendix B: IR spectrum for aiienyl ketene 18 225

Appendk C: NOESY spectrum for l3w 227

Yields and purities

Abbreviations -

Ac

Bu

calcd

cm-'

CF-MAS

OC

DMSO

d

DBU

DCC

dd

DE AD

DIC

DIPEA

EIMS

Et

EtOAc

E

HMPA

acetyl

but y1

calculated

wavenu rn ber (inverse entheters)

crosspoiarization-magie angle spinning

degrees centigrade

dimethy1 sulfoxide

doublet

1,8-diazabicycl0[5.4.0]undec-7-ene

dic yclo hexy Icarbodümide

doublet of doublets

diethyl azodicarboxylate

Diisopropy Icarbodiimide

düsopropylethylamine

electron impact rnass spectrometry (low resolu t ion)

Ethyl

Ethyl acetate

gram

hexameth ylphosphoramide

HRMS

hv

Hz

1 -

IR

3

m

M

M+

Me

PL

mg

mL

mP

mm01

mo 1

MS

m/z

n-

N

nm

NMP

NMR

high resolution mass spectrometry

irradiation

hertz

iso

in frared

coupling constant

multiplet

rnolarity

molecular ion

methyl

microliters

miliigrams

milliliters

melting point

millimoles

moles

mass spectrome try

m a s to charge ratio

normal

normality

nanometer

1 -Methyl-2-p yrro iidone

nuclear magnetic resonance spectroscopy

PEG

Ph

Pr

PS

f-

TBAF

TEA

THF

TMEDA

TMS

UV

VPC

polyethylene glycol

meny 1

P ~ O P Y ~

~ 0 1 ~ stvene

parts per million

quartet

singlet

tertiary

tetrabutylammonium fluoride

triethylarnine

tetrahydrofuran

N,N,N'.NT-tetramethylethytenediamine

trirnethylsilyl

ultraviolet

vapor phase chromatography

Supports for Combinatorid Chemistry

will be used to represent polystyrene crosslinked with divinylbenzene

Wang resin

SASRIN resin

HAL resin

OMe

xii

Rink amide (X = NHFmoc) or ester (X = OH) resin

MBHA resin

TentagelTM resins (X is a hnçtionality)

xiii

xiv

A few definitions

Ail of this thesis deals with polymer-bound chemistry. It appears therefore useh l

to introduce the reader to some of the terminology used.

Library: Set of molecules with common structurai elernents. Generally meant for a

mixture of the molecules in this set. The broader definition is preferred hem.

Deconvolution: Characterization of the moiecules in a library having the desired

properties.

Combinatorial chemistrv; Field of chemistry dealing with the preparation.

characterization, evaluation and deconvo1ution of libraries.

Sup~ort: A substance which can bind, generally (but not necessarily) covalently, a

number of molecules of another substance. and because of its unusual properties can be

easily separated from reaction mixtures.

Polvmer-bound or m l v m e r - s u ~ ~ o n e d r e a ~ e n t k o m ~ o u n d . substance): the product

obtained by bonding a nurnber of small molecules to a polymenc support.

Po lvmer- bound or mlvmer-su~oorted svnthesis t ~ r e ~ a r a t i o n ) : A synthesis (preparation)

in which al1 or some of the steps involve polymer-bound substances.

Solid hase s-ynthesis f~re~aration): A synthesis (preparation) in which ail o r some of the

steps involve substances bonded to an insoluble support.

Linker: A functional group on a support which can react with another substance. thereby

attaching this substance to the support. Sometimes referred to as "handle".

Cleavaee: A process which releases a substance ftom a support, by the destruction of the

bond between this substance and the linker.

Traceless linker; A linker which, upon cleavage. doesn't result in the presence of an

undesired functionai group in the reieased substances,

Chapter One

Introduction

Polymer-Bound Cumulenes

I] Reactivity in volvmer-bound svnthesi~

Frorn its genesis, combinatorial chemistry has had a unique relationship with

polymer supported synthesis. particularly because of the role of peptides in its

development.' The advantages in tems of ease of manipulation and p ~ ~ c a t i o n

associated with polymer- bound chemistry are especially beneficial in the preparation of

large numbers of compounds, be it through paraiiel synthesis or through the making of

complex mixtures of compounds. The trends in drug discovery and other modem

industrial practice to screen large numbers of compounds are reflected by the recent

incrèase in interest in reactions on polymer-bound substrates.

One advantage of using a support is that an excess of reagent(s) can be used to

drive the reactions to completion. without the problems associated with the rernoval of

this excess. or of the solvents and the by-products. In order to benefit M y from this

tcchnique, it is preferable to bind the lest reactive, reagent to the support. This way an

excess of the more reactive. more sensitive, reagent(s) can be used.

This process may be illustrated for example, with the preparation of a polymer-

bound ester by the reaction an acid chloride with an alcohol in the presence of a base

(Scheme 1). The side products of this reaction generally corne from the competing

hydrolysis of the acid chbride by the presence of rnoisture. Therefore if the ester is to be

prepared by using a polymer-bound acid chloride. the cornpethg hydrolysis would

generate the correspondhg polyrner- bound carboxylic acid, and this would Io wer the

yicld and lead to the presence of impunties in the product &er cleavage from the

support. The excess alcohol canno t reverse the h ydrolysis. However. if a polymer-bound

aIcohol is used. excess acid chloride can be used to ensure complete formation o f the

ester, while the hydrolysis products are simply removed by reuieving the supponed

product frorn the reaction mixture-

+ ROH - + ROH(excess)

Polymer-bound acid chloride

Polymer-bound alcohol

Scheme 1

In this exarnple. the fact that botb reagents (acid chloride and alcohol) are readily

available and easily stored is a r d advantage. However, in numerous cases. the most

reactive reagent is not easily synthesized o r stored.

This is particularly tme if the most reactive substance requires a multi-step

preparation, so that it is generally preferable to generate it on the suppon, provided o f

course it c m survive the rehtively harsh environment (such as rnoisture). Furthemore.

reactive intermediates are often valuable synthons in a number of different preparations.

so that if they are properly behaved substances when bound to a polymer. they can prove

to of great use to combinatorial chemists.

Cumulenes belong to this category of compounds which often necessitate

complicated preparations, but are stable enough and yet reactive enough to be of utility in

a variety of synthetic reactions. Hence almost from the beginning, they have received

close attention from combinatorial chemists.

IT] Polvmer-bound carbodiimides

Becausc of their role in the activation of carboxylic acids in peptide synthesis,

carbodiimides have long had a role in solid phase synthesis, starting with Merrifield's

seminal workm2 When carbodiimides mediate the formation of an amide. they give rise to

a urea byproduct, the removal of which is a notoriously tedious matter in standard

solution chemistry. However, in solid phase synthesis. with the sirnplicity of the

purification brought about by the use of a support, they have assurned a dominant role as

CO upling reagents.

It is therefore not surprishg that. initially, most of the interest was directed

towards the use of polymer bound carbodiimides as a way to s h p l i f y the removal of the

urea. In these cases, the carbodiimide does not appear in the skeleton of the frnal product,

but is merely a waste byproduct, so no effort is made in fiding a cleavable linker in

binding it to a polymer, as it wiil never corne off the support.

Early work to prepare polymer-bound carbodiimides was based on the ability of

phosphdene-1-oxides to cataiyze the condensation of isocyanates into syrnmetrical

carbodiimides (Equation l).)

When bis(isocyanate) 1 was used, a polymeric carbodiimide 2 was produced, but

ic tumed out to be axtremely inen to acid. alkali or amines (Equation 2).3 ~ o w e v e r using

bis(isocyanate) 3 gave the more reactive poly(hexamethy1enecarbodiimide) 4 (Equation

3). which was capable of coupling acids with amines to form amides."

Other approachgs to polymer-bound carbodiimides involved the use of the

Merrifield resin (5) as the starting material. In the fust case. carbodümide 8 was made in

a prrparaiion involving the dehydration of the parent urea as the key step (Scheme 2)?

The product 8 proved to be an efficient dehydraring agent in the Moffat oxidation of

alco hols. giving yields of 67-97%.6

In a dil'ferent approach. an amino-carbodiimide 9 was coupled with the Merrifield

rcsin to givc the polymer-supponed carbodiimide 10. also termed P-EDC (Equation 4).'

This ragent was used as a coupling agent in the preparation of amides. in yields of 72-

l00lr.' and of the esters of pentatluorophenol and N-hydroxysuccinimide. in yields of

53-98%' The investipatoa provided a very interesthg study of the effects of the loadhg

of the resin on the efficiency of P - E X . showing that low loadings lead to slower

reactions. whereas very high loadings are detrimental to the reactions by affecting the

ability of the resin to swell in organic solvents.'

i: Potassium phthalimide, DMf, IûûoC. ii: Hydfazine, ethanol. reflux. iii: Isopropyl isocyanate, THF, reflux. iv: TsCI, TEA, C%Ch, reflux.

10, P-EDC

There is another class of polymer-bound carbdümides. which themselves

panicipate in the skeleton of the f ia l product. These are made via the condensation of a

polymrr-bound iminophosphorane with an isocyanate. The iminophosphorane can be

prepared by the reaction of a phosphine with an azide. This can be done in the presence

of a isothiocyanate, as shown in Scheme 3.

1 iii

i: DIC. HOBt, DMF. ii: NaN 3. O M O , 60 W. iii: RNCS, PPh 3, THF. iv: N-Phenylpiperazine, DMSO. v: 95% TFA

Scheme 3

Using the Rink amide resin (11). a polymer-bound azide 14 was prepared. which

in the presenct: of phenyl or isopropyl isothiocyanate is convened to the carbodiimide 15,

9

via the irninophosphorane generated in situ? Bulkier isothiocyanates. such as with the t-

butyl substituent. and acyl isothiocyanates do not react under these conditions. The

carbodiimide is then reacted with phenylpiperazine. and the resulting product is released

from the resin via acid mediated hydrolysis. to give the guanidinium rrifluoroacetates

(17). in 63-96% yields.

1 RR'NH

i: Cs$O3, OMF, KI. ii: PPb, then isopropyl isocyanate.

Scheme 4

A similar approach was applied to the polymer-bound azide 19, prepared from the

Merrifield resin (Scheme 4). This tirne, the irninophosphorane was prepared prior to the

addition of isopropyl isocyanate. which produced the polyrner-bound carbodümide M."

This carbodiimide was designed so that the addition of a nucleophile would bring about

cleavage via cyclization from the resin. giWig rise to quinamlines. in yields of 42-85%.

and with purities of 97-100%.

1 i i i , N

i: DIC, DMAP, DMF/CH2CI2, ii: SnCI2.2H20, DMF, iii: PPh3, DEAD, THF. iv: ArNCO, THF. v: Amine, 23 O C to BO O C . vi: 1 :1 TF A:CH2CI2

Scheme 5

A third sequence utiiizing iminophosphoranes was based on the reaction of

primary amines with phosphines in the presence of diethyl azodicarboxylate." This

approach was applied to the preparation of carbodiirnide 25 fiom amine 24, usine the

Wang resin (21) as the suppon (Scheme 9." In this case. reaction of 25 with secondary

amines leads to a cyclization via intramolecular conjugate addition, which. after cleavage

from the resin. gave quinazolines 26 in 87-1008 yield. and with 83-944 punty.

III) Polvrner- bound diazoalkanq

Diazoalkanes have been a very interesting and versatile group of compounds in

organic chemistry since their discovery by Curtius in 1883.'~ It is therefore not surprising

that they have found an early role in polyrner-bound chemistry. The initial work was

based on the abiiity of diazoalkanes to react with carboxylic acids, leading to esters. The

polymer-bound diazoalkane 30 was prepared from polystyrene crosslinked with 2%

divinyibenzene (27) in a stepwise fashion. relying on the oxidation of the parent

hydrazone 29 (Scheme 3." This diazoakane reacts readily with carboxylic acids. and

thercfore provides an efficient method for their irnrnobilization on a solid suppon.

Cleavage from the suppon is brought about by treatment with TFA.

Diazoaikanes are known for king excellent transition metal-carbenoid precursors.

In addition. the generation of these on a solid support essentially avoids the main problem

associated with iheir formation. that is the metd catalyzed dimerizaion Ieading to the

dkcne.

iii

Ph

i: Benzoyl chloriâe. AICg, &CI4. ii: N2H4.H20, n-BuOH. reflux. iii: AcOOH, AcOH, tek methyl guanidine, h. iv: RCQH.

This ability has ken demonstrated with the polymer-bound diazoalkane 34,14

which was made h m the rnoditied Wang resin 32." via diazo transfer (Scheme 7). The

diazoalkane 34 is then transfonned into the parent rhodium carbenoid, in the presence of

alcohols. so that the subsequent O-H bond insertion and cleavage from the support with

TFA leads to a-alkoxy amides 36. These amides were converted to the parent p-

toluenesulfonamides 37 for isolation. Nthough yields were low ( 10-40%). this

methodology gave excellent purities as assessed by the cmde 'H-NMR spectra of 36.

Othcr catalysts such as CuCN and P ~ ( O A C ) ~ did not give satisfactory'resulrs.

i: p-Ts&, DIPEA, DMF. ii: pynolidine. DMF. iii: ROH, Rb(OAc),. CH2Ch. iv: 1 :1 TFA:CH2CS. v: p-TsCI, pyridine, Ci+&&.

Scheme 7

The use of this kind of methodology was funher applied to the preparation of

substituted furans (Scheme 8).16*17 The polymer- bound diazoalkane 41 was prepared

svpwise from a polymer-bound amine 38 (either ~ e n t a ~ e P - ~ ~ Z ' ~ or Wang m i n 6-

amino hexanoate"). again via diazo transfer. Conversion to the rhodium carbenoid

brings about the generation of an isomünchnone. which reacts with an akyne through a

hetero Diels-Alder reaction (Equation 5). Removal of the reagenü and hating the

polymer gave the desired furans. in 50-708 yields. together with a polymer-bound

isocyanate. Interestingly. ihis reaction. therefore. ieads to the product in a traceless

fashion (no functionality remains as a result of the atmchment to the suppon). A

limitation of this methodology is that only elecuon poor aikynes such as dimethyl or

die t hy 1 acetylenedicarboxylate can be used.

IV] Polvmer-bund isocyanates and isothioc-nates.

Isocyanates are essential to the polymer industry for the preparation of

polyurcthanes. because o f their unique ability to react with nucleophiles without any by-

producis. It is therefore not surprising that they have received considerable attention in

polymer science. One of the most interesting aspects of their chemistry involves the

conccpts of blocking and u n b l o ~ k i n ~ . ' ~ Thus when a polyurethane is made. the temini

of thé polymer are still unreacted isocyanates. and therefore c m be used as ways to

introduci: other tùnctionalities. and hence change the properties of the polymer or build

block copolymers. When an isocyanate is reacted with a nucleophile, it is said to be

blocked (Equation 6).

i II

R' H

38 39 OEt

1 iii

i: RICO,H, DIC, DMAP, DMF. ii: Ethyl malonyl chloride, PhH, 60W. ikp-Ts&, Et,N, CbCL, iv: R~(OAc).,, PhH. v: PhH, reflux.

Scheme 8

Unblocking an isocyanate (or a polyurethane) represents the action of exchanging

a nucleophile for another one on the blocked isocyanate (Equation 7).

One efficient way to block/unblock isocyanates is to use oximes.'" As shown in

Scheme 9, oximes can block isocyanates, giving oxime carbarnates (44). These can be

unblocked via reaction with amines, such as dibutylamine at mild temperatures (refluxing

benzene). to give ureas (45).

Ph Bbcùin R-N-O + HO+ 2

Ph

Scherne 9

This proccss was demonstrated with the polymer-bound isocyanate 48, made

through the reaction of poly(propy1ene oxide) of an average molecular weight of 1040

c.mo1-' 46 with the bis(isocynnate) 47 (Equation 8).Ih L

This type ofprocess, at f r s t mostly of value to polymer scientists. has found itseff

to be of great interest to polyrner-bound chemistry, as it d o w s the use of oximes as

linkers. This has been applied to the De Grado-Kaiser oxime resin (49, Scheme 10).19

The reaction of this resin with bis(isocyanates) gives the polymer-bound isocyanate 50. in

which there is one blocked isocyanate. The second isocyanate is then reacted with an

amine to give the polymer bound urea 51. The product is released from the resin by

unblocking with an excess of a volatile amine, o r a single equivalent of a non volatile

amine. giving bis(ureas) 52, in good yields (50-94%) and purities (77-94%).

Polyrner-bound isocyanates can be made by other means than by using

bis(is0cyanates). One method involves the reaction of an amine with triphosgene in the

prcxnce of a base. This is how the polymer-bound isocyanate 54 was made fiom

aminomethylated polystyrene 53 (Equation 9).20

This polymer- bound isocyanate is of great use as a scavenger resin. for exampk

to remove excess amine from a reaction.

i: Diisocyanate, CbCh. ii: R1R2NH, CH2Cb. iii: R%'NH. PhMe. 75oC.

Scheme 10

Another method of generating a polymer-bound isocyanate is by usine an Fmoc

protected polyrner-bound amino acid (55) (Scheme 1 l)? The Fmoc group c m be

converted by reaction with methyitrichlorosilane. which acts as an oxygen acceptor, to

the isocyanate 56, which is not isolated. but rather directly reacted with an amine.

Cleavage leads to the production of ureas 58. in purities of 76-92%.

i: MeSich, Et3N, CbCh. ii: R1R2NH. CH2Ch. iii: TFA, CYCh. Scheme 11

lsothiocyanates can behave in the same way as isocyanates, and they can be

generated from amines in a similar fashion. by reaction with thiophosgene or a mixture of

carbon disulfide and toluenesulfonyl chloride. in the presence of base. This has k e n

applied to resin 59 (Scheme 12).*~ If the min possesses a secondary amine for the

reaction ( R ~ # H). then a thiocarbamoyl chloride 60 is produced. and if it has a prirnary

amine (R' = H). thrn a isothiocyanate 61 is produced.

In this case, the isothiocyanate is reacted with a stabilized carbanion (2 must be

an electron withdrawing group) to give thioamides 62. These in tum are reacted with a

haloacyl arene (X = Cl or Br. R' = Aryl. others fail), to give the vinyl sulfides 63, the

base mediated cyclization of which gives the thiophenes 64 after cleavage. in good yields

and with purities of 53-85%.

iii - I

i: a) C s , DIPEA. p-TsCI. or b) CSCb, DIPEA. ii: ZCbCN, DBU. DMF. iii: XC&COR3, DMF, 5% AcOH. iv: DBU, DMF. v: 1 :1 TFA:C&Ch

Compared to the above mentioned cumulenes. ketenes are more sensitive. They

react with moisture and with oxygen. and they tend to dimeriz rather easily. It is

therefore not surprishg that there is only one previous report of a poiymer-bound ketene,

in an application of the SmithRloehn eiecuocyciization. which has b e n widely exploited

in recent years. Ketenes occur as transient species in this process. This has been appiied

to the polymer-bound cyclobutenedione 65. prepared from squaric acid and Wang m i n

(Scheme 13).23

Upon sequential treatrnent with an amine and an alkenyllithium, 65 is converted

to the cyclobutenone 67. In retluxing toluene. 67 undergoes an electmcyclic ~g opening

to the polymer-bound ketene 68. which quickly cyclizes to the hydroquinone 69.

Oxidation by air and an acidic treatment kads to the product quinones (70). in rather low

yields (043%) after chromatography.

This survey of the literature has shown that. although reactive. many cumulenes

arc sufticiently stable to survive the environment of a polymeric matrix, and Iead to

satisfactory yields and purities in sorne multistep polymer-bound syntheses. Such

polymrr-bound substances. and the methodologies used to generate them. have great

pro mise for use in combinatonal chemisuy. and ultirnately in drue design.

iii

iv, v - i: RN&, THF. ii: Vinyl lithium, -7tPC. iii: PhMe, reflux. iv: air oxidation. v: 20% TFA in C&Cb.

It is therefore of interest to study the viability of the poiymer-bound versions of

two other classes of cumulenes, nameiy ketenes and allenes. This means not only

examination of the generation of these species on polymenc supports. but also the

development of efficient reaction pathways in an environment where cornpethg reactions

may occur.

Polymer-bound ketenes are precedented by the report on the polymer-bound

ketene 68. described previously. However, one rnust distinguish between intra- and

in termo Iecu lar reac tions. Indeed, the rapid ring opening/ring closure reaction does not

leave muc h room for any other reactions to occur. But when intermolecular reactions are

concerned, the process is obviously much more dependent on the cleanness of the

reaction and the sensitive nature of the reagents. It is therefore evident that generating

ketenes on a support and reacting them in an intermolecular fashion is not guaranteed by

what was done previously in the iiterature.

For these reasons. it is the goal of this thesis to prepare polymer-bund ketenes

and allenes and to evaluate their poremial as synthons for combinatorial chemistry.

VI11 References

( 1 ) See: a) Combinatorial Peptide and Nonpeptide Libraries, a Handbook; Jung, G.. Ed. ;

VCH; 1 996. b) Combinatarial Chernistry, Synrhesis and Application; Wilson, S . R..

and Czarnik, A W.. Ed.; John Wiley and sons; 1997. c) The Combinatorial Index;

Bunin. B. A; Academic Press; 1998. d) Booth, S.; Hennkens. P. H. H.; Ottenheijm.

H. C. J.; Rees. D. C. Tetrahedron 1998.54. 15385- 15443.

(2) Merrifield. R. B. J. Am Chem Soc. 1963,85.2149-2154.

(3) Campbell. T. W.; Monagle. J. I. J. A m Chem Soc. 1M2.84, 1493.

(4) Wolman. Y .; Kivity. S.; Frankel. M. J. Chem Soc. Chem Commun. 1967.629-630.

(5) a) Weinshenker. N. M.; Shen. C. M.; Wong. J. Y. Organic Syntheses. COU. Vol. VI;

Wiley. New York. 1988; 951-954. b) Weinshenker. N. M-; Shen, C. M. Terrahedran

Lett. 1972, 328 1-3284.

(6) a) Weinshenker. N. M.; Shen. C. M. Organic Syntheses. COU VOL VI; Wiley. New

York. 1988; 218-219. b) Weinshenker. N. M.; Shen, C. M. Tetrahedron Lert. 1972.

3285-3288.

(7) Dcsai. M. C.; Stephens Strarniello. L. M. Tetrahedron Lat- 1993.34, 7685-7688.

(8) Adarnczyk. M.; Fishpaugh. J. R.; Mattingly. P. G. Tetrahedron Lert. 1995. 36. 8345-

8346.

(9) Drewry. D. H.; Gerritz. S. W.; Linn. J. A Tetrahedron Lett. 199'7.38.3377-3380.

(. 10) Chucholowski. A.; Masquelin, T.; Obrecht. D.; Stadlwieser. J.; Villalgordo, J. M.

Chimia 1996.50.525-530.

( 1 1 ) Wang, F. ; Hauske. J. R. Tetrahedron Lem 1997.38,865 1-8654.

( 12) Diaz0 Chemistry. VOL 1 and II. Zoiiinger, H.; V.C.H., 1994.

( 13) Chapman. P. H.; Waker, D. J. Chem Soc. Chem Commun. 1975,690-69 1.

(14) Zaragoza, F.; Petersen, S . V . Tetrahedron 199652.5999-6002.

( 15) Zaragoza, F.; Petersen, S. V. Terrahedron 1996,52. 10823- 10826.

( 16) Gowravararn. M. R.; Gallop, M. k Tetruhedrun Lem lm, 38,6973-6976.

( 17) Whitehouse. D. L.; Nelson, K H. Jr.; Savinov, S. N.; Austin D. J . Terrahedron

Lette 1997.38.7 139-7 142.

(18) a) Levine.A. W.; Fech.1. J r . 1 Org. Chem 1972.37, 1500-1503. b) Levine. A

W.; Fech. J. Jr. J. Org. Chem 1972.37.2455-2460.

( 19) Scialdone. M. A, Terrahedron LRrf. 1996.37. 8 14 1-8 144.

(20) Booth. R. J.; Hodges. J. C . J. Am Chem Soc. 1997.11 9.4882-4886.

(2 1) Chong. P. Y.; Petiilo. P. A Tetrahedron Lem 1999.4501-4504.

(22) Stephensen. H.; Zaragoza. F. J. Org. Chem 1997.62.6096-6097.

( 2 3 ) Tempest. P. A.; Armstrong. R W. ' Am Chem Soc. 1997,119,7607-7608.

Chapter Two

Polymer-Bound Acyl Ketenes

Preparation and Attempted Use

I] &plications of ketenes to mlvmer-bund svnthesi~

The preparation and use of a transient polyrner-bound ketene. generated from a

su bstituted cyclo butenone has already been described in the previous c hapter. ' However,

consistent with what was outlined previously about reactivity. it is generally preferable

that such reactions involve the use of an excess of ketene with a pokymer-bound reagent-

The frst example of the use of ketenes in soiid phase chemistry was the

acetylation of alcohols supported on inorganic solid adsorbents. such as silica or alumina,

by ketene itself (Equaiion l).' This approach was motivated by the necessity to fmd

proper catalysts for the acetylation of complex aicohois, and the adsorbents used served

to promote this reaction.

There are numerous examples of the involvement of ketenes in polymer-bound

chemistry, and these can be classified according to the method of generation of these

transient compounds,

The generation of ketenes from an acyl halide by the base mediated elimination of

hydrogen halide is a simple and common approach to the generation of ketenes. This

approach is exemplified by the Staudinger reaction. the [2+2] cycloaddition of a ketene

generated in situ from an acid chloride and an amine base. with an imine to afford a P-

lactarn l (Equation î).'

In a seminal paper. M. A. Gailop and his coworkers used Sasrin. a highly acid

sensitive resin preloaded with an Fmoc protected amino acid. as a starting material 2

(Scheme l).' After deprotection. the resin presents a free primary amine, which c m be

reactcd with aldehydes in the presence of trimethyl orthoformate as a desiccant. to afford

the desued polymer-bound imines 3. These in turn are treated with an acid chloride in

the prescnce of triethylarnine to produce the polyrner-supported p-lactams 4. which are

liberated from the resin by treatment with TFA, in good yields (58-9796). Prior to

cleavage. the [j-lactarns can be tùrther modified via Heck and Suzuki co~piuigs.~

1 iii

i: 30% piperidine in NMP. ii: F?CHO, (MeOhCH, CH2Cb. iii: R3CH2COCI, TEA, CH&. iv: 3% TFA in CYCb.

Scheme 1

Given the importance of B-lactams in medicinal chemistry, the shpl ic i ty o f this

approach has attracted considerable attention. In the same communication,' an

alternative approach was also presented. in which the photolabile m i n TentaGe1 B (6)

was used (Scheme 2). Polyrner-bound p-lactam (7) are built in a similar fashion. and are

released from the resin through irradiation in exceuent yields (7 1-90%).

i: Wh pipendine in NMP. ii: R 'CHO, (Me0)3CH, CH2CI2. iü: R2C&COCI. TEA, CH2CI2. iv: hv. 365 nm, DMSO.

Scheme 2

MPEGO MPEGO ,+qyNHR O O

i: 4- BnOCONH-GH4-OI-l. DCC, DMAP. ii: Y, 10% Pd/C. iii: RCHO, 900C. iv: R=H2COCI, R3N. CH2G12. V: CH30H. H2S04, 60 OC.

Scheme 3

17

RHN

vi l 9 R - = * 2 O R - = H -

O O

i: RINH,. 4 A mol. sieves. or (C&O)&H. ii AcOCl-@OCI. TEA. ChCC. iii: &CO3. CH,OH. CH,Ch. iv: p-nitrophenyl chbrofonnate. OIPEA. CYCh. v: WNH2. CH&. vi: 3% TFA. ChCI

This approach has been extended to the use of poly(ethy1ene glycol) rnonomethyl

cthrr of a molecular weight of SXKl g mof' as a suppon (Scheme 3)?'

Another approach involves usine a polymer-bound aldehyde (15. Scheme 4).' In

this case acetoxyketene was used. and this allowed the authors to hinher modify the

produced P-iactarns (17) via carbarnates. In addition. with this ketene. only the cis-

diastercorners of the lactams were produced.

B-Lactams are not oniy interesting as fuiai targets. but also interesting reagents.

This was demonstrated by using substituted O-nitrobenzaldehydes in the preparation of

imines (23. Scheme 5). bound on MBHA resin (21). as Wang resin was too acid labile.9

After formation of the plactams 24. the nitro-gmups are reduced by tin(I1) chloride. and

the resulting amines open the Crnembered Nig to give dihydroquinolinones (25). as

shown in reaction 3. These are removed from the resin by matment with HFand anisole.

resulting in the desired products 26, in excellent yields (68-108) and A355 pwity.

R ' RNHCO / \ NH

1 iii

i: a) 1-BocNH-RI-COOH, DIC, HOBt, DIPEA. b) 55% TFA, CbCb. c) DIPEA. ii: substituted O-nitrobenzaldehyde. Na2S0,. CH&&,. iii: R30CH2COCl, TEA. CYCh. iv: SnCh, DMF. v: HF/ anisole (95/5).

Scheme 5

b) Acvl Meldrum's acid

Meldrum's acid (2.2-dirnethyl-1.3-dioxane-4.6-dione. 27) reacts with aiiphatic

acyl chlorides in the presence of pyridine. to give, in high yield and without

chrornatographic work-up. acyl Meldrum's acids (28. Equation 4).1°

These reagents are excellent sources of acyl ketenes (29) through their thermal

dccomposition (Equation 5).

These ketenes are of grm interest because of their ability to react with

nucleophiles to give 1.3-dicarbonyl compounds, which are of great use in synthesis. In

addition. the ease of the preparation of their precursors 28 made them of interest to

combinatorial chemists.

Generally. acyl Meldrum's acids have been used in conjunction with polymeric

alcohols to give polymer-bound Pketoesten (JO. Equation 6). which have in tum been

used in the preparation of pyrazolones" and 2.2'-bipyridines."

ref luxing - tduene w'

Polyrner-bound amines 33. generated from polymer-bound amino-acids 31. were

also treated with acyl Meldmm's acids. CO @ive the P-ketoamides 34 (Scheme 6)." These

undergo an intramolecular cyclization. accompanied by cleavage from the resin. to give

3-acyl tetramic acids (35). in mediocre yields (1 1-618). but with excellent punties (80-

100%). This process has been investigated as a method for the medium scale (ca 100 g )

production of these tetramic acids usinp a high loading Wang resin (3.1 meqlg) as a

iii

i: R1 CHO, (C%0)3CH. repeat. ii: NaCNBY, DMF, AcOH. repeat. iii:28, toluene, 1200C. iv: 30% DIPEA, dioxane. 80%

Scheme 6

C) Diazoketones

Thermal or photochemical Wolff rearrangements are well-known methods for the

reneration of ketenes. These reactions stem from the decomposition of diazoketones (36. C

Equation 7).15

This approach has k e n used in the Arndt-Eisten homologation, whereby the

carbon chah of a caboxylic acid is extended by one carbon unit.16 The sequence

consists of the activation of this acid. for instance as its acid chloride, reaction with

diazomethane to give the desired diazoketone, and fmaiiy formation of the ketene in the

presence of a nucleophile to give the desired acid derivative (Scheme 7).

Scheme 7

This method has been applied to a-amino acids. giving the desued enantiopure P-

amino acid derivatives. Once incorporated into peptides (so c d e d P-peptides). these

amino acids g ive rise to unusual pro perties. particularl y very stable secondary

structures. I7

These B-peptides can be made directly on a solid suppon by the reaction of the

diazoketones 37 with amino acids bound on either Wang resin or the 2-chlorotrityl resin.

in the presence of silver benzoate as a mediator (Equation 8). 18.19

d) Chromium carbene corn~lexes

The irradiation of chromium carbene complexes (39) is thought to give rise to a

short-lived chromium-ketene complex (40).~* This ketene complex reverts back to the

carbene complex. except in the presence of a reagent which can trap the ketene (Equation

When chromium aminocarbene complexes (41. Equation 10). with a chiral

auxiliary. were photolyzed in the presence of an amino acid ester. dipeptides (42) formed

in good yields (60-88%). and with good diastereoselectivit y (80-96%).*'

This methodology allows the introduction of nonproteinogenic (unnatural) a-

amino acids in peptides. It has been appiied to both solid-phase peptide synthesis2' and

to the synthesis of peptides bound to a soluble poly(eihy1ene glycol)23 support. On the

solid support (MerX~eld resin or PAM resïn), the coupling reactions did not result in

very good yields (35-608 for dipeptides). but the yields were improved upon use of the

soluble support (54-828 for di-. tri- or tetrapeptides). Although this may not yet be of

use in the synthesis of large peptides, it is certainly of interest in drue design. where small

peptides are generally the standard.

II] Acvl ketenes from 4H- 1.3-dioxin-4-ones

Acyl ketenes (43) are a class of short-lived. but extremely versatile ketenes."

Upon generation. in the absence of trapping reagents. these compounds rapidly form

dimers. They are therefore usually generated in situ by a number of methods (Scheme 8).

Arnong the most valuable are the thermal decompositions of 4H-1.3-dioxin4ones (44),

ac y1 Meldrum ' s acids (28) and 1,2-furand iones (45).

1.3- Dioxin-4-ones (44) have been extensively studied.= They are easily made

from r-butyl P-ketoe~ters .~ or by derivatkation of the parent 2.2.6uimethyl-4H-1.3-

dioxin-4-one (48). This latter substance, also known as diketene acetone adduct, is a

commercially available. and quite inexpensive starting material, Dioxinones decornpose

to the desired acyl ketenes at rehtivety mild temperatures (generaUy refluxing toluene or

xylenas). and c m be trapped by a number of reagents (Scheme 9). For these reasons, they

are considered as very venat.de reagents in organic synthesis, and therefore. if these

substances behave properly on a polymeric support, they could be of extreme value to

combinatorid synthesis.

III] Acvl ketenes bound on a solid SUD DO^

1.3-Dioxin-4-ones with a functional substituent at position 6 are easily made from

the diketene acetone adduct 48? It was therefore decided that the iink to the support

wouid be at position 6.

Our initial approach was based on the use of suifides as traceless linkers in

soluble polymer-bound ~ ~ n t h e s i s . ~ ~ Although ihis approach had not been tested on solid

support. it had two advantages. Firstly, it is attractive to be able to obtain products

without functional groups. such as alcohols and carboxylic acids. used for the atmchment

to the resin- Secondly, the production of a polymeric thiol had akeady been reponed in

the l i t ~ r a t u r e . ~ ~

This approach was first tested using standard solution chernistry. 6-

Chloromethyl-2.2-dimethyl-4H- 1.3-dioxin-4-one (49) was prepared frorn 48, as reported,

by its sequential deprotonation and inverse quenching with hexachloroethane (Equation

1 I ) in 67% yie~d.29

X= H. OR'

1) LDA, THF, -78%

2) GCk, THF. -7WC rn dA w l

48 49

This dioxinone (49) was then treated with thiophenol and triethylamine under

nucleophilic catalysis by sodium iodide with DMF (Equation 12). Such a reaction can

result in direct displacement of the chloride. to give the desired 2.2-dirnethyl-6-

phenyIthiomethyL4H- 1.3-dioxin-4-one (50) or in a nucleophilic displacement at position

5 (via Ssl o r SN2') resulting in compound 51. which is not known to produce any acyl

ketene. In fact from the cmde NMR of the reaction. only 50 is produced and, after

purification, in 95% yield.

PhW, TEA, Nal,

Therefore, the polymeric thiophenol 53 was produced. from polystyrene

crosslinked with 1% divinylbenzene (52). through lithiation foliowed by quenching with

sulfur. and reduction of the resulting polysulfides with lithium aluminum hydride

(Equation 13).~' Titration indicated a loading of 1.9 meq/g.

1) nBuLi, THF, C&i,2, 60%

2) S,. 3) LiAIh, THF, A = ~ S H (13)

This polymeric thiol(53) was then used as the nucleophile in its reaction with 49.

in the prcsence of triethylamine and sodium iodide. to give polymer-bound dioxinone 54

(Equation 14). Aithoueh it could not be titrated, this compound was characterized both

by IR (with the typical ester signal at 17 17 cm-') and by solid sute 13c C R .

The purpose of this synthesis being to study the viability of a polymer-bound

acetyl ketene. this polymer-bound dioxinone was refluxed in toluene in the pmence of

cyclo hexanol to trap the ketene to rnake a polymer-bound 8-ketoester (55. Equation 15).

It appears that the reaction did proceed. as the IR signal at 1724 cm-' disappeared. and a

new ester signal appeared at 1708 cm-'.

The cleavage protocol developed by Ianda and his coworkers on a soluble

polymeric support consists of oxidizing the sulfide to a sulfone by oxonea. followed by

rcduction with a sodium-mercury amalgam (Equation 16)."

O Oxone

*SR N% RH (16)

When the same protocol was applied to 55, there was no sign of any product

cleaving from the polymer. Although oxidation with oxone did not give any significant

changes in the IR spectrum of the polymer, it is the rnercury reduction reaction which

appears to be the pmblern. Indeed. the mercury amalgarn does not seem to dissolve. The

sodium reacts with the rnethanolic solvent giving rise to wuid mercury. which is

immiscible. The reaction is therefore a surface reaction, and surface reactions cannot

occur between two insoluble reagents (the polymer and mercury). Therefore a new

approach had to be devised.

The chlommethyl dioxinone 49. previously prepared. can be easily converted to

alcohol (56). by a slight modification of the reported protocoL which used the parent

bromomethyl-2.2-dirnethyl-4H- 1 -3-dioxin-4-one as a starting material (Equation 17).'*

The chloride is displaced by an acetate, using nucleophiiic catalysis with sodium iodide,

and the acetate is hydrolysed by an equivalent of potassium carbonate in methanol-water.

Although the procedure only gave a low yield (14% overaU) of the alcohol 56, it was

sufticient to allow for the rernaining studies and was never optimized.

There are numerous ways to bind an alcohol to a resin. A polymer-bound silyl

chloride was chosen as it is easiiy prepared from polystyrene.28 and because the cleavage

reaction. essentially a fluorodesilylation3'. is mild enough for most substances.

The support (57) was prepared as reported in the literature. via lithiation of

polystyrene 52 and quenching with dichlorodimethylsilane (Equation 18).

1) n-8uLi, THF, &HI2. 600C I 2) (CH3)zSiCh ws'=ep (18)

52 SI The dioxinone was loaded on the polymer under standard conditions."' to give

the polymer-supponed dioxinone 58 (Equation 19). The loading was measured by

tluorodesilylation and by methanolysis to be 0.19 meq/g.

The viability of SS was tested as before: the dioxinone was reacted with

cyclo hcxanol in retluxing toluene. and the P-ketoester (59) was released from the support

by fluorodesilylation (Equation 20). However. this led to a 1: 1 mixture of cyclohexanol

and 59.

TBAF, AcOH

2) TBAF, AcOH

Since the siloxane bond can be cleaved under methmolysis. it is not surprishg

that it is partially cleaved by cyclohexanoL However. other trapping agents used in this

process. such as nonaldehyde. cyclohexanone. DCC. or even urea3' gave no sign of

products aller cleavage.

An explanation for this result is that the ketene produced frorn the thermolysis can

react with the sumunding water faster than it reacts with the trapping agents. The

resulting polymer-bound Pketoacid can easily decarboxylate to the parent ketone. After

cleavage bot h the resulting hydroxyacetoacetate (60) and h ydrox yacetone (61) are lost in

the workup process, leaving no products in the mixture (Equation 21).

N] Soluble ~o lvmer - su~wr ted 1 .3-dioxin-4-ON

One of the problems associated with soiid supports is the lack of analyticai twls

for the characterization of the products and for following the reaçtions. Typically, the

methods involved are IR^^ and soiid state NMR. In the case of polystyrene. the infrared

spectnim unfortunately is reduced to a restncted range of wavenumbers. as the bands

resulting from the polyrner shield most of the spectrurn. As far as MMR is concerned.

e v m with CP-MAS, the anisotropy resulting from the solid state limits the spectra to

atoms such as carbonY and p h o s p h o m s . 3 ~ e best method to date rernains the

characterization of products afier cleavage, and as seen above with the problem at hand,

this is not always a straightforward task.

There has k e n a recent rise in interest in the use of soluble supports in

combinatorial ~ ~ n t h e s i s . ~ ~ This method allows the use of solution NMR for the

characterization of interrnediary compounds in a synthetic pathway, and so this type of

suppon offers a better understanding of what is happening on the support.

Particular interest has been directed towards poly(ethy1ene glycol) (PEG), for a

number of reasons. Its proton NMR s p t r u m is rnereiy a large singlet at 3.6 ppm.

togcther with small triplets âssociated with the terminal CH2 groups. These do not

usually strongly interfere with the signals generated from the compounds bound to the

polyrner. Secondly. the polyrner is easily separated from the reaction mixture. Indeed,

high molecular weight PEG (>2ûûû) c m be precipitated from a solution by the addition

of large amounts of diethyl ether. Low molecuIar weight PEG can be separated from the

mixture by loading ont0 a silica gel plug. rinsing away the excess reagents with ethyl

acetate. and eluting the polymer off with a small percentage of methanol in ethyl

a ~ e t a t r . ~ ' Finally. PEG is soluble in most of the common solvents (water. methanol.

DMF. dichloromethane ....). with the notable exceptions of diethyl ether and quite

nonpolar solvents such as hexanes and pentane.

This support attracted our attention as it may provide a probe into the behavior of

polymer-bound dioxinones. Suice it is not necessary to cleave the products from the

support. no additional linker was needed. Indeed. for analysis. aii one needs is to obtain

an NMR spectrum of the polymer bound products. Therefore. the polymer-bound

dioxinone 64 was prepared from poly(ethy1ene glycol) monornethyl ether (MPEGOH,

62) according to scheme 10. where the methoxy group serves as an intemal standard to

measure the progress of the reaction. The yields are low in each step (53% and 4 8 8

respectively) due to problems associated with the workups. and they were not optimized

as 64 was not designed aS a me synthetic tooL

The reaction between 64 and benzyl alcohol in refluxing toluene resulted in a

67% yield of a mixture of 29% of the desired P-ketoester 65 and 71% of the

h ydro lysis/deczirboxylat ion product 66. as indicated by the proton NMR (Equation 22).

This approach clearly demonstrates the unsuitability of polymer-bound acyl

ketenes as synthons for combinatorial synthesis, at least when generated from a 1.3-

dioxin-4-one precursor: they react with moisture faster than they could react with other

trapping reagcnts. This is a good indication that standard ketenes are difficult to use as

polymer-bound synthons. because of their extremely reactive nature. particularly towards

watér.

MPEGW MPEGO

i: Succinic anhydride, 100oC. ii: 49, Cs2C03, DMF, 50OC.

Scheme 10

V] Soluble ~olvmer-bound synthesis of 4 - y i d o n e ~

Although the inability of polymer-bund dioxinones to perforrn as useful ketene

precursors has been shown from the previous studies, it remained to be seen whether this

was due to some effeçts associated with the use of a polymenc support. Since the use of

acyl ketenes sternming from dioxinones had not been demonstrated in polymer-bound

chemistry. it was important to evaluate their potential not as substances bound to a

support. but as substances capable of reacthg with a polymer-supported reagent.

Our attention was directed toward the reaction of acetyl ketene. generated in situ

from the diketene acetone adduct 48. with prirnary enamines, in a sequence of two

consecut ive nucleophilic attacks. to yield Cpyridones (67. Equation 23).38 These

compounds are quite interesthg biologically because of their resemblance to nalidixic

acid and LO oxolinic acid, two powerful antibiotics, and also because of their potential as

clinically useful bon che~ators.'~

On a solid polymeric support, enamines are generally prepared fiom P-ketoesters.

by their reaction with an amine in the presence of trimethyl orthoformate as the

d e ~ i c c a n t . ~ ~ '

As previously, the chosen polymer was poly(ethy1ene glycol) monornethyl eiher

with an average molecular weight of 5000 g mol-' in order to pennit the analysis o f the

intermediates by NMR, The polymer was transfonned into its acetoacetate (68) by

reaction with 48 in refluxing toluene (Scheme Il)." This demonstrates the ability of

acetylketene to react with a polymeric alcohoL The treatrnent of 68 with prirnary amines

in the presence of trimethyl onhoformate yielded the polymer-bound enamines (69)."'"'

This reaction was performed successfully with prirnary aliphatic amines. whether the

amine has a primary (n- butylarnine. benzylamine, 2-methoxyethylamine). o r secondary

(1-phenylethylamine) alkyl group. but aniline gave almost no product even d e r

prolonged times.

The reaction between the enamines 69 and 48 proceeded smoothly to give the

polyrncr-bound Cpyridones (70)." with the addition o f 48 in two portions to go to

completion. presumably due to the competing dimerization of acetylketene. The

exception was the bulkier enamine 69e, which was entirely recovered after the reaction.

One can assume that in this case the more crowded reaction centre on the cnamine

disfavoured the formation of the pyridone.

I MPEGOH -

71 (a-d)

ii

MPEGO MPEGO

60 69 (a-e)

iii, R' s H

iv - a: RRCHNH, = "BUNH, b: BnNH2

70 (a-d) C: CH30CH2CH2NH2 d : (CH3)2CHCH2NH2 8: S-Ph(CH3)CHNH2

i: 48. toluene. reflux. Shrs, 96%; ii: RR'CHNh, HC(OMeb, 24hrs: iii: 48, loluene, reflux, 2hrs, repeat. iv: KCN, MeOH. DMF, 667(PC, 60hrs.

Scheme 11

Since the pyridones are linked to the polyrner simply via an ester functionality.

cleaving can be performed easily by potassium cyanide catalysed uansesterification in

the presence of methanoL2'.'' The resulting pyridones (71) were separated from the

polymer by filtration through a pad of silica. rather than by precipitation which resulted

both in slight contamination by MPEGOH and in lower yields. This process gave

excellent yields. and very good purities. detennined by HPLC as percentage peak area

given by UV absorption (Table 1 ) .

Table 1: Preparation of N-slkyl-Z,&dimthyl-4-pyridones

Amine BuNHz a

PhCH2NHz b - CH3OCHzCHzNH2 c ( C H ~ ) ~ C H C H ~ W Z d S-Ph(CH3)CHNH2 e

a: Determined by HPLC as the % area of the peak. detected by absorption at 2 10 nrn

69 92 91 91 94 95

70 88 91 92 94 -

71 (%purity)' 6 1 (97) 75(98) 75(96) 93(9 1 )

- n

b) Attempted use of alternative acvl ketenq

G iven the importance of introducing different su bstituents on the p yridones. the

use of alternative acyl ketenes in the above preparation was investigated (Scheme 12)-

MeOH

Scheme 12

Acyl ketenes can be formed thermaily from other sources, and it was of interest to

try these in this protocol The acyl Meldrum's acids are easily prepared." and hence are

interesting precursors for acyl ketenes. However. the reaction between acetyl Meldmm's

acid (76a. Scheme 14) and the polymer-bound enamine 69a led to a complex mixture of

polymer-bound products. and therefore proved to be a poor method for the preparation of

4-pyridones.

The next attempt was with 5-phenyl-2.3-furandione (74). which was made in two

stcps tiom acetophenone (72, Scheme 13)? This compound ais0 was reacted with

cnamine 69a. with the same result. namely a complex polymer-bound mixture.

i: TEA, Nal, TMSCI, MeCN. ii: (COCQ, &O. iii: Acetone, PhHoa. Scheme 13

In both these cases. it appears that the enamine may react directly with the acyl

ketene precursor. leading to a mixture.

The inability of these alternative acyl ketene precursors to yield 4-pyridones in a

satisfactory manner meant that only 1.3-dioxin-4-ones are effective enough in this

reaction sequence. Therefore the 6-phenyl derivative (75). easiiy obtained from 74, by

thermal reaction with acetone. was exarnined." Here aiso. upon reaction with 69s. a

cornplex mixture resulted on the polymer. Possible explanations to this were that the

phenyl substituent was f a v o ~ g the enol form of the intemediate fomed in the reaction

with the enamine with the ketene, o r that the phenyl group is simply too buky to access

the enamine's reactive centre, Both of these would result in alternative reaction

pathways.

To obtain insight into this, 75 was used to esterify MPEGOH. Unfortunately the

resulting MPEG benzoylacetate did not react with amines to form the desired enamines

under the previous reaction conditions. This result might be evidencc for a significant

en01 character in the 1.3-dicarbonyl compounds gcnerated from 75. but this does not

prove that steric hindrance is not responsible for the failure of 75 to give 4-pyridones.

This experiment though demonstrates that aryl su bstituted 4-pyridones canno t be built

according to this methodology.

i: RCOCI, pyridine, CyCh, O Oc-room temp for a*. i: HC(OEt$, A, then 2N HCI for d. ii: t-BuOH, 8enzene.A. iii: acetone, M O , , 6 0 , O OC.

Scheme 14

In order to investigate the effects of substitution on the acylketenes, 6-substituted

I.3-~dioxin-4-ones w e m made (7s. - Schgme 44),'6* -and applied- to -the symhesis.

However. none of these. including the dioxinone lacking a substituent at position 6 (78d).

gave the desired pyridones. It would appear that two factors are important in this case,

narncIy steric effects which prevent the acyiketene from accessing the nucleophilic

carbon on the enamine, and the stability of the parent 1.3-dioxin-4-one (78d is less stable

than the other dioxinones. for example to silica gel chromatography).

To c o n f m the role played by steric factors in the pyridone foming reaction. 7&

was used to make the propyl substituted N-butyi-enamine bound to the polymer.

Reaction of this enamine with the diketene acetone adduct 48 ais0 gave a mixture.

showing that even the interactions between a methyl group and a propyl group (as

opposed to another methyl group) are enough to prevent the reaction.

Another point to be studied is the substitution at position 5. A 6-trifluomethyl and

5-ethyl substituted dioxinone (79. Equation 24). which gives a presumably longer lived

ketene. and might survive long enough to react with the enamine. was prepared as

reponed." Unfofiunately. this reaction appeared to give several products on the polymer.

presumabty the C and N acylation products.

79

i: TFAA, pyridine, 0.5 hrs then acetone, 20 hm.

To confiim that this was not the result of the destabilizing effects of the

tritluoromethy1 substituent on a carbonyl group. 2.2.5.6-tetramethyl-1.3-dioxin-4-one

(80. Equarion 25)'6 was aiso used and again faikd to give the corresponding pyridone

with enamine 69a.

i: DBU, Mel, PhH, 12 hrs; ii: acetone, &O, WO,, O O C , 12 hrs.

VI] Condus ion

The main message of the previous investigations is that the very fast reaction

k t w e e n ketenes and water is and probably will always be the main barrier to the use of

polymer-bound ketenes. It is close to impossible to eliminate water in a satisfactory

manner from the polyrneric environment, and the use of excess reagents in combinatorkt1

chemistry brings about another source of moisture. ali of which result in unsatisfactory

product yields and purity.

Ketenes are. however. to be funher investigated in iheir potential to give

interesting small moleçule libraries. The work presented in the introduction. and our

preparation of pyridones demonstrate that when used in excess with po lymer- bound

reagents. ketenes can give both good yields and good product punty in the building of

interesting and medicinally relevant sets of substances. The preparation of Opyridones is

a demonstration of the potential of 1.3-dioxin-4-ones as tools in combinatorial chemistry.

and g iven their applications in heterocyclic chemistry, this potential merits further

investigation.

VII] Experimental

The 2.2.6-methyl- 1.3-dioxin4one used was obtained cornmercially and

distilled in vacuo. "Dry" solvents were prepared the foiiowing way. Toluene and pyridine

were dist illed from calcium hydride. Acetone, methanol, dichloromethane and t- butanol

were dried over 4A molecular sieves for at least 24 hours. DMF and HMPA were

dist ilkd in vacuo from calcium hydride. Benzene was dried over sodium metaL THF and

dieth y1 ether were freshly distilled from sodium- benzophenone ketyl. Triethylamine was

distilled from potassium hydroxide. Al1 other reactants were used as available from

commercial sources. 'H NMR and ')c NMR were run on a Varian UNlTY 400

spectrometer. at 400 and 100 MHz respectively. using the solvent residue as interna1

reference (7.26 pprn and 77.00 ppm from TMS for chloroform). IR spectra were nin on a

Perkin-Elmer Fï - IR Spectrum 1ûûû spectrometer. Mass spectra were run by Dr. Alex

Young, using electron impact as an ionization method.

All of the reactions performed under dry conditions were carried out under a

positive pressure of argon.

1 ) Preparation of oolvmer-bound dioxinone 54

To a solution of 24 mL dry THF, 3.2 mL dry HMPA and 8 mL of a 2 N solution

of LDA in THF. cooled in a dry icdacetone bath, was added 2 mL of 2.2.6-trimethyl- 1.3-

dioxin-4-one ( 15.3 mmol), dropwise but fairly rapidly. The mixture was stirred for 1 h at

the same temperature and then was added via canula to a solution of hexachloroethane

(3.85 g. 16.3 mmol) in 19 mL of THF, aiso cooled in a dry icelaçetone bath. The

resulting mixture was stirred at the same temperature for 1 h. and then was left to corne

on its own to room temperature, and to air for 2.5 h. The resulting mixture was taken up

in diethyl ether (100 mL). and washed with 10% HCl. saturated aqueous sodium

bicarbonate, and saturated bruie. The organics were then dried over magnesiurn sulfate,

and the solvents were removed in vacuo. Sika gel chromatography using 5:I

hexanesethyl acetate as the eiuent gave 1.8 g of the desired product as an oil(67% yield).

'H NMR (CDC13. ppm from TMS): 1.7 1 (S. 6H). 4.02 (d. 2H. I = 0.5 Hz). 5.55 (S. 1 H).

6-Chloromethyl-2.2-dirnethyl- 1.3-dioxin4one 49 (486 mg, 2.8 mmol) in 4 mL of

dry THF was added dropwise to a mixture of 500 mg Na1 (2.6 mmol). 290 pL thiophenol

(2.8 mmol) and 1 mL ttiethylamine. Then 8 mL of dry diethyl ether was added slowIy

(-5 min). After stirring for 2 h at room temperature. the mixture was partioned between

50 mL of diethyl ether and 80 mL of water. and the layers separated. The aqueous layer

was cxtracted with another 30 mL of diethyl ether, and the two organic phases were

combincd, washed with brine and dned over magnesium sulfate. The solvents were

rcmovcd in vacuo. and the residue was purified by silica gel chromatography usinp 4:1

hexanes:ethyl acetate as the eluent to give 653 mg of product as a colourless oil (95%

1 yield). H NMR (CDCt. ppm fiom TMS): 1.63 (S. 6H). 3.56 (S. 2H). 5.23 (S. LH). 7.24-

7.33 (m. 3H). 7.37-7.40 (m. 2H). "C NMR (ppm from TMS): 24.90. 36.86. 94.69.

107.03. 127.69. 129.19. 13 1.11. 133.91. 160.73. 166.59. IR (cm-'): 3059. 2997. 2942.

1726. 1634. 1374. EIMS (mlz): 250(M'. 3). 192 (90). 12 (100). 109 (17). 77 (14).

HRMS: m/z calculated for Ci3HI4@S 250.0664. found 250.0658.

Polvmeric thiol53

To a suspension of 1 g of 1% crosslinked polystyrene 52 in 7.4 mL cyclohexane.

in a solid-phase synthesis fiask. was added 1.5 mL (9.9 mmol) of TMEDA and 7.2 mL of

1.75 M n-butyllithium in hexanes (12.6 mmol). The suspension was heated to reflux for

5 h. The solvents were removed by filtration, and the resin, stiii in the solid phase

synthesis fiask. was rinsed once with 10 mL and twice with 5 mL of dry THE The resin

was then resuspended in 5 mL of dry THF and 1 g of powdered sulfur was added. The

suspension was stirred ovemight. and then the polymer was filtered and washed with 50

mL of successively THF:(2 N HCl) (3: 1). THF. methanol. THF:water (2: 1). carbon

tc=trachloride. carbon disulfide. carbon tetrachloride and THF. The beads were dned to

constant weight in vacuo over P205. The polymer and 640 mg (16.9 mmol) of lithium

duminum hydride were suspended in 15 mL of THF. and heated to reflux for 7 h. The

mixture was quenched with ethanol. and then with water and filtercd. The polymer was

then suspended in 250 mL of 2.5 N sodium hydroxide. and the solution was brought to a

boil and tiltered hot. The poiymer was then washed with 20 mL of successively 1 N HCI.

THF:(2 N HC1) (3:1), THF, methmol, water, methanol, and THF. and was dried in

vacuo. The yield was 1.10 g of polymeric thiol(53). IR (cm"): 2564.

The polymer was titrated at 1.9 meq/g by suspending 50 mg of polyrner in 500

mL of n-butyllithium titrated as 2.67 M total base concentration. The polymer was

filtered and then rinsed with water. The combined filtrates were titrated with 0.2 N

s u h r i c acid to a phenolphthalein end point,

Polvmer-bound dioxinone 54

To a suspension of the polymeric thiol 53 (846.4 mg, 1.6 rneq), sodium iodide

(473 mg, 3.2 mmol) in 6 mL of THF was added 6Oû pL of triethylamine (4.3 mmol) and

the resulting mixture was stirred at mom temperature for 0.5 h. A solution of 391 mg of

6-chloromethyl-2.2- dimethyl- 1.3-dioxin-4-one (49, 2.2 mmol) was added to this

suspension. followed by 7 mL of diethyl ether. The mixture was stirred at room

temperature for 5 h. The polyrner was filtered and washed with successively 20 rnL of

watcr. THF:water (2:l). and THF and then was dried in vacuo. The yield was 861 mg

(80% by weight). IR (cm-'): 1724. CPMAS "C NMR (with a spinning frequency of 5

kHz): 15.5. 25.0. 25.8. 40.7 (broad signal). 66.2. 68.3, 107.6. 126.5. 128.8 (broad signal).

146.6.

2) Preparation of D o I v ~ ~ ~ - ~ o u ~ dioxinone

A mixture of 486 mg (2.75 mmol) of 6-chloromethyl-2.2-dimethy1- 1.3-dioxin-4-

one 49.476 m g (3.18 mmol) of sodium iodide and 1.1 g (13.4 mrno1)of sodium acetate in

5 mL of DMF was heated to 70 OC for 3 h The resulting solution was diluted with 30

mL of diethyl ether. and washed successively with 10 mL of water and brine, and the

organics were dried over magnesium sulfate. The solvents were removed in vacuo to

yield the product (238 mg. 1.1 mmoL 43%) as a reasonably pure symp. which was used

1 directiy without hrther purifkation. H NMR (CDCS, ppm from TMS): 1.69 (S. 6H).

2.12 (S. 3H). 4.62 (S. 2H). 5.44 (broad S . 1H).

To a solution of 1.1 g (5.5 mmol) of 6-acetoxymethyl-2.2-dimethyl- 1.3-dioxin-4-

one in 22 mL of methanol. cooled in an ice-bath. was added a solution of 492 mg (3.6

mmoi) of potassium carbonate in 5.5 mL of water. The mixture was stirred a t room

temperature for 0.5 h and the methanol was removed in vacuo. The aqueous solution was

neutralized with a 10 % HCl solution. and was repeatedly extracted with dichloromethane

(6x50 mL). The combined organic Iciyers were dned on magnesiurn sulfate. and the

solvents were removed in vacuo. Purification by chromatography (2: 1 hexanes:ethyl

acetate) gave 306 mg (1.9 mmol, 33%) of product. 'H NMR (CDC13. ppm from TMS):

1.63 (S. 6H). 3.82 (broad S. 1H). 4.1 1 (broad S. 2H). 5.51 (broad S. 1H).

Polvmeric silvl chIoride 57

To a suspension of 2 g of 1% crosslinked polystyrene in 14.5 mL of cyclohexane.

in a solid-phase synthesis flask. was added 2.9 rnL (19.2 mmo1)of TMEDA and 12 mL

(24 mmol) of 2.0 M n-butyilithium in hexanes. The mixture was heated to reflux for 5 h.

The solvents were removed by filtration, and the min, while still in the same flask, was

r insd three times with 10 mL of dry benzene. The resin was resuspended in 29 mL of

benzene, and 3.3 mL (27.2 mrnol) of dichlorodhethylsilani= was added. The mixture

was stirred for 14 h. at room temperature. The solvents are removed by filtration. and the

resin was washed with benzene alone. and dned in vacuo to a constant weight of 2.04 g.

It was used as such in al1 applications.

The resin was titrated at 1.17 meqfg by suspending the beads in water for 1 h. then

filtering off the beads. and rinsing the soiid. The resulting combined filtrates were

titrated with 0.5 N sodium hydroxide to a phenolphthalein end point.

Polvrncr-hound dioxinone

A mixture of 557 mg (3.5 mmol) of 6-hydroxyrnethyl-2.2-dimethyl- 1.3-dioxin-4-

one (56). 2.5 g (2.9 meq) of the polymeric silyl chloride and 1.5 mL of DIPEA in 9.5 mL

of benzene was heated to 60 OC (bath temperature) for 48 h The polymer was then

tïltered and washed with 5 mL of successively THF. THF:water (2: 1). water. THFwater

(2: 1). THF. methanol and fmally dichloromethane. After drying in vacuo. the resin

weighed 1.86 g. IR (cm-'): 1737.

An aliquot of the resin (50 mg) was cleaved by refluxing in methanol for 2 h. The

resin was filtered and washed with dichlororneihane ( 10x5 ml). The combined filtrates

were concentrated in vacuo to give hydroxymethyl dioxinone. Altematively, an aliquot

of resin (50 mg) was suspended in 0.8 rnL of THF, and 200 pL of 2 N TBAF in THF and

200 pL of 1 N acetic acid in THE The mixture was stirred at room temperature for 5 h.

and the resin was filtered and washed with dichloromethane. The residue was

concentrated in vacuo and filtered through a pad of silica gel eluting with 2:l

hexanexethyl acetate. In all cases. the resulting loading was of approximately 0.19

meq/g.

3) Soluble polvmer-su poned dioxinone 64

Poi~(ethv1ene elvcol) succinate (63)

MPEGOH (1 g. ça 0.2 mmol) and 1 g (10 mmol) of succinic anhydride were

meltcd together at 110 OC (bath temperature). for 14 h. The mixture was then taken up in

100 mL of dichloromethane. The volume was reduced to approximately 10 mL in vacuo.

and the resulting solids were filtered off. The filtrate was concentrated again to

approximately 5 mL, and the solids were filtered off again. Then 100 mL of diethyl ether

was added to the mixture. and the precipitated polymer was tïltered, washed with 3x30

mL of diethyl ether and dried. The yield was 552 mg (ca 0.1 1 mmol. 538). 'H N M R

(CDCh. ppm from TMS): 2.63 (m. 4H). 3.37 (s, 3H). 3.44-3.89 (m. MPEGO). 4.252

(broad m. 2H).

Polymer-bound dioxinone 64

A mixture of 170 mg (ca 3.3x10-' mmol) of polymer-bound acid and 125 mg

(0.38 mmol) of cesium carbonate in 400 pL of DMF was stirred for 15 min before the

addition of 120 mg (0.68 mmol) 6-chloromethy~-2,2-dimethyl-1,3-dioxin-4-one (49) in

500 PL of DMF. The mixture was heated to 60 OC (bath temperature) for 3 h. It was

then diluted with 30 rnL of dichloromethane. washed with 10 mL of water, and the

organic layer was concentrated in vacuo. The residue was taken up in 5 mL of rnethanol.

and the polymer was precipitated by the addition of 100 mL of diethyl ether. It was then

filtered. washed with 3x30 mL of diethyl ether. and dried in vacuo. Yield: 82.6 mg (ca

1 1.58x10-~ mmol. 48%). H NMR (CDC13. ppm from TMS): 1.70 (S. 6H). 2.70 (m. 4H).

3.26-4.0 1 (m. MPEGO-). 3.37 (S. 3H). 4.25 (t, 2H. J = 4-6 Hz), 4.65 (d. 2H. J = 4.2 Hz).

5 -47 ( S . 1 H).

3) Prenaration of 2.6-dimethvl ~vridones

Polvmer-bound acetoacetate 68;

A mixture of polyethylene glycol monomethyl ether 62 (5 g. 1 mmole), 5 mL dry

toiuene and 2,2,6-trimethyl- 1.3-dioxin-4-one (1 -5 mL. 1 1.5 mmol) was heated under

reflux (120- 130 OC bath temperature) for 4 hours. The mixture was then diluted with 5

mL of rnethanol and the product was precipitated by the addition of 150 mL of diethyl

ether. The polymer was fdtered and dried in vacuo to give 4.88 g of acetoacetate 68

(96% yield). 'H NMR (CDCl,. ppm from TMS): 2.27 ( S . 3H). 3.37 (S. 3H). 3.57 (m. 2H).

3.64 (m. MPEGO), 4.30 (m. 2H).

Polv mer-bound enamines (69):

To a mixture of 68 (1 p, 0.2 mmol), 2 mL of dry dichloromethane and 6 mm01 of

the amine, was added 8 mL of trimethyl onhoformate. The mixture was stirred at room

temperature for 24 h. The volatiles were removed in vacuo, the resulting residue was

iaken up in 5 mL of methanol and the polymer was preçipitated by the addition of 100

mL of diethyl ether. filtered and dned in vacuo. Yields are given in Table 1.

A mixture of 69 (300 mg. ca 6.1û5 moles). 500 pL of dry toluene. and 100 FL

(0.76 mmol) of 2.2.6-trimethyl-1.3-dioxin-4-one was heated to reflux (120-130 OC bath

temperature) for 2 h. The mixture was cooled to room temperature before another 100

pL of 2.2.6-trimethyl- 1.3-dioxin40ne was added. The mixture was refluxed agah for

another 2 h. The mixture was then diiuted with 3 mL of methanol and the product was

precipitated with 100 mL of diethyl ether. filtered and dried in vacuo. The yields are

given in Table 1.

Cleavaee from the ~olvmer;

A mixture of 300 mg of 70. 1.5 mL of dry methanol. 1 mL of dry DMF and -50

mg (-0.77 mmol) of potassium cyanide were hepted under argon to 80 OC (bath

temperature) for 60 h. The reaction mixture was diluted with 3 mL of diethyl ether. then

tiltered through a pad of s i k a (1 g) packed with diethyl ether. and ruised through with

1 :3 methano1:diethyl ether (20 mL). The fdtrate was then dried in vacuo and taken up in

a very small amount of dichioromethane, and loaded on a silica gel plug (typically 5 c m

of height in a 5%" Pasteur pipette) tightly packed with diethyl ether. The plug was rinsed

with diethyl ether (10 mL), and then the product was eluted off the plug by rinsing with

3:l diethyl ethermethanol (20 mL). Evaporation of the solvents gave the products as

coloured oils. Yields are given in Table 1. Purities were determined by HPLC as the

percentage area as detected by UV absorption at 210 nm (unless otherwise indicated),

using a Supelcosilnf LC- 18 25 cmx4.6 mm HPLC column. packed with C-18 derivatized

silica gel of 5 pm &ad six. The eluent used was 30:70 acetonitrile:water.

N- But$ -3-methcqcarbonyl-2,6-dimethyl-4-o-pyne (7 1 a):

1 H NMR (CDC13. ppm from TMS): 1.00 (t, 3H. 3 = 7.3 Hz). 1.43 (sextet, 2H, J = 7.4 Hz).

1.65 (quintet. 2H. J = 8 Hz), 2.34 (s, 3H). 2.35 (s, 3H). 3.8 1 (t. 2H, J = 8.4 Hz). 3.90 (s,

3H). 6.29 (S. 1 H). IR (cm-'): 173 1. 1637. 1578. 1479. EIMS ( rnfz ): 237 (M'. 50). 222

(24). 206 (531, 194 (27). 179 (100). 167 (41). 150 (41)- 137 (15). 123 (33). 108 (41).

Purity : 97% (mention time 6.49 min).

N- Phenylmethyl-3-methoxycarbonyl-2.6-di- (71 b).

1 H NMR (CDCl3, ppm from TMS): 2.26 (S. 3H), 2.27 (s, 3H). 3.89 (S. 3H). 5.16 (S. 2H).

6.38 (S. 1H). 6.97 (d. 2H, J = 6.9 Hz), 7.33 (t. lH, J = 7.1 Hz). 7.38 (t, 2H, J = 7.3 Hz).

IR (cm"): 3043. 1733. 1639. 1582. 1441. EMS ( m/z ): 271 (W. 37). 256 (12). 240

(20). 2 13 (60). 9 1 ( 100). Purity : 98% (retention time 7.97 min)-

N-(2-Merho~ethy l ) -3 -metho~carbonyl -2 ,6 - thy-4-oxo-pyd ine (7lc):

1 H N?kfR (CDC13, ppm from TMS): 2.37 (S. 6H). 3.33 (S. 3H). 3.59 (t, 2H. J = 5.4 HZ),

3.89 (S. 3H). 4.10 (t. 2H. J = 5.4 Hz). 6.32 (S. 1H). IR (cm-'): 1731. 1637. 1581. 1441.

EIMS (dz): 239 (M'. 55). 224(20), 208(52), 181 (100). 162 (34). Punty : 96%

(retention time 3.74 min).

N-(2 - Merh ylpropyl) -3-merhoxycarbon~v1-2,6-diehyf - 4 - O - p r i d n e (7 Id):

'H NMR (CDCIi. pprn €rom TMS): 0.97 (d. 6H. J = 6.8 Hz). 2.02 (m. 1H). 2.35 (S. 6H).

3.72 (d. 2H. J = 7.7 Hz). 3.89 (S. 3H). 6.33 (S. 1H). IR (cm"): 1731. 1636. 1579. 1440.

EIMS (mlz): 237 (M', 62). 222(17), 206(43). 194(34). 179(100). 162(37). Punty : 97%

(retention time 5.69 min).

To 0.5 rnL (4.3 mmol) of acetophenone in 5 mL of acetonitrile was added 1.25

mL (9 mmo1) of triethylamine, foiiowed by 850 pl (6.7 mmol) of chIorotrirnethylsilane,

and 5 mL of a saturated solution of sodium iodide in acetonitnle- The resulting mixture

was stirred at room temperature for 2 h. Diethyl ether (20 mL) was added. and the

mixture was filtered through celite. Diethyl ether was used to rime the precipitate. This

filtration was repeated a second the . The volatiles were removed in vacuo. and the

residue was taken in a small amount of hexanes, and fdtered through a pad of 5 g silica

gel. usine 200 mL of hexanes as the eluent. Alter evaporation. 610 mg (3.2 mmol. 74%

yield) of product was obtained as a colourless oil. 'H NMR (CDCI3. ppm from TMS):

0.28 (S . 9H). 4.44 (d. 1H. J = 1.7 Hz), 4.92 (d. IH, J = 1.6 Hz), 7.29-7.33 (m. 3H). 7.60

(d. 2H. J = 6.6 Hz).

To 610 mg (3.2 mmol) of 1-phenyl-1-trimethylsilyloxyethene in 6 mL of dry

diethyl ether. was added dropwise (-20 min) a solution of 140 pl (1.6 mmol) of oxalyl

chloride in 4 mL of dry diethyl ether, The mixture was then stirred at mom temperature

for 6 h. The solvents were removed in vacuo, and the residue was triturated with 1.5 mL

diethyl ether and hexanes was added (5 mL). The product was then fdtered off. From

the filtrate. slow evaporation of the diethyl ether gave a second crop. The combined

weight was 180 mg (1.04 mmol. 65% yield). mp: LU)- 133 OC. 'H NMR (CDCI,, ppm

tiom TMS): 6.42 (s, IH), 7.56-7.67 (m. 3H). 7.94 (d, ZH, J = 7.1 Hz).

A mixture of 366 mg (2.1 mmol) of 5-phenyl-furan-2,3-dione in 10 mL of

knzene and 1.3 mL of acetone was refluxed at 80 OC (bath temperature) for 12 h. The

solvents were then evaporated. and the product was purified by silica gel chromatography

using 4: 1 hexanes:ethyl acetate as the eluent. The resultïng oil was crystallised frorn

ether and hexanes at -78OC. This gave 289 mg (1.4 mmol. 67% yield) of soiid product-

mp: 58-60 OC. 'H NMR (CiXl3. ppm from TMS): 1.81 (S. 6H). 5.90 (S. IH), 7.45-7.53

(m. 3H). 7.67-7.73(rn. 2H).

6) Prcparation of 6-alkvl substituted dioxinones via Meldrum's acid

Acvl Meldmm' s acids (76 a-cl

To 1 g of 2.2-dimethyl-1.3-dioxane-4.6-dione (Meldrum's acid, 6.9 mmol) in 5

mL of dry dichloromethane was added 1.2 mL (14.8 mmol) of pyridine. The mixture was

cooled in an ice bath and 7 mm01 of the acyl chloride were added dropwise over 20mi.n.

The resulting mixture was kept in the ice bath for another hour. and then the bath was

removed and the reaction was continued for another hour. The mixture was then taken up

in 50 mL of diethyl ether. washed with 30 mL of 10% HCL and then saturated brine. The

organics were drkd over magnesium sulfate, and the volatiles were removed in vacuo. to

give the resulting product as an oil o r as a soiid.

5-Ace1yl-Z,Z-dirnethyl-1.3-dioxane-4,6dione (764t)?

Solid. Yield: 93%. 'H NMR (CDCl3. ppm from TMS): 1.74 (S. 6H). 2.68 (S. 3H). mp:

80-83 OC (lit. 82-85

Z . Z - D i n t e ~ - 5 - ( 2 - m ~ - p r 0 p ( 1 n 0 y I ) - 1 . 3 - d i 0 e 4 , 6 - d i e (76b)48b.

Oil. Yield: 73%. 'H NMR (CDCl3. ppm from TMS): 1.24 (d. 6H. J = 6.8 Hz). 1.73 (S.

6H). 4.08 (septet. 1 H, J = 6.8 Hz)

5-Buranuyf-2.2-dimethyl-I,3-diomne-4,6-done ( 7 6 ~ ) ~ ~

Oil. Yield: 84%. 'H NMR (CDC13. ppm from TMS): 1.03 (t, 3H. J = 7.4 Hz). 1.73 (m.

overlapping s and scxtet. 8H). 3.06 (t, 2H. J = 7.6 Hz)

-&6 Ethoxvmethvlene Meldrum's acl

Meldnim's acid ( 1 g. 6.9 mmol) was heated in 6 mL of tnethyl orthoformate at 90

"C (bath tempenture) for 3% h. T o the resulting solution pentane was added to

cloudincss. and the solution was cooled in dry icefacetone. The resulting solid was then

ti!tered: 910 mg (4.55 mmol. 6676 yield). mp: 85-88 OC. 'H NMR (CDCl3. ppm from

TMS): 1.52 (t. 3H. J = 7.2 Hz). 1.72 (S. 6H). 4.51 (q, 2H. J = 7.2 Hz). 8.23 (S. IH).

Formvl Meldnim's acid (76d)46

Finely powdered ethoxymethylene Meldnim's acid (904 mg. 4.5 mmol) was

suspended in 75 mL of 2 N HCl. After 0.5 h. sodium chloride was added to saturation

(10- 12 gf . and the resuiting solution was extracted with 4 portions of 40 mL of diethyl

ether. The combined axtract were dried over magnesium sulfate. and the volatiles were

rvaporated. leaving a sticky solid. which was suspended in 2 mL of diisopropyl ether.

and tïltered. This gave 520 mg (3 mmol. 6 7 6 yield) of producr mp: 94-97 OC. 'H NMR

(CDCI3. ppm from TMS): 1.77 (S. 6H). 8.55 (S. 1H).

The acyl Meldnim's acid (5 mmol) was dissolved in a mixture of 10 mL of dry

benzene and 4.5 mL of t-butanol., and the mixture was refluxed for 4 h. The solvents

were removed in vacuo. and the residue was filtered through a plug of silica gel. using

4: 1 hexancsxthyl acetate with 2% TEA as the eluent. Evaporation of the solvents pave

thc products as colorless liquids or oils.

1. I - Dimethyl-ethyl4-rneth~l-3-0x0-pentanmte (77b)48d

1 Yield: 76%. H NMR (CDCl3, ppm from TMS): 1-13 (d. 6H. J = 6.9 Hz), 1.46 (S. 9H).

2.72 (septet. 1H. J = 6.9 Hz), 3.40 (s, 2H).

1, I -Dimethfl-ethyl3-0x0-hemwte ( 7 7 ~ ) ~ ~

1 Yield: 93%. H NMR (CDCl3, ppm from TMS): 0.91 (t. 3H. J = 7.4 Hz), 1.46 (S. 9H).

1.61 (sextet. 2H, J = 7.4 Hz) 2.49 (t, 2H, J = 7.3 Hz), 3.32 (S. 2H).

1.1-Dirnethyl-ethyl3-ou>-propanoate (77d)48f

Yield: 79%. 'H NMR (CDCla, ppm from TMS): 1.49 (S. 9H). 3.30 (d. 2H. J = 2.6 HZ).

9.79 (t, I H, J = 2.6 Hz).

To a solution of 1.1 mm01 of t-butyl B-ketoester. 160 pL (2.2 mmol) of dry

acetone, and 1 0 0 pL (1.06 mmol) of acetic anhydride, cooled in an icdacetone bath. was

added dropwise 300 pL of a solution of 300 pL (5.6 rnmol) of sulfuric acid in 1 mL (10.6

mmol) of acetic anhydride. The mixture was stirred in the same bath for 1 h, and then

was leti in the freezer for 12 h. Then the mixture was cooled in an ice bath. and 3 mL of

a 10% solution of sodium carbonate was added, and the mixture was stirred for 0.5 h,

&fore extracting the organics in 40 mL of dichloromethane. This solution was washed

with 20 rnL of saturated sodium bicarbonate, then dried over magnesium sulfate. before

removal of the volatiles in vacuo. Flash chromatography with 4: 1 hexanes:ethyl acetate

as the eluent gave the desired products as O&.

2.2 - Dimethyl-6-( 1 -methyIe thy1)-4H- Z ,3-dioxin-4-one ( ~ 8 b ) ~ ~ ~

I Y ield: 78%. H NMR (CDCl3, ppm from TMS): 1-13 (d. 6H. J = 6.9 Hz), 1.67 (S. 6H).

2.43 (septet. 1H. J = 6.9 Hz), 5.23 (S. 1H).

2.2-Dirnerhyl-6-propyl-4H- 1.3-dimin-4-one ( 78~ )~ ' '

Yiald: 8 4 4 . 'H NMR (CDCb, ppm from TMS): 0.96 (t. 3 H J = 7.3 Hz). 1.68 (m.

overlapping s and sextet, 8H). 2.19 (t. 2H. J = 7.5 Hz), 5.23 (s, IH).

2.2- Dimethyi-4H- 1,3-diorin-4-one ( 7 ~ ) ~ ~

Yield: 8%. 'H NMR (CDC13. ppm from TMS): 1.71 (S. 6H). 5.40 (d. 1H. I = 5.9 Hz).

7.10 (d, 1 H, J = 5.9 Hz).

7) Prenantion of 5-ethvl-6-tnfluoromethvi-2.2-dimethvl- 1.3-dioxin-4-one (791J7

To 750 pL (5.3 mmol) of trifluoroacetic anhydride and 100 PL (0.96 mmol) of

butyryl chloride in 6 mL of dry diethyl ether under an argon atmosphere was added 630

PL (7.8 mmol) of pyridine. After stirring for 0.5 h at room temperature. 3 mL acetone

was added, and the mixture was stirred for another 24 h. The volatiles were removed in

vacuo (including pyridine). and the remainine residue was purified by silica gel

chromatography in 6:4 hexanes:dichlorornethane, giving 97 mg of the product 79 as a

colourless oil(0.43 mmol. 45% yield). 'H NMR (CDCI,. ppm from TMS): 1.12 (t. 3H. J

= 7.4 Hz). 1.72 ( S. 6H). 2.46 (qq, 2H. I = 7.5, 1.9 Hz).

8) Preparation of 2.2.5.6-tetramethvl- 1.3-dioxin-4-one ( 8 0 1 ~ ~

To 230 pL (1.4 mmol) of t-butyl acetoacetate in 2.75 mL of dry benzene was

added 210 pL (1.4 mmol) of DBU. This was foiiowed byanother 1.4 mL of dry benzene

and 88 pL (1.4 rnmol) of iodornethane. The mixture was stirred for 12 h. The

precipitates were removed by filtration and ~ s e d with diethyl ether. The combined

organics were washed with water. dried over magnesium sulfate. and the volatiles were

removed in vacuo. The resulting residue (179.4 mg) was taken up in 160 ~LL (2.2 mmol)

of acetone and 1 ûû pL of acetic anhydride. and cooled in an icdacetone bath. before 300

pL of a mixture of 300 pL (5.6 mmol) of sulfuric acid in 1 mL (10.6 mmol) of acetic

anhydride was added dropwise. The mixture was stirred for L h at the same temperature.

and then was left in the freezer for 12 h. The resuhing solution was then cooled in an ice

bath, and 3 rnL of a 10% solution of sodium carbonate was added. The mixture was

stirred in the same bath for 0.5 h. and then the organics were extracted in 50 mL of

diethyl ether. washed with 20 mL of saturated sodium bicarbonate. and dried over

rnagnesium sulfate. The volatiles were then removed in vacuo, and 48 mg (0.31 mmol.

22% yield) of the product was obtained through careful silica gel chromaiography. with

1 6: 1 hexanes:ethyl acetate as the eluent. H NMR (CDC13. ppm from TMS): 1.64 (S. 6H).

1.82 (d. 3H, J = 0 . 8 Hz), 1.97 (d. 3H. J = 0 . 8 Hz).

VIII] R e ferences

(1) Tempest. P. A.; Armstrong, R, W. J. Am Chem Soc. 1997,119,7607-7608.

(2) Chihara, T.; Takagi. Y.; Teratani. S.; Ogawa. H. Chem Lett. 19û2, 145 1- 1452.

(3) Georg, G . 1.; Ravikumw, V. T. In "The Organic Chemistry of fLlactams"; Georg, G.

1.. Ed.; VCH: New York, 1993,295-368.

(4) Ruhland, B.; Bhandari, A.; Gordon, E. M.; GaHop, M. A. 1- Am Chem Soc- 1996

1 18. 253-254.

(5) Ruhland. B.; Bombrun, A; Gallop. M. k J. Org. Chem 1997,62.7820-7826.

(6) Molteni, V.; Annunziata, R-; Cinquini, M.; Benaglia. M. Terrahedron Lett. 1998. 39,

1257- 1260.

(7) Benaglia, M.; Cinquini, M.: Cozzi. F. Tetrahedron Lett. 1999,40.2019-2020.

(8) Singh. R.; Nuss, J, M. Tetrahedron k t t . lm, 40. 1249-1252.

(9) Pei, Y.; Houghten. R. A.; Kiely. J. S. Tetrohedron Leu. 1997.38.3349-3352.

(10) Oikawa. Y.; Sugano, EL; Yonemitsu, O. J. Org. Chem 1918,43.2087-2088.

( I 1 ) Tietze, L. F.; Steinmetz, A.; Balkenhohl, F. Bioarg. Med C h e m k t t . 1997. 7.

1303- 1306.

( 1 2) Tadesse, S.; Bhandari. A.; Gallop. M. k 1- Comb. Chem 1999.1, 184- 187-

( 13) Weber. L.; Iaiza. P.; Birïnger. G.; Barbier, P. Synlett 1998, 1156-1 158.

(14) Raillad, S. P.; Ji, G.; Mann, A D.; Baer, T. A. Organic Process Research &

Deve/oprnent 1999,3. 177- 183.

( 15) For a review see: Meier. H.; Zeller, K-P. Angew. Chem /nt. Ed Engl. 1975. 14.

32-43.

( 16) See: Ye, T.; McKervey, M. k Chern Rev. 1994, 94, 1092- 1160 and references

cited therein.

(17) a) Appella. D. H.; Christianson. L. A; Karle. 1. L.; Powell, D. R.; Gellman. S. H.

J. A m Chem. Soc. 1996. 118, 1307 1- 13072. b) Seebach, D.; Matthews. 3. L.; Meden.

A.; Wesxls. T.; Baerlocher, C.; McCusker, L. B. Helv. Chim Acta 1997. 80, 173-

182.

(18) Marti. R. E.; Bleicher. K. H.; Bair. K. W . Tetrahedron &a 1997.38.6145-6148.

( 19) Guichard, G.; Abele. S-; Seebach, D. Helv. Chim A m 1998.81. 187-206.

(20) For a review: Hegedus. L. S. Tetrohedron 1997.53.4105-4128.

(21) Miller. J. R.; Pulley. S. R.; Hegedus. L. S.; DeLomabaen. S. Am Chem Soc.

1992, 114, 5602-5607.

(22) Pulley. S. R.; Hegedus. L. S. J. Am Chem Soc. 1993.115.9037-9047.

(23) Zhu. I.; Hegedus. L. S. 1. Org. Chem 1995.60.583L-5837.

(24) Wentrup. C.; Heilmeyer, W.; Kolienz, G. Synthesis 1994, 12 19- 1248.

(25) Kaneko. C.; Sato, M.; Sakaki, L i . ; Abe. Y . I. Heterocyclic Chem 1990. 27. 25-

30,

(26) Sato. M.; Ogasawara. H.; Oi, K.; Kato. T. Chem Pharm. Bull. 1983. 31. 1896-

1901.

(27) a) Jung, K. W.; Zhao, X.-y.; Janda, K D. Tetrahedron Lat. 1996, 37. 6491-6494.

b) Zhao, X.-y.; Jung, K. W.; Janda K. D. Tetrahedron t e r r , 1 W , 38,977-980.

(28) Farrall. M. J.; Fréchet, J. M. J. J. Org. Chem 1!#76,41,3877-3882,

(29) Boeckman, R K Jr.; Thomas, A J. J. Org. Chem lm, 47, 2823-2824.

(30) Sato, M.; Sakaki, J.-L; Takayama K; Kobayashi, S.; Suzuki, M.; Kaneko. C.

Chem Pharm Bull. 1990.38.94-98-

( 3 1 ) a) Chan. T.-H.; Huang. W,-Q. J. Chem Soc., Chem Commun- 1985,909-9 1 1, b)

Randolph. J. T.; McClure, K. F.; Danishefsky, S. J. 3. Am Chem Soc. 1995. 117.

57 12-5719.

(32) Sato, M.; Yoneda. N.; Kaneko, C. Chem Pharm Bull, 1986.34.621-627.

(33) Sce for example: Yan. B.; Kumaravel, G. Tetrahedron 1996, 52, 843-848.

(34) See for example: Look. G. C.; Holmes. C. P.; Chinn, J. P.; Gallop, M. A J. Org.

Chem. 1994.59.7588-7590,

(35) See for example: Johnson. C. R-; Zhang. B. Tetrahedron k r t . 1995, 36. 9253-

9256.

(36) Graven. D. J.; Janda. K. D. Chem Rev. 1997. 97,489-509.

(37) Jiang. L.; Hartley, R. C.; Chan. T.-H. J. Chem Soc.. Chem. Commun. 19%. 2193-

2194.

(38) Sato. M.; Ogasawara. H.; Kato. K; Sakai. M.; Kato. T. Chem P h a m BulL 1983.

3 1.4300-4305.

(39) Hider. R. C.; Ha4 A. D. Prog. in Med Chem 1991.28.41- 173.

(30) Look. G. C.; Murphy. M. M.; Campbell. D. A; Gallop. M . A Tetrahedron LRK.

1995.36.2937-2940-

(4 1) Zaragosa, F.; Petersen, S. V. Tetrahedron 1996.52. 10823- 10826.

(42) CIemens. R. J.; Hyatt. J. A. Org. Chem. 1985.50.243 1-2435.

(43) Sauvagnat. B.; Lamaty, F.; Lazaro. R-; Martinez. J. Tetrahedron Letr. 1998. 39,

82 1-824.

(44) a) Saitoh. T.; Oyama T.; Sakurai, K.; Niimura. Y.; Hinata, M.; Horigushi, Y.;

Toda J.; Sano. T. Chem Pharm BulL lm, 44. 956-966. b) Hnach. M.; Aycard, J.

P.; Zineddine, H. BulL Soc. Chim Fr. 1991,128,393-396.

(45) a) Andreichikov, Yu. S.;Gein,L. F.; PlakhinaG. D.J. Org. Chem CISSR(Eng1.

Trans.) 1980, 16, 1995-1998. b) Andreichikov,Yu. S.; Gein, L. V.; Kozlov. A. P.;

Vinokurova, O. V. J. Org. Chem. USSR (Engl. T r a m ) 1988,24. 189- 1%.

(46) a) Bihlmayer, G. A.; Derflinger. G.; Derkosch, J.; Polansky, O.E. Monatsh. Chem

1967, 98. 564-578. b) Zawacki, F.L; Crirnmins. M. T . Tetrahedron Lem 1996, 37,

6499-6502.

(47) Boivin. J.; El Kaim, L.; and Zard, S. 2, Tetrahedron 1995. S I , 2585-2592.

(48) a) Sato, M.; Ogasawaa, H.; Kato, T. . Chem Pharm Bull. 1984, 32, 2602-2608.

b) Grayson, D.H.; Tuite. M.RJ J. Chem Soc. Perkin Trans. I 1986, 2137-2142. c)

Bradbury. R.H.; Allott, C.P.; Dennis. M.; Girdwood, J-A; Kenny, P.W.; Major, J.S.;

Oldham. ASA; Ratcliffe, A.H.; Rivett, J.E.; Roberts, D.A; Robins, D.J. J. Med Chem

1993. 36, 1245- 1254. d) Meyer, W.L.; Brannon, M.J.; Burgos, C. da. G.; Goodwin,

T.E.; Howard. R.W.; J. Org. Chem 1985. 50. 438-447. e) Gribble, G.W.; Switzer.

F.L.; Soll, R.M. Org. Chem. 1988. 53, 3164-3170. f) Sato, M.; Yoneda. N.;

Katagiri, N.; Watanabe, H.; Kaneko, C. Synthesis 1986, 8, 672-674. g ) Sato, M.;

Ogasawara. H.; Komatsu. S.; Kato. T. . Chem Pharm Bull. 1984.32.3848-3856.

Selected 'H-NMR specvd

if- --

Seiected IR spectra

CP-MAS 13c-NMIt spectrum for 54

3 3 u < I O -

25E Y V: 1 m l 0 1 *

d E V i 5 - l L * - h - - > . ' u L - = a = ~ : ~ = ~ g ~ ~ ~ = - = ~ - - - - - - r n ~ œ - ~ - - ~ ~ ~ = ~ ~ ~ ~ ~ ~ - i a

Chapter Three

Stable Polymer-Bound Silylated Ketenes

I] Introduction:

The inability of polymer-bound acetylketenes to be used as effiçient synthons

stemmed from their moisture-sensitivity. However polymers and other reagents c m be

dried to a very large extent. and so if a ketene has some stability to moisture, it could

presumably be used as a polymer-bound reagent. and siiyl ketenes do have such a

po tential,

Silyl ketenes are a class of unusually stable ketened Their dirnerization has not

ken reported so far, and the simple parent trimethylsilyl ketene 1 is somewhat stable to

moisture wirh a half-life of approxirnately 3 minutes in water.' Silyl ketenes were fnst

prepared close to thirty years ago by the pyrolysis of e thoxy(trimethylsily1)acetylene 2

(Equation l).' The chemistry of siiyl ketenes has since then k e n extensively studied. and

it has round numerous synthetic applications.

The stability of this ciass of ketenes has ken explained by hyperconjugative a-x

donation from the Si-C bond to the C=C bond (Structure 3). and altematively by back-

donation frorn the n bond to the d orbital of silicon (Structure 4. Scheme 1 )1

Scheme 1

Although semi-empirical studies were interpreted to support the resonance form

4.' NMR data. which suggest that the silicon is relarively electron poor and the oxygen is

relatively electron rich. support the resonance Tom 3.' This is also supported by ab initio

studirs which show that more elcctropositive substituents resub in more stable ketenes6

There has been a previous attempt at the making of a polymer-bound silyi ketene

(6). by the pyrolysis of the pofyrner-bound ethyl ethynyl ether (5). by analogy to the route

described above (Equation 2).'

Even though this ketene has been observeci by IR spectroscopy. the band ascribed

to the ketene was rather weak. and. although the ketene was quenched with methanof. the

preparation of products generated from this ketene and cleaved from the support has not

yet been demonstrated.

111 Preparation and nucleoohilic reactions of a soluble ~olvrner bound siivl ketene

In the fust chapter. a preparation of polyrner-bound isocyanates by the reaction of

his(isocyanates) was described (Chapter 1, Scheme 10)~' By analogy. the recent

drvelopments in bisketene chemistg made this approach ideal for the preparation of a

polymer- bound silyl ketene,

2.3-8 is(trimethytsily1)- 1.3- butadiene- 1 +dione (8) is a stable and indefuiitely

pcrsistrnt bisketene in the absence of moisture and o ~ c ~ g e n . ~ . ' ~ It cm be generated

thermaliy or pho tochernicaiiy by the ring opening of 3.4- bis(trirnethylsily1)-3.4-

cyclobutrne-1.2-dione (7. Equation 3).1° Investigations on the reactivity of 8 with

alcohols have indicated that the reaction of the f m t ketene moiety is much faster than that

of the second. and this is an extrernely efficient way of generating a-ketenyl esters (9.

Equation 4). This reaction can be done with a large excess of a volatile alcohol in the

absence of a catalyst. foliowed by removal of the alcohol in vacuo.1° o r with l e s volatile

alcohols, by the reaction of a single quivalent of the alcohol in the presence of

excess ROH

or ROH (1 eq. ), - A N S

(4)

TEA R

The polymer chosen was polyet hylene glycol monomethyl ether (MPEGOH. 10)

with an average molecular weight of 5000 g mol-'. As was outlined in the previous

chaptcr. this polymeric support gives the possibility of usine N M R to analyse the polymer-

bound products. The reaction of 8 with the MPEGOH in the presence of triethylamine

gave a rcasonable yield (82%) of the desired product (11, Equation 5). with the presence

of the ketene functionality contirmed by an IR band at 2086 cm-'. The loading as judged

by NMR is quantitative.

MPEGOH +

To demonstrate the use of th% polyrner bound ketene, an array of amides (12) was

synthesised (Equation 6). The reaction of ketenes with amines is well known. and

provides a simple way of testing Our poiyrner. This reaction has been demonstrated with

the a-ketenyl esten 9" to be nearly quantitative. and proceeds extremely rapidly. The

polymer- bound ketene 11 was treated with simple primary (n-butylamine, benzyiamine).

bulky ptimary (1-S-phenylethylamine) and secondary (piperidine, morpholine) amines.

The reaction with anilines was a h attempted, although these do not react with the a-

ketenyI esters 9 as fast as aliphatic amines. With the polymer-bound ketene II , the

reaction of anitines took three days.

NMR indicated that these amides (12) were partiaiiy desilylated, so for the sake of

purity, they were subjected to fluorodesilyhtion, to yield the polymer-bound amides 13

(Equation 7).

This approach of generating the polymer-bound ketene has an advantage: there is

no need for the addition of a linker to the polyrner. Esters can be reacted quite e a i e n t l y

w ith amines. yielding the correspondhg amides. '' Therefore one can easily cleave the

polymer with an amine, and n-butyiamine was chosen. as it is volatile enough to d o w its

use in large excess foilowed by its removai in vacuo. and yet it can be used at reasonably

high temperatures. Thus the desilylated amides (13) were subjected to the n-butylamine

treatment. yielding the desired N-substituted N'-bu tyl- 1 ,dbutanediamides (14) in

moderatr yield and good pudy. without the use of any other form of chromatography.

bcsides a silica gel plue to remove residual MPEGOH (Scheme 2).

Another form of cleavage is transesterification with methanol. in the presence of

KCN. l 3 This method was applied successfully with the teniary amides to give the mked

ester-amides (15). However. this reaction with the secondary amides led to cyclization to

the CO rrespo nding N-su bstituted succinimides (16). Here again respectable yields and

purities were obtained (Scheme 2).

MPEGO )+MW

\XRR O 14

t OMe

NRR'

O 1s

i: rrBuNH2, PhMe, 800C. ii: KCN. MeOH, DMF, 6BC

Scheme 2

Table 1: Yields for the preparation of 14 and 15 from 11

Benzylamine n- butylarnine S- 1 -p henyl- et h y lamine Piperidine

Morp holine Aniline

4-Bromoaniline 3-hinoacetc~

siiylated amide 12

1 phenone 1 a: dctermined by HPLC as the % area detecte by U.V. absorption al 310 nrn. b: deiected at 254 nm

desiiylated amide 13

91 87 85

Product 14 (9% puritya)

30(97) 66(84) 4499)

Product 15 or 16 (%puntya)

16 59(99) 16 65(66) 16 5 l(92)

This work dernonstrates the preparation of a polymer bound ketene in a simple and

straightforward fashion, The ketene is suffiçiently stable to be used as a synthon in the

preparation of arrays of smaü molecules, and is stable enough to be stored for prolonged

periods of tirne (> 1 week). It reacts with amines without cornpetition from hydrolysis.

and the products can be cleaved in a simple and efficient fashion. and are of good punty.

III] Solid-sub~orted siivl ketenes;

The preparation of the ketene is based entirely on the previous work on a soluble

polymer. Two polymer supported alcohols are used. The fmt one is the so-caiied Wang

resin. ' " or po lymer- bound 4- benzyloxybenzyl alcohol (17). cornmercially available with a

loading of 1.3 meq/g. This polymer uses an electron rich benzylic linker, and, when

esteritied or ethenfied. the products can be cleaved with various arnounts of T'FA in

dichlorornethane. The second one was prepared (Scheme 3) from the Wang resin via a

treatment with DBU and trichloroacetonitrile to yield the polymer supported imidate 18.

foiiowed by a reaction with ethylene glycol. yielding the polyrner-bound alcohol 19."

Reaction of either of these alcohols with bisketene 8, in the presence of

tricthylarnine. yields the polymer bound ketenes 20a and 2Ob with IR bands ascribed to the

ketenes at 2083 cm-' and 2077 cm-' respectively (Equation 8). "

17 18

i: CCSCN, DBU. W C . ii: Ethylene giycol, B5.OEb Scheme 3

TEA - mcrs

b) Reaction with amines

The polymer bound ketenes react quite readily in the presence of amines. to yield

polymer supported amides (2l(as) and 22(a-c). Scheme 4)." Cleavage at this stage

yields a mixture of silylated. partially silylated and/or fuîiy desilylated products. so a

fluorodesiiylation step is rcquired here. in a fashion simiiar to the soluble polyrner-bound

ketenc. Cleavage then gives the products contarninated with what appears to be

tetra bu tylammonium sdts. This can be explained if the resin behaved as an polyanion, and

so a mild acidic wash is necessary to remove any teuabutylammoniurn ions present. When

this is carried out. foiiowed by cieavage, the products mas) and 24(a-c) are obtained.

and are free liom any visible contaminants.

RR'NH -

1 TBAF, AcOH

TFA

RR'NH = BuNH2 a (-) - Ph(Cb)CHNH2 b

Table 2: Yields for the preparation of amides fmm 2ûa a d 20b

C) Reaction with alcohok

Ketene

îûa VI

I V

2Ob II

1)

The reaction with akohols is a more interesthg measure of the reactivity of

polymer bound ketenes. There are two masons for this. Firstly. aicohols do not react

Amines

n -B u t y lamine S- 1-

Phenyle thylamine Morpho line

n- Bu tylamine S- l-

P henykthylamine Morpho line

readily with silyiated ketenes in the absence of cataiyst, so they are a better choice of a

nucleophile to compare solution and soiid phase properties. Secondly, their nucleo-

amides 21 and 22

99% 21a 83% 2lb

86% 2lc 92% 22a 91% 22b

91% 2%

philicity is comparable LO that of water, which gives an insight into one of the main

problems in polymer supported ketene chemistry. namely competing hydration.

Deslylated amides 94% 88%

94% 97%

quant-

quant.

Two categories of catalysts hasten the reaction of ketene with alcohols: Bransted

products 23 and 24

quant. 23a 83% 23b

, 86% 23c 43% 24a 46% 24b

45% 24c

bases and Lewis acids. Both of these have been studied with ketene 2Oa.

The tïrst basic catalyst examined was triethylarnine as this was the catalyst chosen

to load the ketene ont0 the support. However, even afier prolonged reaction times. there

wert: no visible signs of any product ester or of the disappearance of the ketene in the IR

spectra, A stronger base. DBU. was then selected. This catalyst aliowed the alcohol to

react with the ketene ma within 30 min. yieldîng polymer bound esters ZS(a-c). Longer

reaction times in fact iead to some l o s of product. presumably through transesteritication

(Scheme 5). Desilylation and cleavage give the succinic acid monoesters 2m-C)

contaminated with varying arnounts of succulic anhydride (27). This seerns to be due to

the competing hydration. which l ads to polymer supported carboxylate. which under the

cleavage conditions cyclizes to the succinic anhydride. In fact. good evidence for this is

the fact that the less reactive the alcohol. the less it can compete with water and h e m the

hig her the percentage of succinic anhydride in the product (Scheme 6).

ROH TMS

ho%o - DBU ho* OR

m s m s O

1 TBAF, AcOH

80% TFA - -R = -CH3 (a)

Scheme 5

From the initial stages of ils development, silicon stabilized ketene chemistry has

relied on Lewis acids as catalysts.' Using benzyl akohol as a nucleophile. the

esterification of 20a under catalysis various Lewis acids was atternpted. The standard

Lewis acid used is boron trifiuoride etherate? Indeed. this Lewis acid was able to effet

the esterification of 20a. but. dter desilylation and cleavage. there was only a smaü

amount of product. contaminated with benzyl alcohoL The resin king acid sensitive,

miider Lewis acids were sought. and it has been reported that zinc chlonde can be used in

instances where the dcohol is acid sensitive.16 However. this Lewis acid failed to yield

any product. even after prolonged reaction thes. The sarne results were obtaùied when

the slightly more reactive zinc iodide is used. Stannic chloride and chlorotrimethylçdane

both gave only smdi amounts of product. with the advantage that the product was in this

case tice of benzyl dcohol contaminant.

The main difference between base cataiysis and acid catalysis is that the base

weakly activates the nucleophile. whereas the acid strongly activates the ketene.

There fore. moisture cm interfere with the acid catalyzed reaction more e fficiently than

when a Lewis base is used. Evidence for this supposition is provided by the production of

tram-2.3-bistrimethylsilyl succinic anhydride (28) in 84% yield. upon treatrnent of the

resin-bound ketene 2ûa with chlorotrimethyisilane in the absence o f benzyl alcohol

(Equation 9).

TMSCl - Table 3: Yields for the preparation of monoesters fmm 2ûa in the presence of DBU.

Table 4: Yields of 2Sb fmm 2Oa in the ptesence of Lewis acids.

N c o ho 1s

me thano 1 a benzylalcohol b cyclohexanol c

esters 25

91 93 89

Desilylated esters Quant. Quant. Quant.

Lewis acid BF3.OEtî

SnCL TMSCl ZnCl? Zn12

Y ield ,

36% 25% 27% N.R. N.R.

products 26

80 75 74

5% succinic anhydride

6% 12% 36%

IV] Conclusion

This study demonstrates that a silyl ketene is stable enough to withstand a

polymenc environment without decomposing. It also demonstrates that polymer-bound

silyl ketenes can react efficientiy with nucieophiks. even with akohols, without excessive

cornpe t ing hydrolysis.

Nthough succinic acid derivatives have been prepared from these polymer-

supported ketenes, the Full potential of these substances as polymer-bound synthons has to

be tùrther investigated, particularly in regards to medicina1 and biological chernistry.

In addition to the above. siiyl ketenes give rise to organosiliçon cornpounds, and

the exploitation of the silicon fûnctionality must also be fûnher investigated.

One characteristic of this type of polymer-bound ketene is of particular interest. As

was stated in the second chapter, it is generally simplet to add an excess of the ketene to a

po lymer bound reagent. in the formation of interesthg polyrner- bound moIecules. This

approach dows one to utilize both of the ketenyl groups of 8 in combinatoriai chernistry.

By involving bisketene 8. one may use one ketene moiety in linking the ketene to a

polymer-bound functional group. givhg a functionalized polymer-bound ketene. which

can bc used further. A potential example is the reaction of 8 with aldehydes, leading to

ktenyl (3-lactones." Thus a polymer-supported aldehyde. such as 29, which has an acid

stable. basesensitive M e r (Scheme 7), could be treated with bisketene 8. giving a

functionalizcd poIymer-bound ketene 30. In tum this ketene could potentiaiiy be used

both in ketene chemistry and in B-Iactone chemistry.

1 Lewis acid

p- hctone chemistty ketene chemistry Scheme 7

Dry dichloromethane and dry methanol refer to these solvents kept on 4A

molecular sieves for at least 24 hours. Triethylamine and n-butylarnine were distiiled from

calcium hydnde. N.N-Dimethylformarnide (DMF) was distiiled from calcium hydnde

under 10-15 mm Hg pressure. MPEGOH was dried in vacuo over KOH for 24 hours.

3.4-Bis(trimethyisi1yI)-3.4-cyclobutene- 1.2-dione 7 was prepared by Dr. L. Mernetea

according to the pubLished procedure.1° Bisketene 8 was made by injection of a solution

of 7 in pentane (approximately 300 pL per 200 mg) through a Varian Aerograph mode1

920 pas-chromacograph with an injector temperature o f 200 O C and an OV-17 column

heated at 120 OC. Ail other reagents were used directly from commercially avaiiable

1 sources. H-NMR and "c-NMR specua were run on a Varian UNITY 400 spectrometer.

at 400 and 100 MHz respectively, using the solvent residue as interna1 reference (7.26

ppm and 77.00 ppm fiom TMS for chloroform). IR spectra were run on a Perkin-Elrner

FT-IR Spectrum 1000 spectrometer. Mass spectra were run by Dr. Alex Young. using

electron impact as the ionization rnethod. Whenever indicated. purities were deterrnined

by HPLC as the percentage area as detected by UV absorption at 210 nm (unless

otherwise indicated). using a Supelcosilm LC- 18 25 cm x 4.6 mm HPLC column. packed

with C-18 derivatized s k a gel of 5 pm bead size. The eluents used were either 5050

acetonitrile: water (solvent system A), or 30:70 acetonitriie:water (solvent system B), or

1 O:9O acetonitrile: water (solvent system C).

1) Soluble ~ol-mer-bound ketene

Polymer-bound silvlated ketene (1 1):

Prior to use, the polyethylene glycol is dissolved in a small amount of dry

dichiorornethane, and -10 volumes of toluene are added, and then removed in vacuo. The

addition of toluene and evaporation sequence is repeated four times.

To a solution of 2.3-bis(trimethylsily1)- 1.3-butadiene- 1 -4-dione (8. 166 mg. 0.73

mmol) in 2 mL of dry dichloromethane. cooled in an ice bath and under an inert

atmosp herc. was added a solution of polyethylene glycol monomethyl ether (294 mg.

0.059 mmol. treated as above mentioned) in 3 mL of dry dicholorornethane. foUowed by 1

mL of triethylamine. The soiution is then stirred for 2-3 min before the ice bath is

removed. The mixture is stirred for another hour. and graduaily darkens. The polymer is

then precipitated by the addition of 500 mL of diethyl ether. and removed by vacuum

fiitration. using an inverted funnel to keep the inen atmosphere over the funneL The

polyrner was further washed with 2x100 rnL of diethyl ether. before king dried in vacuo.

A dark grey solid is then obtained (11,248 mg, 0.048 mmoL 82%).

Polvmer-bound silvlated amides ( la

The polymer-bound ketene (11. ca 300 mg. 5.7x10-' mrnol) is taken up in 3 rnL of

dry dichloromethane and 0.2 rnL (liquids) or 0.2 g (solids) of the amine is added. The

solution is stirred for 1.5 h (aliphatic amines) or 3 days (aromatic amines) at room

temperature. and then diluted with 5 mL of methanoL The polymer is precipitated with

200 mL of diethyl ether, fütered . washed with 100 rnL of ether and dried in vacuo.

Polvmer-bound amide (13):

The polyrner-bound amide (12. ca 250 mg. - 5x10'' mmol) is dissolved in 0.5 mL

of methanol. and 0.5 mL of a 1M solution of acetic acid in THF and 0.25 mL of a 1M

solution of TBAF in THF were added. The solution is stirred for 1 h, before king diluted

with 5 mL of methanol. The polyrner is precipitated with 100 rnL of ether, and fdtered. It

is then redissolved in 6 rnL of methanol and precipitated again with 100 mL of ether. The

solid was t'uiaîly filtered. washed with 2x50 mL of ether and dtied in vacuo.

N-alkvl- or N-arvl-N'- butvl- 1.4- bu taned a . iamides (14)

The polyrner-bound amide (13. ca 2 0 mg, -4x10-' mrnol) is suspended in 1 mL of

toluene. and 0.5 mL of n-butylamine was added. The mixture was then heated to 80 OC

for 15 h. The resulting solution is then diluted with 5 mL of rnethanol and the polymer

was precipitated with 150 mi, of ether. The solids were removed by filtration and rinsed

with 2x50 mL of ether. The volatiles were then removed from the filtrate in vacuo. and

the residue was loaded on a tightly packed plug of sika gel in dichloromethane (typically

5 cm of silica gel in a 5" Pasteur pipette). and rinsed with 10 mL of dichloromethane. and

10 rnL of diethyl ether. The product was then removed from the plug by rinsing with 20

mL of a 4:1 mixture of ether and methanol. Evaporation leads to the product as a synip

or as a gum. Yields are given inTable 1.

N- ben pl-N'-butyl- 1.4-burunediamide (14a)

I H-NMR (CDC13. ppm from TMS): 0.91 (t. 3H, J = 7.3 Hz), 1.33 (sextet. 2H. J = 7.4

Hz), 1.46 (quintet, ZH, J = 7.5 Hz). 2.54 (m. 4H). 3.2 1 (dd. 2H. J = 7.2. 13 Hz). 4.42 (d.

2H. J = 5.6 Hz). 5.92 (broad S. 1 H). 6.35 (broad S. 1H). 7.24-7.34 (m. 5H). l3c-lUlM~

(CDC13, ppm ti-om TMS): 13.72. 20.03. 31.61, 3 1.93. 31.94. 39.36, 43.63, 127.44.

127.66. 128.67. 138.20. 17 1.99. 172.08. IR (cm-'): 3445. 1669. EIMS: d z 262 (21).

190 (33). 156 (7 1). 106 (100). 9 1 (93). HRMS: d z cakd for CISHzzNz@ 262,168 1.

found 262.1670. Purity : 97% (solvent system A. retention time: 4.38 min).

IV, NI-Dibutyl- l,4- butanediamide ( 14b)

'H-NMR (CDCI,. ppm from TMS): 0.91 (t. 6H. J = 7.4 Hz). 1.33 (m. 4H). 1.46 (m. 4H).

13 2.49 ( S . 4H). 3.23 (m.4H). 5.93 (broad S. 2H). C-NMR (CDC13. ppm from TMS):

1 3.7 1. 20.03. 3 1-64, 32.1 1. 39.34. 172.1 1. IR (cm''): 3447. 1669. EIMS: mlz 228 (7).

199 (6). 156 (100). 128 (30). 100 (54). 72 (36). 57 (31). HRMS: rnlz calcd for

C I ~ H Z J N K ~ 228-1838. found 228.1841. Purity : 84% (solvent system A, retention time:

3.94 min).

N-Butyl-NI-((S)-2-pheny1ethyI)-l,4-butanediamide ( 1 4 ~ )

'H-NMR (CDCI3. ppm from TMS): 0.91 (t. 3H. / = 7.3 Hz :), 1.32 (sextet, 2H. J = 7.4

Hz),, 1.44 (overlapping signal at 1.44 (quintet. 2H. J = 7.3 Hz) and 1.47 (d. 3H. J = 6.9

Hz)), 2.50 (m. 4H). 3.20 (m. 2H). 5.08 (quintet. 1H. J = 7.3 Hz). 5.89 (broad S. 1H). 6.27

(broad S. 1H). 7.23-7.35 (m. SH). "c-NMR (CDC13. ppm from TMS): 13.7 1. 20.03.

22.03, 31.59. 32.01. 32.15. 39.36. 48.95, 126.05. 127.27, 128.63. 143.27. 171.25.

172.03. IR (cm"): 3442. 1654. EIMS: rn/z 276 (4). 204 (68). 156 (55). 120 ( 100). 105

(49). Ml (36). 72 ( 17). 57 (19). ). HRMS: m/z calcd for Ct&iz~Nz02 276-1838, found

276.1834. Purity : 99% (solvent system A. retention tirne: 4.83 min).

N- Buql- N'-piperidino- ï,4-butanediamide (14d)

1 H-NMR (CDC13. ppm from TMS): 0.91 (t, 3H. J = 7.5 Hz). 1.33 (sextet. 2H. J = 7.4

Hz), 1.43-1-57 (m, 6H). 1.63 (m. 2H). 2.51 (t, 2H. / = 6.4 Hz), 2.65 (t, 2H. J = 6.4 Hz).

3.22 (q. 2H. J = 6 . 7 Hz), 3.41 (t. 2H. J = 5-4 Hz), 3-54 (t. 2H. J=5.5 Hz). 6.16 (broad S.

13 1 H). C-NMR (CDCl,. pprn from TMS): 13.74. 20.04, 24.49, 25.55, 26.34. 29.03,

31.63. 31.81. 39.23, 42.93.46.42. 172.30. 172.68. LR (cm-'): 3446. 1660. 1626. EIMS:

m/z 230 (13). 168 (32). 156 (33). 140 (26). 128 (11). 112 (7). 1 0 (30). 84 (100). 69

( 13). 55 (22). HRMS: m/z cakd for CUH~&@ 240.1838. found 240.1836. Purity : 90%

(solvent system B. mention tirne: 4.31 min). Purity : 88% (solvent system A. retention

time: 4.14 min).

N-Buvl-N'-morpholino- 1.4-butar~ediamide (14e)

'H-NMR (CDCh. ppm from TMS): 0.92 (t. 3H. J = 7.3 Hz). 1.34 (sextet. 2H. J = 7.3

Hz). 1.47 (quintet. 2H. J = 7.3 Hz), 2.51 (t. 2H. J = 6.5 Hz), 2.66 (t, 2H. J = 6.5 Hz).

3.23 (q, 2H, J = 7 Hz). 3.49 (t. 2H. / = 4.9 Hz). 3.60 (t. 2H. J = 4.8 Hz), 3.67 (two

13 overlapping d. 4H. J = 4.7 Hz), 5.91 (broad S . 1H). C-NMR (CDC13. ppm from TMS):

13.72. 20.04, 28.59, 31.49, 31.65, 39.31, 42.12, 45.79, 66.55, 66.84, 172.11, 172.95. IR

(cm-'): 3442. 1642. EIMS: rnk 242 (30). 170 (39). 156 ( 1 0 ) . 142 (17). 128 (1 1). 1 14

(6j. 100 (43). 86 (35). 72 (19). 57 (35). HRMS: rn/z calcd for C1?Hg_&03 242.1630.

found 242-1638. Purity : 90% (solvent system B. retention tirne: 4.3 1 min).

'H-NMR (CDCL. ppm from TMS): 0.89 (t. 3H. I = 7.3 Hz), 1.32 (hextet. 2H. J = 7.4

Hz). 1.47 (quintet. 2H. J = 7.4 Hz), 2.59 (m. 2H), 2.70 (m. 2H). 3.26 (q. 2H. J = 6.8 Hz),

5-80 (broad s, IH), 7.08 (t. 1H. J = 7.4 Hz), 7.30 (t, 2H. J = 8 Hz). 7.52 (t, 2H, J = 8.1

13 Hz). 8.42 (broad S. 1 H). C-NMR (CDCI3, ppm from TMS): 13.64, 20.0 1, 3 1-60, 3 1.88.

33.18. 39.53. 119.80. 124.09. 128.91, 138.14. 170.58. 172.23. IR (cm"): 3438. 1687.

EiMS: m/z 248 (1 1). 176 (17). 156 (100). 148 (9). 120 (8). 100 (53). 93 (87). 77 (10). 72

(14). 57 (25). HRMS: d z calcd for CirH2&02 248.1525. found 248- 1533- Purity : 99%

(solvent system A. retention the : 4.7 1 min, detected at 254nm).

N- f 4- Bramopheny1)-N'-butyl- i ,4- butanediamide (Mg)

1 H-NMR (CDC13, pprn from TMS): 0.90 (t. 3H. J = 7.3 Hz). 1.32 (hextet. 2H. J = 7.4

Hz). 1 -47 (quintet. 2H, J = 7.3 Hz). 2.59 (m. 2H), 2.69 (m. 2H). 3.26 (q, 2H. 1 = 6.6 Hz).

5.73 (broad S. 1H). 7.32 (d, 2H. J = 9 Hz), 7.44 (t, 2H. J = 9 Hz), 8.82 (broad s, 1H).

"c-NMR (CDCl,. ppm from TMS): 13.64. 20.00. 31.55. 31.70. 33.09, 39.56. 1 16.46.

12 1-28. 13 1.80. 137.38. 170.64. 172.35. IR (cm-'): 3438, 1689. 127 1. 1259. EIMS: d z

328 (8). 326 (8). 256 (7). 254 (7). 173 (44). 171 (47). 156 (100). 128 (5). 100 (43)- 72

(9). 57 f 17). HRMS: m/z calcd for Ci4Hi9NzaBr 326.0630, found 326.06 19. Purity :

99% (solvent systern A. retention tirne: 6.99 min, detected at 254nm).

N-(3-Ace~lphenyl)-N'-butyl- 1,4-butanediamide (14h)

'H-NMR (CDCI,. ppm from TMS): 0.89 (t. 3H. f = 7.4 Hz), 1.33 (hextet. 2H. J = 7.4

Hz). 1-48 (quintet. 2H. J = 7.4 Hz). 2.61 (overlapping signals at 2.59 (S. 3H). and 2.61

(m. 3H). 2.74 (m. 2H). 3.27 (q. 2H. f = 6.7 Hz). 5.84 (broad S. 1H). 7.39 (t. 1 H. J = 8

Hz). 7.66 (d. IH. J=7.7 Hz). 7.81 (d. IH. J = 7.3 Hz). 8.11 (S. IH). 8.97 (broad S. IH).

"c-NMR (CDCb. ppm from TMS): 13.66. 20.01. 26.68. 31.58. 31.70. 33.10. 39.57.

119.45. 123.72. 124.30. 129.14. 137.82. 138.75. 170.98. 172.28. 197.89. IR (cm-'):

3439. 1684. EIMS: ml+ 290 (5). 218 (8). 176 (5). 156 (100). 135 (29). 128 (8). 120 (13).

10 (37). 84 (6). 72 (14). 57 (16). HRMS: mlz calcd for CisH2NzO~ 290.1630. found

290.1627. Purity : 97% (solvent system A retention lime: 4.24 min. detected at 254nm).

. . . 4- Met hoxv-4-0x0- butanamides and N-akvl or N-;-i-succinunides (1 5 and 161

To the desilylated polymer-bound amide (ca 200 mg. 4x 1 û 5 mmol) and 35 mg of

porassium cyanide were added 1.5 rnL of dry methanol and 1 mL of DMF. The mixture

was then stirred for 36 hours at 60 OC (bath temperature). Then 2 mL of dichlorornethane

were added and the mixture was fütered through a smaii plug of celite ( 4 . 5 cm in a 5"

Pasteur pipette ). and this plue was hinher rinsed with -5 mi, of dichloromethane. The

solvents were then evaporated to approxirnately 5 mL. and ether (150 rnL ) was added to

prccipitate the polymer. The solids were then fdtered and ~ s e d with 2x50 mL of ether.

The volatiles were removed in vacuo (including the DMF). and the residue was loaded on

a tightly packed plug of s i ln p l in dichloromethane (typicaliy 5 cm of silica gel in a 5'

Pasteur pipette). ïhe product was then removed from the plug by Mshg with 10 mL of

dichloromcthane. 10 mL of diethyl ether, and 20 rnL of a 4:l mixture of ether and

methanol. Evaporation leads to the product as a symp or as a gum. Yields are given in

Table 1.

N-Benzylsuccinimide (16s)"

I H-NMR (CDClt. ppm frorn TMS): 2.71 (S. 4H). 4.66 (S. 2H), 7.28-7.33 (m. 3H). 7.39-

7.4 1 (m. 2H). Purity : 99% (solvent system A. retention time: 4.87 min).

N- Butylsuccinimide (16b)18

1 H-NMR (CDC13. pprn from TMS): 0.93 (r. 3H. I = 7.3 Hz). 1.32 (hextet. 2H. 3 = 7.6

Hz). 1.55 (m. 2H). 2.69 (S. 4H). 3.5 1 (t. 2H. J = 7.4 Hz). Punty : 66% (solvenr system A.

retention tirne: 4.47 min).

N-(S)-( P henyfeth yl)succinimide (16~) '~

1 H-NMR (CDCl,. ppm from TMS): 1.82 (d. 3H. 1 =-7.3 Hz). 2.64 (S. 4H). 5.43 (q. 1 H, J

= 7.4 Hz). 7.25-7.34 (m. 3H). 7.45-7.47 (m. 2H). Purity : 92% (solvent system A.

retention tirne: 5-78 min).

N- pipe ridino-4-methoq-4-oxobutanamide ( 15d)

I H-NMR (CDCI3, ppm from TMS): 1.53-1.66 (m. 6H). 2.64 (m. 4H). 3.41 (t. 2H. J = 5.5

Hz). 3.54 (1. 2H. f = 5.6 Hz). 3.69 (S. 3H). ' 3 ~ - ~ ~ ~ (CDCIi. ppm from TMS): 24.54.

25.5 1. 26.35. 27.98. 29.23. 42.87. 46.36. 5 1.69. 169.31, 173.77. IR (cm"): 3052. 1735.

1638. EIMS: m/z 199 (41). 168 (47). 140 (70). 126 (24). 1 15 (40). 112 (19). 100 (16).

84(100). 69 (18). 55 (26)- HRMS: m/zcalcd for CioHi7N03 199-1213. found 199.1218-

Purity : 93% (solvent system A. retention tirne: 4.04 min).

N-Morpholino-4-meiho~y-4-oxobutmamide (Me)

1 H-NMR (CDCl3. pprn from TMS): 2.62 (m. 2H). 2.68 (m. 2H). 3.49 (t. 2H. J = 4.9 Hz).

3.6 1 (t. 2H. J = 4.8 Hz). 3.68 (m made of two signais 3.68 (q. 4H, J = 5.5 Hz), and 3.70

(S. 3H)). 'V-NMR (CDCli. pprn from TMS):27.75. 28.99. 42.09. 45.72. 51.77. 66.52.

66.87. 169.87. 173.53. IR (cm-'): 3051. 1736. 1647. EIMS: mh 201 (37). 170 (61). 142

(29). 115 (100). 86 (60). 70 (20). 55 (48). HRMS: m/z cdcd for C9H15NOJ 201.1005.

found 20 1.1005. Purity : 97% (solvent system C. retention time: 9.08 min).

N- P henyisuccinimide ( 1 6oZ0

IH-NMR (CDCl,. pprn from TMS): 2.91 (S. 4H). 7.29 (m. 2H). 7.40 (m. IH). 7.49 (m.

2H). Purity : 89% (solvent systern B. retention tirne: 6.1 1 min).

N- (4- Bromophenyl)succinimide (Mg)

1 H-NMR (CDC13. pprn from TMS): 2.90 (S. 4H). 7.20 (d. 2H. J = 8.6 Hz). 7.6 1 (d. 2H. I

= 8.6 Hz). "c-NMR (CDCl,. pprn from TMS): 28.39. 121.14. 127.93. 13 1-78, 132.37.

174.94. IR (cm"): 1720. EIMS: mlz 255 (99) 253 (100). 227 (1 1). 225 (12). 199 (28).

197 (28). 173 (36). 271 (44). 146 (32). HRMS: mlz calcd for C I O H ~ N O ~ ' ~ B ~ 252.9738.

found 252.9739. Purity : 89% (solvent system B. retention tirne: 13.96 min).

N-(3-Acetylpheny1)succinimide (16h)

1 H-NMR (CDCL. pprn from TMS): 2.6 1 (S. 3H). 2.93 (S. 4H). 7.5 1 (d. 1H. J = 7.8 Hz).

13 7.59(t . lH.J=7.9Hz) .7 .90(~. 1H).7.99(dq lH.J=7.7Hz). C-NMR(CDC13.ppm

ïrom TMS): 26.61. 29.68. 126.47. 128.31. 129.50. 130.93, 138-17. 175.78. 197.04. IR

(cm-'): 1721. 1690. EIMS: mlz 217 (44). 202 (100). 174 (22). 146 (8). 132 (23).

HRMS: m/z cdcd for C&IiiNO3 217.0739. found 217.0734. Purity : 86% (solvent

system B. retention t h e : 5.67 min).

Wang. resin irnidatet 18);

Wang resin (200 mg, 0.26 meq ) was suspended in 3.2 mL o f dry dichloromethane.

cooled in an ice bath, and 600 pL (6 mmol) of trichloroacetonitrile was added. followed

by the dropwise addition of 100 PL (0.67 rnmol) of DBU. After stirring for 40 min at the

sarnt: temperature. the resin was filtered. rinsed four times with each of 4 rnL

dichloromethane. 4 rnL DMSO, 4 mL THF and 4 mL dichloromethane and dried in vacuo.

The resulting solid 18 weighed 238 mg (0.26 meq, quant. ).

IR (KBr d i x . cm-'): 1655.

Spacer modified Wanp resin (19):

Wang resin imidate (320 mg, 0.35 meq ) was carefully rinsed six times with 10 mL

dry THF, and suspended in a mixture of 5.25 mL of cyclohexane. 5.25 mL of dry

dichloromethane and 120 PL (2.15 mmol) of ethylene glycol. The mixture was stirred at

room tcmprature for 5 min. betore 30 pL (0.24 mrnol) of boron trifluoride diethyl

ctherate was added dropwise. After 15 min. the resin was fdtered, carefuiiy washed twice

with each of 4mL THF, 4 rnL I:1 THF:methanol, 4 mL methanol. 4 mL 1: 1

THF:methanol. 3 mL THF and 4 mL, dichlorornethane. and dried in vacuo. The product

19 weighed 276 mg (0.34 meq, 97%).

Pre~aration of nolvmer-bound ketenes l2Os and mbl;

Bisketene 8 (150 mg. 0.66 rnmol) in 2 mL of dry toluene was added to a

suspension of the polymer bound aicohol(0.13 meqs) in 1 mL of dry toluene, cooled in an

ice bath. then 1 mL of triethylamine was added, and the reaction mixture was stirred at the

same temperature for 15 min. and at room temperature for 1 h, nie dark resin was then

txtered under an inert aunosphere, washed with dry toluene (4 x 5 mL) and dry

dichloromethane (8 x 5 mL). and dried in vacuo. Yields were quantitative for 2Oa. and

88% for 20b.

20a IR (KBr d i x , cm"): 2083. 1718

2Ob IR (KBr disc, cm-'): 2077, 1718

Preparation of ~olvmer bound amides (21 la-c) and 22(a-c))

To the polymer bound ketene (0.12 meq) suspended in 3 mL dry toluene, 0.3 mL

of thc amine was added. After stirrinp at room temperature for 1 hr. the resin was fdtered.

rinscd with toluene (4 x 5 mL) and dichloromethane (8 x 5 mL). and dried in vacuo.

Yields are given in Table 2.

Desilvlation of m l - m r - b u n d am-

The resin (7x IO-' eq) was suspended in 0.8 mL of THF. and 0.5 mL of L. 1 N

acetic acid in THF and 0.25 rnL of 1 N TBAF in THF were added successively. The

mixture was stirred at room temperature for 3 hrs- The resin was filtered, and rinsed with

THF (2 x 5 mL), 5%(v/v) acetic acid in THF (4 x 5 mL), THF (4 x 5 mL), 1: 1

THF:methanol (2 x 5 mL), methanol (2 x 5 mL), 1:l THF:rnethanoi (2 x 5 mL). and

dichloromethane (4 x 5 mL). The resin was fmdy dried in vacuo. Yields are indicated in

Table 2,

Cleava~e from resin (2Xa-cl and 24ta-cl)

Wang resin suppon (from ketene ma): The resh (ca 6x 1 O-' eq) was suspended in

1.5 mL of a mixture of TFA:dichloromethane:water (80:15:5 v/v). and stirred at room

temperature for Ih. The resin was fdtered and rinsed with dichloromethane (10 x 2 d).

The combined fdtrates were then dried in vacuo, giving the products as oils or gurns.

Y ieIds are indicated in Table 2.

Spacer modified support (from ketene Nb): The resin (ca 5x10-' eq) was

suspended in 1.8 mL of dichloromethane and 0.2 mL of TFA was added. After stirring for

1 h at room temperature. the resin was fitered and rinsed with dichloromethane (10 x 2

mL). The tltrates were combined. and the volatiles were removed in vacuo. The

resulting residue wris taken up in methanol (ca 2 mL). water (ca 20 mL) was added. and

the volatiles were removed again in vacuo. This was repeated once more. to give the

producr as a gum. Yields are given in Table 2.

N- Bur);lsuccinumic acid (23~)"'

'H-NMR (CDC13. ppm from TMS): 0.92 (t. 3H. J = 7.4 Hz). 1.34 (sextet. 2H. J = 7.5

Hz). 1 A9 (quintet, 2H. J = 7.3 Hz), 2.52 (t, 2H, J = 6.3 Hz), 2.70 (t , 2H. J = 6.1 Hz),

3.26 (q, 2H. J = 6.6 Hz), 6-00 (broad s, 1H).

N-(S- I - Phenylethy1)succinoniic acid (ab)''

I H-NMR (CDC13. pprn from TMS): 1.48 (d. 3H. / = 6.8 Hz). 2.49 (m, 2H), 2.67 (m. 2H).

5.09 (quintet. 1H. J = 7.1 Hz), 6.14 (broad d, IH, J = 6.9 Hz), 7.24-7.35 (m. 5H).

N- Morpholinosuccinamic ncid (23~)~''

1 H-NMR (CDCG. ppm from TMS): 2.70 (m. SH), 2.73 (m. 2H). 3.54 (broad S. 2H). 3.66

(m. 2H). 3.72 (m. 4H).

2 -&droqethyl N- butylsrrccinumate (24a)

1 H-NMR (CDCG. ppm from TMS): 0.92 (t. 3H, J = 7.3 Hz), 1.33 (sextet. 2H. J = 7.4

Hz). 1.47 (quintet. 2H. J = 7.6 Hz), 2.52 (t. 2H. J = 6.5 Hz). 2.67 (t. 2H. J = 6.5 Hz).

3.24 (q. 2H. J = 6.7 Hz). 3.82 (t. 2H. J = 4 3 Hz). 4.25 (t, 2H, J = 4.6 Hz). 5.68 (broad S .

1H). IR CHIC^^. cm"): 3604. 3440. 1736. 1670. EIMS (EL rn/z): 217 (M'. 21). 199 (1 1).

187 (8). 156 (90). 145 (lûû), 101 (99). 84 (19). 72 (24). 55 (35).

2 -&droqerhyl N-(S- 1 -phenylerh y l ) s u c c i ~ m t e (24b)

1 H-NMR (Cm&. ppm from TMS): 1.48 (d. 3H. / = 6.9 Hz). 2.53 (m. 2H). 2.67 (m. 2H).

3.78 (r. 2H. 1 = 4.5 Hz). 4.23 (m. 2H). 5.10 (quintet. 1H. J = 7.1 Hz). 5.96 (broad d. IH.

J = 6.8 Hz). 7.28-7.36 (m. 5H). IR (CHzCh. cm-'): 3603, 3429. 1736. 1670. 15 13. EIMS

(EI. mfz): 265 (M'. 17). 247 (21). 203 (30). 175 (13). 160 (52). 142 (37). 120 (100). 105

(65). 77 (25).

2-Hydroqethyl N-morpholinosuccinamare (24c)

1 H-NMR (CDCb. ppm from TMS):2.67 (S. 4H). 3.49 (t. 2H. / = 4.9 Hz). 3.61 (t. 2H, J =

3.8 Hz). 3.68 (m. 4H). 3.82 (t. 2H. J = 4.5 Hz), 4.27 (t. 2H. J = 4.5 Hz). IR (<=&CI2. cm'

'): 361 1 . 1735. 1644. EIMS (EI. mlz): 231 (M+, 48). 201 (22). 188 (21). 170 (100). 145

(39). 101 (96). 86 (62).

Pre~aration of the ~olvmer-bound esters (2Xa-cl);

The poiymer bound ketene 20s (7.5x10-~ eq) was carehilly rinsed with dry THF (4

x 5 mL). and was suspended in 2 rnL of dry THF. n ien 0.25 mL of the alcohol were

added, and the mixture was stirred for 5 min. before the addition of 20 PL (0.13 mmol) of

DBU. Aller stirring for 30 min at room temperature. the resin is fdtered. rinsed with THF

(4 x 5 mL) and dichloromethane (4 x 5 mL) and dried in vacuo. Yields are indicated in

Table 3.

Perfonned as indicated for the amides. Yields are given in Table 3.

Mono me thyl succino te (a)" 1 H-NMR (Cm&. ppm from NS): 2.63 (m. 2H). 2.70 (m. ZH). 3.7 1 (S. 3H).

Monobenql succinote (26b)"'

I H-NMR (CDCh. ppm from TMS): 2.70 (m. 4H). 5.15 (S. 2H). 7.35 (m. 5H).

MonocycIoheqd succinore (26~)" ' 1 H-NMR (CM-b. ppm fiom TMS): 1.25-1.84 (m. 10H). 2.61(m. 2H). 2.68 (m. 2H).

478(septet. 1 H. J = 4.3 Hz).

Trans-2.3- bis( trimet ~~~~~~~~~succinic anhydride (28110

The polymer-bound ketene 20a (54.4 mg. 5 . 5 ~ l o 5 eq) was rinsed with dry M F (4

x 5 mL). and suspcnded in 2 mL of dichloromethane. Then 1 0 pL (0.79 mmol) of

chlorotrirnethylsilane were added. and the mixture was stirred for 1 h. The resin is then

t'iltcred and rinsed with dichloromethane (10 x 1 mL). The filtrates were combined and

the volatiles were removed in vacuo. to give 11.2 mg (4.6 x 10 -~ moles. 84%) of the

anhydride. 'H-NMR (300 MHz. CDC13. ppm from TUS): 0.19 (S. 18H). 2.46 (S. 2H).

VI] References

1 ) For a review: Pommier, A; Kocienski. P.; Pons. J.-M. ' Chem Soc.. Perkin Trans- 1

1998.2 105-21 18.

2) Allen, k D.; Tidweli. T. T. Tetrahedron Lett. 1991.32, 847-850.

3 ) Ruden. R. k J. Org. Chem 1974.39,3607-3608.

4) Runge, W. Progr. Phys. Org. Chem 1981,13,315-484.

5 ) Men, k D.; Egle, 1.; Janoschek. R.; Liu. H. W.; Ma, f.; Marra, R. M.; TidweU, T. T.

Chem Lett, 1996.45-46

6 ) Gong. L.; McAUister. M. A; Tidweii, T. T . J. Am Chem Soc. 1991,lf 3,6021 -6OS8.

7) Liu. R. Ph-D. Thesis , University of Toronto, 1997.

8) Scialdone, M. A. Tetrahedron Lert. 1996,37, 8 141-8 144

9) Allcn. A. D.; Ma, J.; McAUister, M. A.; TidweU, T. T.; Zhao. D.-c. Acc. Chem Res.

1995.28. 265-27 1.

10) Zhao. D.-c.; Allen. k Dl; Tidweii. T. T. J. Am. Chem. Soc. 1993. 115. lO97- 10103.

1 1 ) Allen. A. D.; Moore. P. A; Missiha S.; Tidweli. T. T. Org. Chem. 1999.64,4690-

4696.

1 2 ) For examples. sec a) Kibler. C. J.; Weissberger, A Org. Synth., CoiL Vol. III; Wiley.

New York 1955; 108- 109. b) Allen. C. F. H.; Humphlett. W. J. Org. Synfh-, CUL Vol.

IV; Wiiey. New York 1963; 80-83.

13) a) Zhu. I.: Hegedus. L. S. J. Org. Chem 1995, 60. 5831-5837. b) Sauvagnat, B.;

Lamaty. F.; Lazaro. R.: Maninez I. Tetrahedron Lett. 1998.39.821-824.

14) Wang. S . J. Am Chem Soc. 1973. 95. 1328- 1333.

15) Hanessian. S.. and Xie, Fa. Terrahedron Lett.. 1998.39.733-736 and 737-740.

16) Kita. Y. . Sekihachi. J.-i.. Hayashi. Y.. Da. Y.-2.. Yamamoto. M.. and Akai. S.. J.

Ors. Chem.. 1990.55. 1 108- 11 12.

L7) Colomvakos. J. D.; Egle. 1.; Ma. J.: Pole. D. L.: Tidwell. T. T.; Warkentin. J. J. Org.

Chem, 1996.61.9522-9527-

18) Puertas, S.; ReboUedo. F.; Gotor, V. Tetrahedron 1995.51. 1495- 1502.

19) Wakabayashi. T.; Saito, M. Tetrahedron Lett. 1977.93-96.

20) Watanabe, Y.; Tsuji Y.; Kondo. T.; Takeuchi. R. J. Org. Chem 1984. 49. 445 1 -

4455.

2I)a) Kometani. T.; F i a T.; Watt, D.S.; Tetrahedron Let?. 1986, 27, 919-922. b)

Pressman. O.; Bryden, J.H.; Pauling, L. J- A m Chem Soc. 1945-67, 1219-1222. c )

Boyd. GY.; Monteil, R.L- J. Chem. Soc. Perkin Trans. 1 1978, 1338- 1350. d) Bone;

Sudborough; Sprankling J. Chem Soc. 1904. 539. e) Kita. .; Maeda, H.; Talcahashi.

F.; Fukui. S. J. Chem. Soc. Perkin Trans. 1 1993, 2639-2650. f) Brunel. Bull, Soc.

Chim Fr. 1905,33,273.

Selected 'H-NMR spectra

&mendix B

Selected IR spectra

4 A

9- N Ir, rn

Chapter Four

Polymer-Bound Allenecarboxylates

II Introduction

Aiienes represent a class of cumulenes which have recently gained in interest, and

have not yet k e n investigated in polymer-bound chexnistry.' Aithough these are

uncornmon in naturaiiy occurrîng substances. theû versatitity in electrophilic. nucleophilic

and cycloadditions reactions has tumed them into valuable synthetic tools. They are

generaiiy more stable than other cumulenes. but accordhg to their substitution patterns,

c m have widely different reactivity. As part of Our interest in the generation and the use

of polymer-bound cumulenes, aknes appeared to be interesthg moleçules to study.

il] Soluble ~olvrner- bound allenecarboxvlatq

AUenes can prepared by a number of rnethods, but the one which caught our

attention was the reaction of ketenes with Wittig ~ a ~ e n t s . 2 mainly because of the

excellent yields generally involved and because of our ongoing interest in the applications

of ketenes in polymer-bound synthesis. The chosen polyrner was polyethylene glycol

monomethyl ether (MPEGOH).

The initial approach was to use the soluble polymer-bound stable silyiated ketene

( 1). w ith the stabîlized Wittig -gent. (carbethoxymethylene)triphenylphosp ho-

(Equation 1). This reaction does no< proceed at room temperature. whik at higher

temperatures. as indicated by the 'H NMR spectrum. there is almost exclusively cleavage

from the support.

MPEGO

O TMS

As has often been the case. the process can be reversed. In other words. the aüenes

can po teniialiy be prepared from a polymer-bound Wittig reagent.)

It is known that ailenecarboxylates (4) c m be prepared from the reaction of a

s t a b i i k d Wittig reagent (2) with an aiiphatic acid chloride (3) in the presence of a t e r t i aq

amine base (Scheme I).'.' The mechanism of this process is not very weii understood. as

the allene can be produced via condensation of the Wittig reagent with the acid chloride,

foiiowed by an elimination (path a), or via dehydrohalogenation of the acid chloride to a

ketene. which can undergo a typkai Wittig reaction (path b).

Scheme 1

The chosen yiid is the soluble polymer-bound version of the stabilized Wittig

reagrnt (7. Scheme 2). This one can presumably be prepared via the reaction of the

polymer-bound haloacetate with tnphenylphosphine. The polymer was treated with

chlororicetyl chlotide or bromoacetyl bromide5 and Hünig's base (which was used instead

of the reponed triethylamine. to avoid formation of the quatemary ammonium salt by-

product) to give the desired haloacetates (Sa-b). There is a s m d arnount of

decomposition of the polymer in the case of Sb. as indicated by the NMR spectrum.

Reaction with triphenylphosphine gives the desired phosphonium salt (6) in the case of the

bromide Sb, but in the case of the chloride Sa. no reaction was observed. even with

prolonged reaction times. and higher temperatures eventuaiîy led to decomposition.

Conversion to the yiid 7 was eflected by the treatment of this phosphonium salt with

DBU.

i ii MPEGOH -

MPEGO MPEGO B i

MPEGO ,A,/% MPEGO

i: DIPEA. XCH&OX. C&Cb. ii: PPb. CH2Ch. iii: DBU, Ci+&. iv: R1CH2C0CI. TEA, C&Cb.

Scheme 2

This Wittig reagent was treated with 3 different acid chlorides. in the presence of

t ric thylamine. giving the desired polymer-bound denes (sa-c). without any visible

polymcr-bound by-products and in excellent yields (Table L).'~.' Altematively. the allenes

can be prepared by the direct reaction with the phosphonium sait. by using a larger amount

of trie thylarnine.

Table 1 : Formation of sllenes 8(a-c). 96 Yields

L --

RI 1 Yield from 7 7 ~ & l d from 6 1

b) Reactions with amYies, Pre~aration of ~vridones and &iactams,

The ailenes 8 are exceiient acceptors for a conjugate addition, whïch leads to 48-

unsaturated esters. When primary amines are used. the resuiting products are enamines

(9).6 These enamines are thernselves quite interesthg molecuies. which can be applied to a

number of preparations. They have been used in polymer-bound chernistry to produce

dihydro pyridines," pyrazolones.mc pyridines.7d and triazoles. In Chap ter 2 (Section Va.

Scheme 11). the preparation of 4-pyridones by the reaction of acetyl ketene with polymer-

bound enarnines had been demonstrated using MPEGOH." This appeared as a good test

of the usefulness of the polyrner-bound allenecarboxylates 8 (Scheme 3).

Reaction of 9 with acetyketene leads to polymer-bound pyridones (10). with the

cxception that the bulkier enamines generated from & resulted mainly in premature

cleavage. This is consistent with our previous observations of the sensitivity of this

reaction to steric factors. The standard methanoiysis mediated by potassium cyanide gave

the desired pyridones (11, Tabk 2).

iii

i: R2CH2NH2, CH2CI2. ii: 2,2,6-Trimethyl-4H-1,3-dioxin4-one, toluene, reflux, then repeat. iii: KCN, MeOH, DMF.

Table 2: Preparation of pyridones basd on poiymer-bound sllenes Yields (puritya)

I R'

H a

Et b

''bctermined by HPLC as Ihe 8 area of the paît. derected by absorption at 210 nm.

R' n- Pr a Ph fi

CH30CH2 Y n-Pr a Ph B

CH3OCHi Y

Pyridones 10 84 90 92 94 83 93

Enamines 9 90 91 92 89 88 91

Pyridones 1 1 74(85%) 8 1(90%) 50(86%) 72(92%) 60(96%) 54(88%)

The sarne enamines 9 can be used with acryloyl imidazole. preformed in the

reaction mixture from acryloyl chloride and imidazole. to $ive the polymer bound 6

lactams 12(b-c)(a-y) (Scherne 4).' With Our simple enamines. the reaction proceeds

cleanly. except that as has been previously observed the aza-annulation is foiiowed by a

shift in the position of the double bond.' However. when a bulky secondary enamine. such

as the one obtained from 1-phenykthylamine, is used, the reaction results in Little

formation of the laçtam, and essenrially leads to premature cleavage. The product lactams

13(b-c)(a-y) are O btained by KCN catalysed methanolysis, after chromatography (Table

3). The structure has been confmed through 2D NMR experirnenu on 13b& including

NOESY which confirmed the stereochemistry at the double bond. In the case of

compound 13by. the double bond shifts back upon chrornatography, giving the rearranged

product.

Table 3: Preparation of &Iactams basai on pdymr-bound dlenes. Yields.

R'

Et b-

PhCHz c

R' n-Pr a Ph B

CH30CH2 Y n-Pr a Ph B

CHJOCH~ Y

Lactams 12 90 92 90 91

~~ 89 91

Lactams 13 30 54 33 29 46 36

MPEGO

R ' 5,

i: acryloyl chbride, imidazole. THF, reflux. ii: KCN, MeOH, DMF. Scherne 4

In] Soluble ~olvmer-bound stable ailenvi kereng

Allenyl ketene chemistry, generdy h t e d by the intrinsic instability of these

reagcnts. has recently regained some attention. by anaiogy to the case of the b i~ketenes . '~

A se t of persistent and stabilized allenyl ketenes (15) have been prepared by the

photochernical ringopenhg of substituted bis(trimethylsilyl)methylenecyclobutenon (14.

Equation 2) .

These su bstitu ted me thylenec ycio butenones were prepared from 2-3- bis(trirnethy1-

sily1)-cyclobutenedione (16). either via Wittig reactions or via methylenation reac~ions . '~

The availability of polymer-bound Wittig r a g e n t 7 made the preparation o f a

soluble po1ymer-supported aiienyl ketene easily avaiiable. The reaction of cyclobutene-

dione 16 with 7 gave the polymer-bound methyleneçyclobutenone 17 (Scheme 5). By

analogy to the Literature, the stereochemistry of the exocyclic double bond S r n s to be

largely cis (>10/1 with what seems to be the tram isorner). Photolysis of a solution o f 17

in dichloromethane gave the polymer- bound ailenyl-ketene 18, although some slight

photodecomposition of the polyrner was encountered. A broad IR band a t 1968 cm"

(allene) and a sharp band at 2083 cm-' (ketene) contirmed the structure.

Since these molecules are ketene substituted allenecarboxylates. they offer the

same possibiiities in synthesizing heterocyclic structures. Because the reaction leading to

4-pyridones was sensitive to steric factors. the preparation of Glactams was selected to

test the viability of this dlenyl ketene as a polymer-bound synthon.

MPE kTMs i: C&Cb. ii: CH&h, hv (350 nm)

Scheme S

AUenyl ketene 18 was treated with p h a r y alipha itiç amines, to aEord the enamines

19 (Scheme 6) . In this teaction, the amine reacts both with the ketene to yield an amide

and with the allene to give an enamine. There is extensive desilylation d u ~ g this reaction-

These enamines (19) were then subjected to the sarne aza-annulation described

previously.8 and the desired polyrner-bound &laciarns (20) were produced. In this case.

thc migration of the double bond was more sensitive to the particuiar ena~n ine .~

Funhermore. the desiiylation was almost complete. therefore the lactams were released

[rom the support without further removal of the siiyl groups, by KCN catalysed

methanolysis (21. see Table 4). In this case the f ia l products also had to be funhcr

purifïed by chromatography. and were obtained in low yields for the aliphatic amine

iii

MPEGO

(1~s NH

I

MPEGO 4 - 7

i:RChNH2, CH&. ii: acryloyl chloride, imidazole, THF, reflux. iii: KCN, MeOH, DMF.

Scheme 6

Table 4: Prepantion of &lactans fmm poiyrner bound allenyl ketene 18. Yields of

deavage.

R n- Pr a Ph b

(CH3)zCH c -

lactam 21 22 57 10

double bond 1

endoc yclic exocyciic

endocyclic

IV] A t t e m ~ t s towards the ~qgparation of allenes on a solid subbofi

The successhI preparation and uses of the aiienecarboxylates 8 showed that

po lyrne r- bo und ailenes could be of s i g d c a n t value to corn binato rial c hernistry- It

appeared of interest to study the translation of this chernistry to an insoluble support.

As in the soluble case. the initial viais were done on the polyrner-bound ketene 22.

prepared as in Chapter 3 on a Wang resin support (23). using both unstabilized and

stabilized Wittig reagents (Scheme 7)."

In the € n t case. using ( phen ylmeth ylene)triphenylphosphorane. the ylid derived in

situ from benzyltriphenylphosphonium brornide ied to the disappearance of the ketene. but

no ailene signal was obtained in the IR spectrum. and cleavage afforded a complex mixture

of products,

With the stabilized Wittig reagent, (carbethoxymethylene)triphenylphosphorane. at

room temperature. the ketene signal in the IR remained unchanged, and a t high

temperature. although a smaU but ~ i g ~ c a n t allene signal did appear afier a short period, it

disappeared as the reaction was driven to cornpietion.

The ketene is found to be stable to triethyl phosphonoacetate under Horner-

Wadswonh-Emmons conditions." This lack of success was expected given the inability of

the same processes to convert the soluble polyrner-bound ketene 1 to the parent altenes.

'47 cornpiex mixture. no alienes

TMS m w p b ho*o . - cornplex mixture. no allenes

O TMS II

Elo&,,P(OEt)Z 22 \ no reaction

Scheme 7

By analogy to the process used with the soluble polymeric support. it was thought

that the reaction of an acid chloride with a polymer-bound Wittig reagent would be a

better strategy. This polyrner bound reagent (25) was then prepared from Wang resin

(23). via the bromoacetate5 (24. Equation 3).

23 24

i: BrCH2COOH, PPh3, DEAD. THF. ii: PPh,, THF. A.

The reaction of this polymer-bound Wittig reagenc wilh butml. acetyl.

phenylacccyl or diphenylacetyl chlorides did not give any signs of the presence of an diene.

In fact. clravap with 804 TFA gave what appears to be a triphenylphosphonium acetate

The explanation for t h lies ùi the lack of reactivity of s t a b h d Wittig reagents on

an insoluble If this reagent cannot react qukkly enough with the acid chloride

or with the parent ketene. this latter wiii simply dimerize, leaving no product on the resin.

AUenes have been prepared from ketenes and phosphonates." and because of the

success of the Horner-Ernmons-Wadsworth reaction on a polymeric this

approach seemed of value to try.

The polymer-bound phosphonoacetate 26 was prepared from Wang resin (23) via

the Mitsunobu reaction (Equation 4).

PPh,. (E10hP(0)CH2COOH

OH DEAD. THF (4)

Treatment of this resin with diphenylacetyl chloride. in the presence of

triethylanine and of lithium brornide gave the desired adduct 27 (Equation s)." Although

there is no signifcant difference in the IR spectra between 26 and 27. CP-MAS "P solid

state NMR and cleavage both ïndicated that it had forrned.

However. atternpts to convert 27 to the desircd d e n e by refluxing at different

temperatures. even in the presence of base. were unsuccessfuL

One approach to making allenes, which has been met with succpss recently. is the

conversion of substituted propargylic aicohols in the presence of O-nitrophenyisulfonyl-

hydrazine. tnphenylphosphine and DE AD. l2 Therefore if a polymer-bound propargyl

alcohol could be buiit. one would presurnably be able to generate the parent allene.

Schemr 8 shows the pmcedure, which was designed for this purpose.'3

i: propargylic alcohol, B6.0Et2. ii: nBuli, then a ketone. iii: AiSQiUHNH2, PPb, DEAD.

Scheme 8

The Wang resin tnchloroacetimidate (ts)." prepared as in Chapter 3 (Section

IIIa), was treatrd with propargyl alcohol in the presence of Lewis acid. CO $ive the

polymer-bound terminal acetylene 29. The structure was c o n f i i d by a small but

significant IR band at 2 116 cm". assigned to the acetylene.

However. the iithiation by n-butyUithium foiiowed by addition of either

knzaldehydc or acetophenone failed to give any product. even at elevated temperatures,

in the presence of HMPA or TMEDA"

The process was then reversed. The polyrner bound aldehyde 32 was prepared by a

Mitsunobu reacùon between 4hydroxybenzaldehyde and Wang m i n (23. Equation 6).15

The reaction of this aldehyde 32 with phenyiacetyiide, generated from

phenylacetylene and n-butyllithium, did not give any of the desired propargylic alcohol

product. In this case cleavage shows that the aldehyde is stiU present, without any major

arnounts of product. In this case again the use of higher temperatures, even in the

presence of TMEDA or HMPG and even for prolonged reaction t h e s , did not change the

outcome.

It appears chat novel methods for the addition of acetylides to aldehydes or ketones

on a solid support wiii have to be developed prior to making this chemistry possible.

VI Conclusion

The previous studies demonstrate the ease with which soluble polymer-bound

aiienecarboxylates can be prepared and how they can be used as escient P-ketoester

equivalents in the generation of enamines.

This type of aiiene has a much broader potential chan just as electrophik towards

amines. They undergo cycloaddition reactions to give a number of carbocyclic and

heterocyclic structures.' In pankular. as electron poor substituted alkenes. they are very

good dienophiles in the Diels-Alder ceaction.'" The potentiai of these reagenu as tools in

combinatorhi chemistry needs to be further evaluated.

One aspect of polyrner-bound chemistry. which is gathering attention is the

involvement of traceless linkers to avoid the presence of functional groups resulting from

severing t hese linkages. AUenecarboxylates could po tentially O ffer a way to make

butenolides in a traceiess fashion. by involving an intramoiecular cyclization (Scheme

9)-'b-i ' In this process. E-Y is an electrophile which induces the cleavage and could

potentially be a weak Br~nsted acid or a Lewis acid.

This methodology would aiso benefit by its extension to soiid-supports. Our

preliminary studies have shown some of the shortcomings which need to be overcome to

buiId solid supported aiienes. One of the avenues to explore would be the use of resins

such as TentageP or SPOCC". which are alternatives to the usual crosslinked

polysryrene. and which may aiiow a better access of the soluble reagents CO the polymer-

bound reagents.

VI] Exxrimental

The 2.2.6-trirnethyl- 1.3-dioxin-4-one used was O btained cornrnercially and distilled

in vacuo. "Dry" solvents were prepared the foilowing way. Toluene was distilled from

sodium/benzo p henone ket yL Dichloromethane. methanol and düsoprop ylethylamine were

dned over 4A molecular sieves for at least 24 hours. DMF and DBU were dist ikd in

vacuo from calcium hydnde. Triethylamine was distilled from calcium hydnde. Acid

c htorides were distiiied pnor to use. 3.4-Bis(trimethylsily1)-cyclo but-3-ene- 1.2-dione was

prepared by Dr. L. Memetea according to the published procedure.'9 AU other reactants

1 were used as available from commercial sources. H-NMR spectra were run on a Varian

UNITY 4 0 spectrometer. at 400 MHz, usine the soivent residue as interna1 reference

(7.26 ppm from TMS for chloroform). IR spectra were run on a Perkin-Eher Fï-IR

Spectrum 1ûûû spectrometer. Mass spectra were nin by Dr. Alex Young. using e k t r o n

impact as the ionisation method.

AU of the reactions performed under dry conditions were carried out under a

positive pressure of argon.

lvcol a-chloroacetate-wmethoxv (Sa)

To a mixture of MPEGOH (470 mg, 9.4xl0-~ moles), 1 mL of C H F l z and 30 pL

(0.17 mmoles) o f dhpropylethyiamine cooled in an ice bath was added dropwise 160 pL

(2 rnmoles) of chloroacetyl chloride. The mixture was stirred on ice for 15 min, and then

rit room temp. for 24 h. The resuiting solution was diluted with 5 mL of CH2C12, and the

polymer was precipitated by the addition o f 150 mL o f diethyi ether. Fiitration, rinsing

with 3x30 mL of diethyl ether. and drying in vacuo resulted in 439 mg (8.6~10-' moles,

92%) of the product Sa. 'H-NMR (CDC13, ppm from TMS): 3.37 (s, 3H). 3.44-3.82 (m.

MPEGO-). 4.1 O (S. 2H). 4.34 (t, 2H. J = 4.6 Hz),

Polvethvlene elvcol a-bromoacetate-omethoxv (Sb)

To a mixture of MPEGOH (500 mg, 0.1 mrnoles). 1.5 mL of CHzClz and 30 pL

(0.17 mmoles) of diisopropylethyJamine cooled in an ice bath was added dropwise LOO VL

( 1.1 5 mmoles) of bromoacetyl brornide. The mixture was stirred on ice for 15 min, and

then at room temp. for 17 h. The resulting solution was diluted with 5 mL of CHzCI?, and

1 0 mL of diethyl ether were added. The resulting precipitate was filtered and air-dried.

It was then taken up in 50 mL of hot (-60-70 OC) toluene. and fütered thtough a pad of

celite ( 1 g). The pad was rinsed with hot toluene ( LOO mL added in 20 rnL portions). The

fdtrates were combined. and the toluene was removed in vacuo. The resulting solidifjhg

s p p was taken up in 5 mL of CHzClz, and the polymer was precipitated by the addition

of 1 ûû mL of diethyl ether. Fdtration. k i n g with 3x30 mL of diethyl eiher. and drying in

vacuo gave 4 15 mg (8. 1x105 moles. 81%) of the product Sb. 'H-NMR (CDCb. ppm from

TMS): 3.37 (S. 3H), 3.44-3.82 (m. MPEGO-), 3.87 (S. 2H). 4.32 (t, 2H. J = 4.8 Hz).

A mixture of polymer-bound bromoacetate Sb (300 mg, 5 .9~18 ' moles) and 150

mg triphenyiphosphine (0.57 mmoles) in 1.8 mL of CHzCla was stirred for 17 h- The

mixture was diluted with 5 mL of CHzCl? and 1 0 mL of diethyl ether were added, The

resulting precipitated polymer 6 was fdtered. rinsed with diethyl ether (3x30 mL), and

1 dned in vacuo. Yield: 28 1 mg ( 5 . 2 ~ IO-' moles. 898). H-NMR (CDCIi. ppm from TMS):

3.37 (S. 3H). 3.45-3.82 (m. MPEGO-). 4.14 (m. 2H). 5.66 (d. 2H. J = 13.7 Hz). 7.67 (dt.

6H. J = 3.6, 7.9 Hz). 7.77 (m. 3H). 7-92 (dd. 6H, J = 7.3. 13-3 Hz).

Po l~ner-bound tri~henvl hos~horanvlidene acetate (71

To a solution of the polymer-bound phosphonium salt (250 mg. 4.7~10" moles) in

1.8 mL of CH2C12. was added 50 PL (0.33 mmoles) of DBU. The mixture was stirred for

45 min at room temperature. The mixture was diluted with 2 mL of CHzClz. and 75 mL

of diethyl ether were added. The resulting precipitate was fütered and air-dried. It was

then taken up in 20 mL of hot (-60-70 OC) toluene. and fütered through a pad of celite

(-0.5 g). The pad was rinsed with hot toluene (100 mL added in 20 rnL portions). The

fitrates were combined, and the toluene was removed in vacuo. The resulting residue was

t a k e n up in 2mL of CH2Clz. and the polyrner was precipitated by the addition of 75 mL of

diethyl ether. Filtration. rinsing with 3x30 mL of diethyl ether, and drying in vacuo gave

232 mg (4.4~10-* moles, 93%) of the product. 'H-NMR (CDCl3, pprn from TMS): 3.37

(S . 3H). 3.45-3.82 (m. MPEGO-). 4.15 (broad S. 2H). 7.45 ( dt, 6H, J = 2.8, 7.6 Hz), 7.54

(rn, 3H). 7.64 (dd, 6H. J = 7.0. 12.6 Hz).

Po lvmer-bound ailenes (Sa-cl

To a mixture of the polymer-bound Wittig reagent 7 or phosphonium salt 6 (250

mg. -5x 10' moles). 2 mL of CH2Cl2 and 70 PL (0.5 rnmoles) for 7 or 140 pL (1 rnmole)

for 6 of triethylamine. was added dropwise 0.40 mmoles of acid chloride. The mixture

was stirrcd a t room temp. for 2 h. The mixture was diiuted with 2 mL of CH2C12. and 75

rnL of dicthyl ether were added. The resulting precipitate was fdtered and air-dried. It

was then taken up in 20 mL of hot (-60-70°C) toluene. and fdtered through a pad of celite

(-0.5 g). The pad was rinsed with hot toluene (100 mL added in 20 mL portions). The

rdtrates were combined, and the toiuene was rernoved in vacuo. The resulting residue was

taken up in 2 mL of CH2CL. and the polymer was precipitated by the addition of 75 mL of

diethyl ether. Filtration, rinsing with 3x30 mL of diethyl ether, and drying in vacuo gave

the product. Yields are indicated in Table 1.

Poiyethylene glycol a-(buta-2.3-den- 1 -oute)-omethoxy (&): ' H-NMR (CDCIi. ppm

from TMS): 3.37 (s, 3H), 3.44-3.82 (m. MPEGO-). 4.28 (t. 2H. J = 4.8 Hz). 5.23 (d. 2H.

J = 6.4 Hz), 5.66 (t, lH, 3 = 6.5 Hz).

Po-ethyiene glycol a-nuthoxy-~(5-phenyl-pentu-2.3-dien-l-) (Sb): ' H-NMR

(CDCb. ppm from TMS): 1.06 (t. 3H, J = 7.3 Hz), 2.15 (m, 2H). 3.37 (s, 3H). 3.45-3.82

(m. MPEGO-), 4.28 (m, SH), 5.67 (m, 2H).

Poiyethylene glycol a-(hem-2.3-dien-1 -oute)-@met+ (&): ' H-NMR (CDCI,. ppm

from TMS): 3.36 (m. 4H). 3.44-3.82 (m. MPEGO-), 4.29 (m, 2H), 5.63 (m. 1 H), 5.77 (m,

1 H), 7.28 (m. 5H).

To the polymer-bound allene (4x IO-' moles) in 1 mL CH2C12 was added 0.9

mmoles of amine. The mixture was stirred at room temp. for 1 h and then diluted with 2

mL of CHICI,. The polyrner was precipitated with 100 mL of diethyl ether. fdtered, rinsed

with 3x30 mL of diethyl ether. and dried in vacuo. Yields are indicated in Table 2.

Poivmer bound ~widones (10)

A mixture of 9 (3ûû mg. ca 6x10-' moles). 500 pL of dry toluene. and 100

(0.76 rnrnoles) of 2.2.6-uimethyl-1,3-dioxin-4-0ne was heated to reflux (120-130 OC bath

temperature) for 2h. The mixture was cooled to room tempemure before another LOO pL

of 2.2.6-trùnethyl-1.3-dioxin-4-one was added. The mixture was refluxed again for

another 2 h. The mixture was then diluted with 3 rnL of methanol and the product was

precipitated with 1 0 rnL of diethyl ether. fütered. Nised with 3x30 rnL of diethyl ether

and dried in vacuo. The yields are given in Table 2.

Cleavaee from the ~olvmer (11)

A mixture of 30mg of the polymer-bound pyridones. 1.5 mL of dry methanol. 1

mL of dry DMF and -50 mg of potassium cyanide were heated under argon to -80°C

(bath temperature) for 60 h. The reaction mixture was diiuted with 3 mL of diethyl ether,

then filtered through a pad of silica (-lg) packed with diethyl ether, and rinsed through

with 1 :3 methano1:diethyl ether (20 mL). The fdtrate was then dried in vacuo and taken

up in a very s m d amount of CHsl2. and loaded on a silica gel plug (typicaliy 5 cm of

height :In a 5%" Pasteur pipette) tightly packed with diethyl ether. The plug was rinsed

with diethyl ether (10 mL). and then the product was eluted off the plue by ~ s i n g with

3: 1 diethyl ether:methanol (20 mL). Evaporation of the solvents gave the products as

coloured oik. Yields are piven in Table 2. Punties were determined by HPLC as the

pcrcentage area as detected by UV absorption at 2 10 nm. using a Supelcosilnf LC- 18

25cmx4-6mm HPLC column. packed with C- 18 derivatizd sika gel of 5 pm bead size.

The eluents used were 30:70 (A) or 5050 (B) acetonitri1e:water.

N- Butyi-3-methu~carbonyl-2,6-dimerhyl4-om-~~dine ( 1 laa)

1 H-NMR (CDC13, ppm from TMS): 1.00 (t, 3H, J = 7.3 Hz), 1.43 (sextet. 2H. J = 7.4

Hz). 1-65 (quintet. 2H. J = 8 Hz), 2.34 (S. 3H), 2.35 (S. 3H), 3.8 1 (t. 2H, J = 8.4 Hz). 3.90

(S. 3H). 6.29 (S. 1H). Purity : 85% (eluent A, retention time 7.00 min).

N- Pheqlmethyl-3-methoqcu t b o n y l - 2 . 6 - d i m e y l - 4 - o p y d i n e (1 las)

'H-NMR (CDCl,. ppm from TMS): 2.26 (S. 3H). 2.27 (S. 3K). 3.89 (S. 3H). 5.16 (S. 2H).

6.38 (S. 1H). 6-97 (d, SH, J = 6.9 Hz), 7.33 (t. lH, J = 7.1 Hz), 7.38 (t. 2H, 3 = 7.3 Hz).

Purity : 90% (eluent A. retention tirne 7.83 min).

N-(2 - M e t h o ~ e ~ - 3 - m t h o q c a r b o n y ~ - 2 , 6 - d i m e t h y 1 - 4 - o - p y ~ e (1 lay)

'H-NMR (CDCI,. ppm from TMS): 2.37 (S. 6H). 3.33 (S. 3H). 3.59 (t. 2H. J = 5.4 Hz).

3.89 (S. 3H). 4.10 (t. 2H. J = 5.4 Hz), 6.32 (s, 1H). Punty : 86% (eluent A, retention time

3.89 min).

N- B n ~ I - 3 - m e t h o ~ c a r b o n y l - 2 - p r o p y l - 6 - ~ e (1 1 ba)

I H-NMR (CDCh. ppm from TMS): 1.01 (apparent q. 6H. J = 7.3 Hz). 1.42 (sextet, 2H.

J = 7.5 Hz), 1-65 (m. 4H). 2.35 (S. 3H). 2.5 1 (m. 2H). 3.78 (m. 2H). 3.90 (S. 3H). 6.30 ( S .

IH). IR (cm"): 1729. 1634. 1577. EIMS: 265 (M'. 33). 234(42). 222(34). 208(100).

l78(2O). l64(37), 123 ( 18). Purity: 92% (eluent B. retention tirne 7.22 min)

1 H-NMR (CDCl,. ppm from TMS): 0.95 (t. 3H. J = 7.4 Hz). 1.66 (m. 2H). 2.23 (S. 3H).

2.46 (m. 2H). 3-91 (S. 3H). 5.13 ( S . 2H). 6.37 (S. 1H). 6.96 (d. 2H. J = 7.3 Hz). 7.34 (d.

IH. J = 7.1 Hz). 7.39 (t. 2H. J = 7.3 Hz). IR (cm''): 3386. 1730. 1636. 1581. 1454.

E M S : 29%M'.36). 268(19). 242(39). 2 13 (18). 91(100). Purity: 96% (eluent B.

rerention tirne 6.38 min)

N42 -Merhqerhyl)-3-methoxycarbonyl-2 -butyl-6-methyl-4-oxo-pyridine (1 1 by)

I H-NMR (CDCL. ppm from TMS): 1.00 (t. 3H. J = 7.4 Hz), 1.63 (m. 2H). 2.36 (S. 3H).

2.59 (m. 2H). 3.32 (S. 3H). 3.57 (t, 2H. J = 5.7 Hz), 3.89 (s, 3H). 4-05 (t. 3H. J = 5 . 7

Hz). 6.29 (S. 1H). IR (cmm1): 3387. 1729. 1636. 1578. 1467. EIMS: 267(w.46).

236(6 1). 224(30). 2 lO(100). 18 l(42). 123(53). 59(38). Purity: 88% (eluent A. retention

timc 6.97 min)

Polvmer bound &lactams (12)

To a solution of 26 mg (0.38 mmoles) of imidazole in 680 PL of THF was added a

mixture of 16 pL (0.19 mrnoles) of acryloyl chloride in 450 pL of THF. After stirring for

1 h at room temperature. the resulting suspension was added to 250 mg (ca 4.8~10"

moles) of polymer-bound enamine 6. The mixture was heated under reflux (- 65-70 OC

bath trmpcraturc) for 20 h. Toluene (2 mL) was added and the mixture was fdtered

rhrough a smail pad of crlite. The pad was rinsed with hot (-6070 OC) toluene (40 mL

added in 10 mL portions). The filtrates were combined, and the toluene was removed in

vacuo. The resulting residue was taken up in 2 rnL of CH2Clz. and the polymer was

precipitated by the addition of 75 mL of diethyl ether. Filtration, rinshg with 3x30 mL of

diethyl ether. and drying in vacuo gave the product. Yields are indicated in Table 3.

Cleavage from the ~olvrner (131

A mixture of 200 mg (-3.8~10-~ moles) of the polymer-bound &lactams. 1.5 mL

of dry methanol. 1 mL of dry DMF and -50 mg of potassium cyanide was heated under

argon to -80°C (bath temperature) for 60 h. The reaction mixture was diiuted with 3 mL

of diethyl ether, then tidtered through a pad of silica (1 g) packed with diethyl ether, and

rinsed through with 1:3 methano1:diethyl ether (20 mL). The filtrate was then dried in

vacuo. The resulting product was punfied by chromatography on silica gel (except 13by.

for which basic dumina was used) using 5: 1 hexanes:ethyl acetate as the eluent. Yields

are given in Table 3.

N- B~iryI -2 -oxo-6-propy f idene-pipe ridine-5-crboic acid methyl ester (13ba):

1 H-NMR: 0.93 (t. 3H. J = 7.3 Hz). 1.02 (t. 3H, J =7.4 Hz), 1.33 (sextet, 2H, J = 7.4 Hz).

1 - 4 - 1-62 (m. 2H). 1.94 (m. 1H). 2.08 (quintet. 2H, J = 7.4 Hz), 2.20 (m. 1H). 2.45 (m.

1H). 2.56 (m. 1H). 3.62 (septet. lH, J = 4.8 Hz). 3.69 (S. 3H). 3.8 1 (m. 2H), 5-05 (t. lH,

J = 7.4 Hz). IR (cm"): 3684. 1733. 1632 (broad). 1458. EIMS: 253 (M'. 61). 224 (89).

3 10 (75). 194 (100). 182 (32). 169 (3 1). 154 (32). 141 (40).

N-Phe~l~ne~l-2-oxo-6-propyfidene-piperidine-5-corboiic ocid rnethyl ester (13bp):

i H-NMR: 0.87 (t. 3H. J = 7.5 Hz). 2.01 (m. 3H). 2.28 (double quintet, 1H. J = 3. 13 Hz).

2-6 1 (m. 1 H), 2.72 (m. 1 H). 3.65 (s, 3H). 3.84 (broad t. 1 H. J = 4.1 Hz). 4-98 (m made of

4.95 (d. 1H. J = 16.8 Hz).4.98 (t, 1H.J=7.5 Hz) and 5.02 (d. 1H. J = 16.4 Hz)). 7.17

(d. 2H. J = 7.4 Hz). 7.22 (d. 1H. J = 7.3 Hz). 7.29 (t. 2H. J = 7.4 Hz). "c-NMR: 14.29.

20.67, 22.08, 29.52. 39.78. 46.88, 52.27. 114.92. 126.66. 126.73, 128.39, 133.32.

137.32. 169.03. 172.22. IR (cm-'): 3680. 1732, 1666. 1636 (broad), 1496. 1454. EMS:

287 (M'. 36). 272 (12). 259 (9). 244 (24). 230 (20). 200 (36). 196 (64). 172 (19). 91

(10Q.

N d 2 - Methogethy1)-2-oxo-6-propyl- I , 4 , 5 , 6 - t e y d r o p y i n e - 5 - c r b i c acid methy L

ester (13b):

1 H-NMR: 0.99 (t, 3H. J = 7.5 Hz). 1.48 (sextet. 2H. J = 7.6 Hz). 2.46 (m. 2H). 2.56 (m.

2H). 2.88 (broad t , 2H. J = 7.9 Hz), 3.32 (s, 3H), 3.46 (t, 2H, J = 5.9 Hz). 3.73 (s, 3H),

3.91 (t. 2H. J = 5.9 Hz). IR (cm-'): 3684, 1678 (broad). 1613. 1458. EIMS: 255 (W,

67). 224 (56). 2 10 (100). 197 (54), 182 (88). 168 (77). 156 (7 1). 136 (46).

N-Bu yl-2 -oxo-6-(2-phenyLe t h y 1 i d e n e ) - p i p e n e - 5 - c r b o i c acid methyl ester (13ca):

' H - N M R : 0.9 1 (t, 3H. J = 7.3 Hz). 1.3 1 (sextet, 2H. I = 7.4 Hz), 1.54 (m. 2H). 1-98 (m.

1H). 2.24 (m, 1H). 2.50 (m. 1H). 2.60 (m. 1H). 3.46 (d. 2H. J = 7.6 Hz). 3.65 (m made of

3.65 (m. 1H). and 3.67 (S. 3H)). 3.84 (m. 1H). 3.92 (broad t, 1H. J = 4.2 Hz), 5.27 (t. 1H.

J = 7.6 Hz). 7.19 (t. 2H. J = 7.3 Hz), 7.23 (d. 1H. J = 7.3 Hz), 7.31 (t. 2H. J = 7.4 Hz).

IR (cm"): 3684. 1734. 1670. 1636 (broad). 1454. EIMS: 315 (M'. 66). 287 (24). 258

(26). 244 (16). 230 (47). 224 (lOo), 200 (46), 144 (41). 91 (49).

N-(Phe~methyl)-Z-oxo-6-(2-phenyle~hylidene)-piperidine-5-car~lic acid methyl

ester (1343):

1 H-NMR: 2.06 (m. IH). 2.31 (m. lH), 2.66 (m. lH), 2.78 (m. IH). 3.35 (d. 2H. J = 7.7

Hz) 3.59 (S. 3H), 3.92 (broad t, IH, J = 4.1 Hz). 4.95 (d, lH, I = 15.9 Hz), 5-15 (d, lH, J

= 15.9 Hz). 5.21 (t, 1H. / = 7.7 Hz), 6.91 (d, 2H. J = 7.1 Hz). 7.13-7.31 (m, 8H). IR

(cm*'): 3684. 1732. 1669, 1636 (broad). 14%. 1454. EMS: 349 (M'. 14). 258 (100).

230 (32) . 172 (18), 91 (58).

N- (2 - Met~erh_vl)-2-oxo-6-~2-phenyle~hyiidene)-pipendine-5-carbo~lic acid methyl

ester (l*):

'H-NMR: 1.99 (m. 1H). 2.25 (m. 1H). 2.50 (m. 1H). 2.61 (m. 1H). 3.32 (S. 3H). 3.45 (d.

2H.J=7.6Hz).3.55 (m. 2H). 3.68 (S. 3H). 3.94(m. 3H), 5.49(t. LH,I=7.7 Hz), 7.19

(t. 2H. J = 6.6 Hz). 7.22 (d, 1H. / = 7.3 Hz). 7.30 (t. 2H. J = 7.4 Hz). IR (cm"): 3684.

1736, 1678 (broad), 1604, 1454. EIMS: 317 (M'. 511, 258 (26). 244 (24), 226 (100).

198 (24). 144 (44). 9 1 (62).

Determination of the eeometrv of the exocyclic double bond on l3ba

A 2D NOESY experirnent was performed on 17a on a Varian UNITY 500

spectrometer with a mixing time of 800 rns. a relaxation delay of 1.000 S. and an

acquisition time of 0.135 S. Gaussian apodization of the data was performed. The

resulting 2D spcctmrn indicates that the protons Ha and Hb (figure SI) are close enough

to affect each other via nOe. which confirms the geometry at the double bond.

Pol-mer- ho und methvlenecvclobutenone ( 17)

A mixture o f 2 g (0.38 rnrnoies) of the polyrner-bound Wittig reagent 7 and 450

mg (2 mrnoles) o f 3.4-bis(trimethylsily1)-cyclobut-3-ene- 1.2-dione 16 in 12 mL o f CHzCh

was stirred in the dark for 17 h. The solution was diIuted with 5 mL of CHCI2 and the

polymer was precipitated by the addition of 200 rnL of diethyl ether. The product was

then tidcered. rinsed with 3x50 rnL of diethyl ether. and dned in vacuo. Yield: 1.9 g (0.36

mmoles. 95%).

1 H NMR: 0.27 (S. 9H). 0.32 (S. 9H). 3.37 (S. 3H). 3.43-3.82 (m. MPEGO). 4.40 (t. 2H. J

= 5.0 Hz). 5.47 (S. 1H).

Pol-mer- bound allenvl ketene (18)

The polymer-bound rnethylenecyclobutenone (250 mg. 4.8~10;' moles). in 20 mL

of CH2C12. was irradiated with 350 nm Light. The CHiC12 was evaporated in vacuo. The

residue was redissolved in 5 mL of CHzClz and the polyrner was precipitated with 1 0 mL

of diethyl ether. The product was fütered. rinsed with 3x30 rnL of diethyi ether. and dried

in vacuo. Yield: 210 mg (4x 10" moles. 83 4).

1 H NMR: 0.20 (S. 9H). 0.21 (S. 9H), 3.37 (S. 3H). 3.44-3.82 (m. MPEGO). 4.26 (m. 2H).

5.46 (S. 1H). IR (cm-'): 2083. 1968. 1718.

Reactions performed as in the preparation of the allenecarboxylates 8 and their

conversion to 9. 13 and 14. Y ields are indicated in Table 4.

N- Bu ~ l - 6 - ( N-Butyl-3-amino-3-oxopmpyl)-Z-om- 1,4,5,6-tetrahydropyridine-5-carborylic

acid methyl ester (21a):

I H NMR: 0.93 (m made from two overlapping signals at 0.92 (t, 3H, 3 = 7.3 Hz) and 0.93

(t. 3H. J = 7.3 Hz). 1.35 (m. 4H). 1.49 (m. 4H). 2.35 (m. 2H). 2.45 (m. 2H). 2.54 (m.

W . 3-12 (m. 2H). 3.25 (m, 2H). 3.74 (S. 3H). 3.76 (t. 2H. J = 8.0 Hz), 6.04 (broad S.

W. IR (cm-'): 3685.3440. 1678. 1609. 1521. EIMS (m/z): 338 (M'. 57). 279 (17). 263

( 16). 238 ( 100). 224 (64). 210 (66).

N - p h e n y l m e r h y l - 6 - ( N - p h e n y i m e t h y l - 3 - a m i n ~ -

cwrbo-viic ucid met&/ ester(2 1 b) :

1 H NMR: 2.02 (m. 1H). 2.33 (m. 1H). 2.72 (m. 2H). 2.98 (m. 2H). 3.48 (S. 3H). 3.83

(broad t , 1H. J = 3.7 Hz). 4.06 (dd. lH, J = 5.5, 15.0 Hz). 4.27 (dd, IH, J = 6.6. 14.7

Hz), 4.73 (d. 1H. J = 16.1 Hz), 5.04 (t. IH, J = 8.4 Hz), 5.39 (d. 1H, J = 16.1 Hz), 5.64

(broad S. 1H). 7.12-7.33 (m. 1OH). IR (cm-'): 3684, 3402, 1735. 1666. 1643. 15 17.

N-(2-Methy(propyl)-6-(N-(2-methy/propyl)-3-m~no-3-ompropy1)-2-om- l,4,S,6-

te tra hvdropyridine -5-carboqIic acid methy f ester (2 le):

1 H NMR: 0.89 (d, 6H. J = 6 . 8 Hz). 0.91 (d, 6H, J = 6 . 6 Hz), 1.78 (septet. 2H, J = 6.7

Hz), 2-34 (m. 2H), 2.46 (m, 2H), 2.56 (m, 2H), 3.12 (m, 4H), 3.67 (m, 2H), 3.75 (S. 3H).

6.13 (broad S. 1H). IR (cm-'): 3684. 3446. 1678. 1608, 152 1. ELMS: 338 (W. 36). 307

(19), 282 (2% 279 (32), 251 (29). 238 (54), 224 (100). 210 (76), 168 (44). 86 (43). 74

(64).

To a mixture of Wang resin (500 mg. 0.65 meq). bromoacetic acid (450 mg. 3.2

mmo les) and triphenylphosphine (850 mg, 3.2 mmoles) in 8 mL of THF. was added 5 12

CIL (3.25 mmoles) of DEAD in 2 mL of THF. The resulting suspension was siined in the

dark, at room temperature, for 24 h. The resin was then filtered, rinsed with 4x5 mL of

THF and CH2CI2 respectively, and dried in vacuo. Yield: 535 mg (0.6 meq, 92%).

IR (cm"): 1736.

A mixture of the polyrner-bound bromoacetate 24 (104 mg, 0.12 meq) and 150 mg

(0.57 mmoles) of triphenylphosphine in 1 rnL of DMF was heated to 70 OC for 24 h. The

resin is t'iliered. washed with THF (4x2 mL) and CH2C12(10x2 mL) and dried in vacuo.

Yield: 1 19 mg (O. 1 meq. 83%)-

IR (cm-'): 1734

Po 1 y e r - bound diethvl~hosbhonoacetate (26)

To a mixture of Wang resin (200 mg. 0.26 meq) and 320 mg (1.2 mmoles) of

triphenylphosphine in 2 rnL of THF was added sequentiaiiy 200 pL (1.2 mmoles) of

diethylphosphonoacetic acid. foliowed by a solution of 205 pL ( 1.3 mrnoles) of DEAD in

2 mL of THF. The suspension was s t h d . in the dark, at room temperature for 20 h. The

rcsin was t'iltered. washed sequentiaiiy with 8x2 mL of THF and CHzC12 and dried in

vacuo. Yicld: 237 mg (0.25 meq. 96%).

CP-MAS "P NMR (with a spinning frequency of 6 kHz): 19.7 ppm. IR (cm-'): 1734.

Rcaction of 26 with dinhenvlacetvl chloride (27)

T o a mixture of the polymer-bound phosphonoacetate (50 mg. 5.2x10-~ eq).

lithium bromide (50 mg. 0.55 mmoles) in 1.5 mL of acetonitrile was added 150 pL (1.1

mmoles) of triethylamuie. foUowed by a solution of 130 mg (0.56 moles) of

diphenylacetyl chloride in 1.5 mL of acetonitrile. The reaction is quite exothermic. and

after 6 h. the resin is fdtered, washed with 2x4 mL of each of methanol. CH2Ch, l:!

met hanoVCHKIz. methanol, 1 : 1 methanoUCH2Clz, and fmdy CH2C12 and dned in vacuo.

Yield: 50.6 mg (4.4~10" meq. 85%).

CP-MAS P N M R (with a spinning frequency of 6 kHz): 9.8 ppm IR (cm-'): 1936. 17 W .

Pol-mer-bound acetvlene (29)

Wang resin irnidate (100 mg, O. I l meq ) was carefuiiy rinsed six times with 4 mL

of dry THF. and suspended in a mixture of 1.6 mL of cyclohexane. 1.6 rnL of dry

dichloromethane and 75 PL (1.3 mmoles) of propargyl alcohol. The mixture was stirred

at room temperature for 5 min., before 10 pL (0.08 moies) of boron trifluoride diethyl

etherate was added dropwise. After 20 min, the m i n was f'iitered, carefùliy washed twice

with each of 4 mL THF, 4 mL 1:l THF:methanoI, 4 mL rnethanol. 4 mL 1:l

THF:methanol. 4 mL THF and 4mL dichloromettiane. and dried in vacuo. Yield 82 mg

( 1.02 meq. 93%).

IR (cm"): 21 16.

Pol-mer- bound benzildehvdc (321

Wang resin (200 mg, 0.26 meq) was washed carefuUy.with 4 rnL CHzCh ;ind 8x4

mL of dry THF. The resin was then suspended in 1.7 mL of THF. and 100 mg (0.38

mmoles) of triphenylphosphine and 110 mg (0.9 mmoles) of 4-hydroxybenzaldehyde were

added. The suspension was stirred for 10 min. before 70 pL (0.44 rnmoies) of DEAD

were added dropwise over 2-3 min. The resulting mixture was stirred for 15 h, at room

temperature. The resin was filtered. rinsed with 3x3 mL of each of CHÎ_C~~. THF. DMSO.

methanol. THF/methanol ( 1 : 1). THF and fmdy CHzClz and dried in vacuo. Yield: 242 mg

(0.1 8 meq. 70%).

IR (cm-'): 1686.

Cleavage of 51.6 mg of this resin with 50% TFA in CH2C12 gave 4.6 mg of 4-

hydroxybenzaldehyde, which represents a loading of 0.73 meq/g.

VI11 Re ferençes

1) For reviews on ailenes see: a) "The Chemistry of the Allenes", VOL 1-3; S . R. Landor.

Ed.; Academic Press, London. 1982. b) "The Chemisrry of Ketenes, Allenes. and

Related Compoundr", Vol. 1-2; S. Patai, Ed.; John Wiley & Sons; New York. 1980.

2) a) Kita. Y.; Tsuzuki. Y.; Kitagaki. S.; Akai. S. Chem Pharm Buii. 1994. 42. 233-

236. b) Marshall. J. A.; Wolf, M. A.: Wallace, E. M. J. Org. Chem. 1997. 62. 367-

37 1 . c ) Runge. W.; Kresze. G. Liebigs Ann. Chem 1975, 1361 -1378.

3) a) Johnson. C. R.: Zhang. B. Terrahedron Lerr. 1995. 36. 9253-9256. b) Salvino, J.

M.; Kiesow. T. J.; Darnbrough, S.; Labaudiniere. R. Comb. Chem 1999. 1. 134-

1 39. c) Biaskovîch. M. A; Kahn. M. I. Or. . Chem 1998.63. 1 1 19- 1 125. d) Barco.

A.; Benetti. S.; De Risi. C.; Matchetti P.; Polihi, G. PI; Zanirato. V. Tetrahedron

Lett. 1998.39, 759 1-7594.

4) Lang. R. W.; Hansen. HA. Helv. Chim. Acta 1980.63.438-455.

5 ) Nouvet. A; Lamaty, F,; Lazare. R Tefruhedron Lm. 1 W . 39, 3469-3470.

6) For exarnple: Eglinton. G.; Jones. E. R. H.; Mansfield. G. H.; Whitting, M. C. J.

Chem Soc. 1954.3 197-3 199.

7) a) Gordeev, M. F-; Patel. D. V.; Gordon. E. M. J. Org. Chem 1996, 61, 924-928. b)

Tietze, L. F.; Steinmetz. A. Synfert 1996. 667-668. c) Tiecze. L. F.; Steinrnetz. A,;

Balkenhohl, F. Bioorg. M e d Chem Letr. 1997. 7, 1303- 1306. d) Tadesse. S.;

Bhandari. A; Gailop, M. A. J. C o d Chem 1999. 1, 184-187. e) Zaragoza. F.;

Petersen. S. V. Tetrahedron 1996. 52. 10823- 10826. f) Rafai Far, A; Tidwell. T . T .

J. Org. Chem 1998.63, 8636-8637.

8) a) Paulvannan. K.; Stiiie. J. R. J. Org. Chem 1992, 57, 5319-5328. b) Paulvannan, K;

Schwarz. 3. B.; StUe, J. R, Tetrahedron Le11- 1993. 32, 215-218- c ) Paulvannan. K.;

Stilic. J. R. J. Org. Chem 1994.59. 16 13- 1620.

Y) Brunerie, P.; Celerier. LP.; Huché. M.; Lhommet. G. Synrhesis 1985. 735-738.

10) a) Huang, W.; Fang, D.; Temple, IC; Tidweii. T. T. J. Am Chem Soc. 1 W . 119,

2832-2838. b) Huang. W. Ph-D. Thesis, University of Toronto 1999.

I l ) Corbel. B.; L' Hostis-Kervek L; Haelters. J.-P. Synth. Commun. 1996. 26. 2561-

2568.

12) Myers. G G.; Uieng. B. J. Am. Chem Soc. 1996.118.4492-4493.

13) For the use of acetylides in polymer-bound chemistry see: Fyles. T. M.; Leznoff, C. C-;

Weatherston, J. Can. J. Chem 1W7, 55, 4135-4143.

14) Hanessian, S.; Xie. F. Tetrahedron Len. 1998, 39, 733-736 and 737-740.

1 5 ) Harnper. B. C.; Dukesherer. D. R.; South, M- S. Tetrahedron Lett. 1996, 37, 367 1 -

3674.

16) For examples s e : a) Jones, E. R. H.; Manstield, G. H.; Whiting, M. C. J. Chem Soc-

1956. 4073-4082. b) Ismail. 2. M.; Hoffmann. H. M. R, J. Org. Chem 1S1, 46.

3549-3550.

1 7) See for instance: a) Marshaii, J. A; Bartliey, G. S. J. Org. Chem 1994,59,7 169-7 17 1.

b) Marshall. J. A.; Wolf. M. A J. Org. Chem 1996. 61, 3238-3239. c) GU, G. B.;

Idris. M. S. Hj. Terrahedran Lett. 1985,26.48 1 1-48 14.

18) Rademann, J.; Grotli, M.; MeIdaL M.; Bock. K Am. Chem- Soc. 1999. 121. 5459-

5466.

19)Zhao. WC.; Allen. A, D.;TidweU, T. T. 3. Am Chem Soc. 1993,115, 10097-10103.

Selected 'H-NMR spectra

IR speftmm for allenyl ketene 18

NOESY spectrum for l3be

Yields and Purities

On polvethvlene elvçol

The yields on polyethylene glycol were detennined by using an average

molecular weight of MOO g mol-' to calculate for each individual reaction the average

molecular weights of both the polymer-bound s t a r h g material and product. and in tum

using these average molecular weights to calculate yields. Hence if w, and Ms are

respective1 y the experimental weight and molecular weight o f the starting polymer-bound

substance, and w+d Mp those of the product. then

The same average rnolecuIar weights were used to calculate the yields of cleavage

in a similar fashion.

A knowledge of the loading (number of reactive tùnctional groups per gram) is

neccssary here. Whenever the loadings were known by titration or as supplied

commercially. these were used. Whenever the loadings were not known, esiimated

loadings were obtained by assuming a complete reaction and calculating a weight gain

per reactive Functionality. From these rneasured o r estimated loadings. yields can be

calculated. If w, and 1, are respectively the experimentai weight and loading of the

starting polymer-bound substance and w, and b are those of the product, then

% yield = (w&,)/(w,xl,)x 100%

The same loadings were used to cakulate the yields of cieavage in a similar

fashion.

Purities were determined by HPLC at the indicated wavelength as

%purity = (area of pmduct peak)/(total area of chromatogram)xlûû%

One musc emphasize that this does not represent purity in terms of mol% or

weight%. In our view. and as often found in the literature. this approach is both simple

and convenient for obtaining an index of the purity of a sample. A more accurate

approach would require a calibrarion curve relating the product to an internai standard. a

method which would be irnpractical as it requires the use of a nther large amount of

chromatographically pure product. The 'H NMR spectra which were obtained for each of

the products provide a independent estimate of purity.