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A NEW METHOD FOR GENERATING THE CYCLOPROPYLMETHYL

RADICAL, ANI) GENERATION OF KETENES WITH

PROTON SPONGE~

Michael H. Fenwick

A thesis submitted in conformity with the requirements

for the degree of Master of Science

Graduate Department of Chemistry

University of Toronto

O Copyright by Miduel H. Ftnwick (2001)

National Libraiy 1*1 ofCanada Bibliothèque nationale du Canada

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A NEW METHOD FOR GENERATING

THE CYCLOPROPYLMETHYL RADICAL, AND

GENERATION OF KETEKES WITH PROTON SPONCE@

by Michael H. Fenwick

Abstract

Generation of cyclopropyketene (28) ïrom a WollT rearrangement and reaction

with a stable aminoxyl radical such as TEMPO (10). has provided a new method ro

gencrate a cyclopropylmethyl radical clock. Aikr initial attack on the ketentl by the

radical at the carbonyl carbon generating an enolic radiçtiI. this radical can either be

trapped by TEMPO leading to ring closed products, or can ring open and subsequentIy bc

irapped. The rate of ring-opcning can thcn be calculritcd [rom the ratio of producrs. the

rate constant for dilfusion controlled procesxs and ~ h e concentration OCTEMPO.

Generation of ketenes from th& con*csponding acid chloridcs with Proton

Sponge has [cd to a new method by which to produce kctenes in high yieIds without

dimcriza~ion (Leckta. et ai., J. Am Chem. Soc. 2000, 122, 7831). Heptritùlvenone (IO),

vinykerene (Il), butadienylketcne (12). allenylketene (13). and the novel bisketene (14)

have al1 been generated by this protocol wirh Proton Sponge and obscrvcd as rrither long-

lived species in solution. Trapping with tht: free radical TEMPO has led to some rrither

unusual products.

ACKNOWLEDGERIENTS

1 would Iike to thank a few people who have made this degree program a success.

Frst, 1 wouId üke to thank Professor Tidwell for allowing me the opponunity to work in

his liiboratory. From his patience when things go wrong to his knowledge of chemistry

when things go right. 1 don't think 1 could have made a kt ter choice for a supervisor.

Secondly, I would like to mention a few people who made my time hcre al1 the more

speciaL Annette (Mom), for always willing to lend a hand and an idea. Huda (sister), for

her gregarious nature and Our prodigious philosophical discussions. Adel. for tcaching

me so many things. and not just chemistry. Dr. Saidi. for our long worldly discussions.

Suc. for our cottage discussions, and the ~ s t of rhc undqrriduates (Amir. Huztiih.

Austin ....) for kecping the lab a fun place. To the rnany striîY who kwp Lash h4iller

running (Dan. Tim. Patricia, Fi-ed, Ken...). thlink you for al1 your help. Lastly. 1 would

like to thank my family for thcir support and encourtigement. Dad, for driving me to the

subway every morning, Grandma and Mom. for kceping my dinner warm. and my

brothers (Rob, John. Al and McKay) for hclping me keep a balance in lifc.

Mike Fenwick-20C) 1

TABLE OF CONTENTS

Abstract Acknowledgements Table of Contents List of Abbreviations

Chapter 1. A New Method for Generating the CyciopropyImethyl Radical

Introduction

Rcsults and Discussion

Experimental

Rc ferences

Appendix A: Selected IR Spectra of Observed Ketencs

Appcndix B: Selected 'H NMR Spectn of Isolrited Compounds

Appendix C: Selccted 13c NMR Spectra of Isolated Compounds

Appendix D: Selected 2D NMR of Spccrri Isolated Compounds

Chapter 2. Gencration of Ketcnes with Proton pr on^^^

Introduction

ResusuIts and Discussion

Experimental

References

Appendix A: Selected IR Spectra of Observed Ketenes

Appendix B: Sekcted 'H NMR Spcctra of Isolated Compounds

Appendix C: Srlccted "C NMR Spectra oCIsolated Compounds

Appendix D: Selected 2D NMR Spectra of Isolated Compounds

Appendix E: Sclected Mass Spectra of Isolated Compounds

Abbreviations

Ar

Ac

Bu

calcd

cm-'

O C

d

dd

EIMS

Et

EtOAc

E

HRMS

hv

Hz

1 -

IR

J

LDA

m

M

M+

ûromnt ic

ace t yl

butyl

calculrited

wave number (inverse centimctcrs)

degrees Celsius

doublet

doublet of daublrlts

electron impact mass spctrometry (low resolution)

zthyl

ethyl acetate

gram

high resolution m s s spectrornétry

hadirition

hertz

iso

in frmd

coupling constant

lithium diisopropyhmide

multipkt

molarity

molecular ion

Me

mg

rnL

mP

mm01

mo 1

MS

mlz

n -

N

nrn

rn1R

Ph

Pr

PPm

9

s

f-

TEA

THF

UV

methyl

milligrams

milliliters

meiting point

millirnoles

molcs

mass spectrornetry

mriss to charge ratio

normal

normaiity

nanometer

nuclear magnetic resonance spectroscopy

phcnyi

P ~ O P Y ~

parts per million

quartet

singlet

tcniary

tnethylrimine

tetriihydrofuran

ultrriviolet

Chapter 1

Free Radical Attack on Ketenes and A New Method to Generate the Cyclopropylmethyl

Radical Clock

In 1905 Herman Staudinger serendipitously prepued and characterized the tlrst

ketene. diphenyketene (1). in his atternpt to prepue the stable orgmic radical 2.'

P h 2 C C 1 C O C 1 Zn P h 2C=C=0

1

P ~ ~ ~ C O C ~

2

Staudinger proceeded to synthesize many more ketenes including dirnethylkctenr

(3)' and dibenmpentafulvenone (4).3 Subsequent to his discovery of diphenyktene.

Staudinger obsewed that (1) reactrd with rnolccular oxygcn. eventually producing a

polyester.4 This was the tirst evidence that ketenes are susccptible to fret. radical atttick.

Recently, free radical addition to ketencs hiis k e n a subject of investigation in our

After Staudinger's discovery that ketenes react with molecular oxygen. very littlc:

research has focused on the fret: cidicai addition to ketenes. In 1970. Satchell

investigated the effect of added radicals in the nuclcophilic addition of crhrinethiol to

dirnethyketene. Upon addition of di-isopropyl peroxy dicarbonate (5) which

decornposes spontmeously to form isopropyl radicals (6). SatcheU found that the

dimethylketene (3) disappeared at an accelerated rate.'

Satchell postulated that the accelerrition was due to a radical mechanism rather

rhan nucleophilic addition, as seen in Scheme 1.'

SCHEME 1 6 R S H - R S .

slow R S . + Me2C=C=0 -

3

f a s t alsR + R S t i - Me2C Me2CH

O t k r evidence for radical addition to kctenes was observed from the ESR

specuum of a reaction mixture formed using azibenzil(7). Upon heating, azibenzil loses

N2, and with a subsequent phenyl group migration, diphenylketene is formed.

A signal was observed in the ESR spectrum in which the coupling constants and g

values were consistent with a radical fragment having the structure B.^

8 Due to the iack of information on the free radical addition to ketenes. a thorough

investigation of radical reactions with shon lived ketene intermediates was undertriken in

this Iaboratory, and some of the results are alrcady published.7.Y

Ketenes are prepared t'or these experiments via Wolff rearranpement. It has Iong

been known that a-diazo carbonyl compounds. upon heating or irradiation, lose

molecular nitrogen, perhaps with generation of a carbene intermediate. and form a ketcne

upon subsequcnt R group migration.

We have determined that many reactive ketenes which have k e n pnerated via a

Wolff remangement are nevenheless relatively stable, long-livcd species in diiute

hydrocarbon solution. and have sufficient iifetimes in solution to permit the observation

of the characteristic ketene IR stretching frequency.

Recent calculations in our laboratory have shown that attack of free radicals such

as He, CH3*, Cl.. and HO. on ketenes is predicted to be highly exothermic? Reaction of

stabIe aminoxyl radicals can occur at the a or B carbons of a ketene. Attack on (9) by the

arninoxyl radical H2NO* at the P carbon leads ro the acyl radical (10). and is predicted to

be endothermic by 7.5 kcailmoL Attack of (9) at the acarbon kads to the radical (11)

and is expected to be exothermic by 18.7 kcal/rno~.~

Long-livcd carbon centred fret. rridicals have k e n known since Gomberg's

preparation of Ph3C. in 19W The main challenge in isolating frce radicrils is to prevent

coupling of two radicais to form dimers.

2 R-R

Stabilizing a free radical compared ro its dimer crin t~ cffected in a nurnber of

ways, including i) stabilizing the incipienr radical (usurilly by delocalizritirin). ii)

destabilizing the dimer by steric effects. and iu) dcstribilizing the dimer by other

electronic effects. as in peroxides ROOR." The two rridicals utilized in this investigation

employ a combination of these factors. 2.2.6-6-Tctrrimcthylpi~ridinyL-N-oxyl radical

(TEMPO, TO.) (12) and 1.1.3.3-tetrmc3thyIisoindolyl-N-oxyl radical (TMIO. I n O ) (13)

are stable nitroxyl radicals.

The stabiiity of these free radicals as opposcd to their dimers is a result of il

deiocalization of the unpaired electron between O and N (12, 11). Ü) the buky rnethyf

groups providing steric hindrance, and üi) the relatively weak peroxy bond of the dimcr

TEMPO (12) is a stable red crystalline solid that is commercially available at ri

relatively inexpensive cost. Isoindoly 1 radical (13) is not commercially available and

requires a rather long synthesis with low yields."." Advantages of (13) as opposcd to

(12) are the UV chromophon, which allows for HPLC aniilysis, as welI the k t that i t

separates by chromatography more easily from reactions as compared ta (12).

In out investigations, it ha been shown experimentcilly that attack of ~ h c rridiçal

occurs at the a-cwbon of a ketene, leading to an intermedioie radical at the P-carbon (16).

Subsequent trapping with a second equivalent of radical usually Ieads to the bisiidduct

(17) in these reactions.

As mentioned above, tiee radical attack of ketenes was caIculated to occur at the

carbonyi carbon and to be exothermic by -18.7 kcallmoi7 for the aminoxyI radical

H2NOe. This was confirmed experimentaiiy in Our hboratory by reacting diphenylkztene

with TEMPO, which attacks at the carbonyl carbon leaving the a-acyl radical (18h which

upon exposure to moleculu oxygen resutts in the peroxide (19h7

O

This result providèd experimental evidence for initial tiee radical attack at the

a-civbon of the ketene, followed by trripping of the formed carbon radical by molecular

oxygen. In unpublished work, it has also k e n t'ound thar ketent: i t d f reacts wirh

TEMPO forming TOCH~CO~T."

Radical probes are molecules with functiond groups that can interact

intramolecularly with radical sites leading to radical rearrangcments. The determinrit ion

of the rate constants of such rearrangements h a led to the dcvelopment of radical clocks.

A well known example of a radical probe is the 5-hexenyl cyclization. After generation

of a radical at the C-5 position (20). this intermediate can either be trapped with

tributyltin hydride at the 1-position producing 21 or can cyclize to 22, forming a five

membered cycloaikane which upon tnpping forms 23. ''

The second order rate constant of hydrogen abstraction. kab. can thrn easily be

calculated from the concentration of tributyltin hydrids, the known rate of cyclization k,.

and the ratio of products 21/23.

Another well known probe for this 'radical clock' technique is the

cyclopropylmethyl radical (24).'5a.b,c Formation of a radical centre at the methyl position

leads to ring-opening of the cyclopropanc: ring. resulting in formation of the 1-but-3-enyl

radical (25). A similar kinetic analysis permits the detçrrnination of kab.

Generation of the cyc~opropylmethyl radical (14) has ken accomplished in

numerous ways, with one method involving the use of the Banon's aikyl-PTOC esters

(26). which after chain initiation leads to (14) through free radical fragmentation and

decarb~x~lation. '~

-

Similarly. (24) cm be generated by thermal decomposition of a cyclopropyl

substituted diiizene (27). The synthesis of diazcnes involves many strips and ihus

preparation of the required precursor (27) can be laborious."

H2NNHz

OH OTS NHNH2

h h _I__) B2 + N-N +

N-N-CH ( C H 3 ) I

2 7 OH 2 4

These two methods wock well in the generation of (24), but both have thêir

drawbacks. The former procrss crin kad 10 interking produçts as radical chah

propagation c m o c c ~ r . ' ~ whilr the latter scheme involves a long and irdious synihesis."

In this investigation, a new method t'or generating carboxy substituted derivat ives

of (24) was envisriged. As already seen. free radicrils rcact wilh ketenes with initial

attack on the a-carbon. Generation of cyclopropylketene (28) and reaction with a stable

free radical such as TEMPO shouid lead to ester substituted derivatives (29) of the

cyclopropylmethyl radical. OT I

The products of this reaction would be expected to be the ring-closed

bis(TEMP0) adduct (M) and the ring-opened E/2 bis(TEMP0) adducts (31). If it is

assumed that combination of the carbon radicals with TEMPO is a diffusion controlled

process, then from the ratio of products, the concentration of the radical and the known

rate constant for the diffusion controiied process (presumably a function of temperature

and solvent), the rate constant for ring-opening of (29) c m be calculated with the

equation shown below.

These types of radical reacrions would provide a facile method in which to

prepare derivatives of (24), as the preparation of the a-diazo kctone prccursors to kctenes

is rather straightforward. Beginning from the crirboxylic acid (32). the acid chloride (33)

could be erisily synthesized with oxdyl chloride. and 33 in tum could be cunverted to the

a-diazo ketone (34) with diazomethane. W hile diazomethane is extrcmely toxic and

potentially explosive. its risk can be kept CO a minimum when handled wirh care.

Results and Discussion

As a test of the methodology, 1-diiizo-2-hexanone (35) wlis irradiated for ten

minutes with 350 nm light and a sharp IR band at 2120 cm" was obsemed and assigneci

to n-butylketene (36). The ketene was then trapped with two equivalents of TEMPO by a

mechanism typical of that discussed. O - nBuCH-C-O TO* ,

n0u

3 7

Whcn the 'H NMR of the reaction mixture w u taken. a poorly resolved signa1

was observed at 4.5 pprn, a signal that is consistent for the a-hydrogen of the bisadducr

(37). It is well known that the unpaired electron of a free radical. such as residual

TEMPO. results in line brorideninp in 'H NMR. thus causing rather poorly resolved

s p e c t n ' ~ x c e s s TEMPO is usualiy sublimed off prior CO chmmatography and in the

cilse of n-butyikctene, excess TEMPO was removed by Kugelrohr distillation followcd

by column chromatography to purify the product. This procedure afforded (37) as an

orange oil in 74% field. A proton spectrum of the bisadduct (37) revealed a wel[

resolved triplet at 4.51 ppm, consistent with the a-hydrogen of the bisadduct. The two

TEMPO moieties are not resolved in 'H NMR as the eight methyl groups appear as a

multiplet from 1.0-1.4 ppm, while the ring protons of TEMPO appear as a multiplet from

1.4-1.8 ppm. i 3 ~ NMR confumed the presence of a carbonyl carbon u 170 ppm while

the a-carbon is observed at 84 ppm.

As noted earlier. the isoindolyl radical has the benetits of a strong UV

chromophore, making it suitable for HPLC analysis, and is also sepliratcd more wiily

from the reaction mixture by chromatography in most instances. However, the radical is

not commercially available and its synthesis as shown is rather time consuming with low

To compare the reactivily of TMIO to TEMPO, n-tiutyketene (36) wris trripped

with TMIO, Ieading to a similar product. Contrary to the TEMPO reaction. the isolation

of the bisadduct was performed with ease on radial chromatography affording the product

(38) as yellow crystals in 3 8 8 yield, with recovery of excess TMIO. The characteristic

triplet at 4.6 1 ppm permitted easy identification of (38). The eight aryl hydropens as weII

as the eight methyl groups did not resolve well and are seen as mdtiplets. The

diastereotopic P-hydrogens of the n-butyl group are clearly seen as two multiplefi

between 1.8-2.0 ppm.

O I n

To determine the reactivity of the isoindolyl radicd with ketencs. thc kinetics of

reaction were measurcd for n-butyiketene (36) and phcnylketrino (39). and compared to

the known rate constants for TEMPO reaction with these ketcncs.8' To determine the rait:

constant for TM10 attack on n-butylketene. the rate of disappearance of n-butyketene

was mcasured by the decrease in absorption at 355 nm with convcn~ional UV in diffcring

concentrations of TM10 solutions. as reported in Table 1. The rate limiting sicp in these

reactions is attack of the isùindolyl radical at the cürbonyl carbon forrning thc a-acyl

radical, as the reaction of this incipiently formed carbon radical with TM10 is diffusion

controlled.

TABLE 1 110.1 M

Values of kQlc determined for each concentration of indolyl radical used are given

in TabIe 2 which were calculated using a k s t line linèar fit of the data The slopé of the

plot of the data in Table 1 as shown in Figure 1 gives the rate constant for TM10 attack

on n-butyketene.

FIGURE 1

O.Oe+O 1 .Oe-2 2.0e-2 3.0e-2 4.0e-2 5.0e-2

lndolyl (M)

It may be seen that the y-intercept of the plot is not zero. This is assumcd to be

due to the reaction of the ketene with adventitious writer present in the sarnples.

In cornparison with the known rate constant of1.22 x 10" MIS-' for n-butylketenr

with TEMPO," the rate constant for n-butyketene with TM10 was calculated to k 6.95

x IO" M"s-' . resulting in a ratio of 0.57 for TM10 reactivity compared to TEMPO. This

is in contrast to evidence that TM10 reacts marginally faster than TEMPO with carbon-

centred radicals." This must reflect a slower rate of initial attack on the ketcne by TM10

compared to TEMPO. for as discussed earlier, this step is rate determining A possible

explanation for this reversa1 of relative reactivity is that since the reaction of a ketene

with a nitroxyl radical is lesa exothermic than radical capture by the nitroxyl then the

transition state is later and there may be greater steric effects in the rigid TM10 radical.

The kinetics of phenyketene (39) with TM10 were dso examined to hnher

compare the relative reactivity. It was dcterrnined that phcnylketent: (39) also rericts

smoothly with TMIO, affording the bisadduct (JO) as colourlt.ss crystals in 30% yield.

The chiuactenstic singlet of the a-hydrogen at 5.39 ppm in the 'H NMR spcctrum

provided good evidence that the bisadduct (40) hiid indeed formed. The many aryl

hydrogens and eight methyl groups wcre not well resotved. Conventional UV

measurements of the kinetics of TM10 reaction with phenylketene wcre obtained as fisr

n-butyketene. Observation of the decreasc: in absorption of phenylketene at 249 nm

against time gave good fusst-order m e constants with a range of concentrations of TMIO,

as given in Table 2.

When the data are plotied as shown in Figure 2. a reasonable linear depcndence of

ks agriinst [TMIO] is observed. and the rate constant cm bé calculated as the dope.

9e5 -

8e5 -

7e5 -

@ - - L ses -

j es -

3e5 -

The rate constant for reaction of phenylketenc with TEMPO has a value of 1.26

M-lS-1 8~ , while for the reaction of phenylketene with TM10 the rite constant was

calculated to be 0.699 M-'s-'. Cornparison of thex rate constants gives a

k[TMIO]/k[TEMPO] ratio of 0.57, emntiaily the sarne ratio for the rate constants of n-

butylketene, indicating that TM10 has a consistent reactivity relative to TEMPO with

these ketenes.

When a dilute solution of cyclopropyl diazomethyl ketone (41) was irradiated for

10 minutes with 254 nm light and the IR specrrum of the sample measured. a sharp band

at 2120 cm-' was observed and assigned to cyclopropykett.nt. (28). This has bzen

previously rcponed as 21 10 cm". pnerated by irradiation of 2-cyclopentrnone." Upon

addition of TEMPO to the ketene solution and work up of the reaction. three products

were eventually isolated.

Column chromatography gave the ring-closed bisadduct (30) as an orange oil in

78 yield which was rather easy to characterize. The distinctive cyclopropyl hydrogens in

the 'H NMR spectnim at 0.3-0.8 ppm were clearly evident. as well as the doublet of the

a-hydrogen at 3.64 ppm. The ring-opened bisadducts (EIZ-31) wcre mort: diftïcult to

purify due to the fact that the products would not stain with iodine on TLC plates.

Switching stains from iodine to p-anisaldehyde allowed for visualization and isolation of

the ring-opened bisadducts. The ring-opened products were isolated as a mixture of E

and Z isomers in a ratio of 4:l. The oletinic peaks of the ring-opened bisadducts wcre

easily identifiable in an 'H NMR spectnim. The oletinic a-hydrogen of both isomers

appeared as a doublet at 5.90 ppm. while the 0-hydrogen of the E isomer appeared at 7.05

ppm and the Z isomer at 6.40 pprn.

Calculation of the ratio of ring-closed to ring-opened products from isolated

yields tends to be inaccurate due to substantial loss of product upon chromatography.

Aliernatively the ntio of products can be calculated by comparing the perik intqrations

of a cmde sample in an 'H NMR spectnim. resulting in more xçurite valucs. An

approximation of the ratios frorn the crude EJMR using pcak integrations resulted in a

ntio of L:2 for ring-closed to ring-opened products. However. with excess TEMPO in

these reactions. the unpaired electron on the free radical causes line broadening and thus

skews the integrations leading to inaccurate value^.'^ Thecefore to accurately measure

the ratio of products in a crude sample, m HPLC analysis rnust te perforrned and

consequently UV active samples are required. Unfonunately. the TEMPO adducts do not

possess a UV sensitive chromophore and thus to perfonn HPLC the isoindotyI radical

was employed.

A reaction of cyclopropyl ketene (28). generated in the aforementioned hshion.

and TM10 was performed leading to similar products. With the products k i n g LW

active, radial chromatography with UV detection was utilized making purification more

facile. The ring-closed bisaddduct (42) separated easily by chromatography as a. white

solid in 29% yield. Again. the most characteristic 'H NMR peaks for this type of

bisadduct are the cyclopropyl hydrogens htween 0.5-0.9 ppm and the doublet of the a-

hydrogen at 3.85 ppm. The ring-opened E isomer (43) was purificd as a colourltss oii in

8% yield, while the Z isomer is assumed to have formed but could never bt: purified or

identified. Small peaks that were observed in the crude 'H NMR spectrum could have

corresponded to the Z isomer, but these were never identitlcd. If these ptiriks were

assumed to bc the Z isomer, the En ratio would bt: caiculated CO bt. 4 1 . the same

isomeric ratio as for the rcaction with TEMPO, The E isomcr was crisily identitiribk

from its olefinic a-hydrogen appearing as a doublet at 6.20 ppm. while the hydrogens

attached to the carbon bearing the indolyl group appeared as a tripkt at 4.07 pprn.

I O I n

From 'H NMR integntion, the ratio of ring-closed (42) to ring-opened (E-43) was

approximately 5 2 . if the peaks assumed to be (2-43) are included in this calculation. the

ratio of ring-opened to ring-closed products changes to approximately 2:l. Obscjrving

more ring-closed product compared to the corresponding TEMPO reaction is consistent

with other results suggesting that TM10 reacts faster with carbon based radicakL9 TM10

would therefore trap more ring-closed product before it had a chance to nng-open,

consistent with the 2:l ratio. However, this value is inaccurate because of the

aforementioned fact that residual t'ree radicals affect the peak integrations in a proton

spectrum. Funher. the fact that the Z isomer could never be identified would lead to a

skewed ratio, as it is assurned thrit the Z isomer would form.

That the Z isomer couId be never identified manifests itself in HPLC analysis as

pure samples of products are nceded for cornparison to the reaction mixture. While the

peaks corresponding to the ring-closed (42) and E isomer (43) bisadducts could be

identified in an HPLC analysis, the Z isorner could not be positively identified in a

standard HPLC due to the prescnce of mriny smaller peaks that might have corresponded

to the Z isomer.

When HPLC was utilized to determine the ratio of products in a reaction at

mixture perforrned at 25 OC. two peaks were identified as the ring-closed product (42)

and the ring-opened product (E-43), in a ratio of 5 2 , the exact ratio from 'H NMR

integrations. However, as the E isorner appeared as a very smali peak, it was assumed

that if the Z isorner were in fact produced, a peak corresponding to it would be hidden in

the baseline. To increase the amount of ring-opened products, the reaction was run at 50

OC. Ring-opening has r positive AS' and thus when the reaction temperature CI increased.

a comsponding decrease in the free energy subsequently leads to an increase in the

amount of ring-opening. This was indeed observed as the ratio of ring-closed to ring-

opened E isomer increased substantially, to approximately 2:3, based on HPLC analysis.

A small peak was obsewed that may have conesponded to the Z-isomer which would

subsequently change the ratio to 1:2, however, even with this substantial increase in ring-

opening, the Z isomer still could not be positively detected and our research focused on

other cyclopropyl derivatives.

Substrates were then ernplo yed which would increase the arnount of ring-opcned

product. A phenyl substituent is known to ring-open at a much faster rate due to the

stabiliziig effect of the phenyl on the formed radical, which therefore should lead to

more ring-opened product in the presence of radical traps." When a dilu te hydrocarbon

solution of 2-phenyl-l-cyclopropyl diazomethyl ketone (41) was irradiatod h r 7

minutes with 254 nm light. a s h q IR band at 2120 cm-' w u observed and assigned to 2-

phenyl-l-cyclopropylketene (45). Reaction of 45 with TEMPO led to a mixture of

products.

Purification of these products was rather facile using radial chromatography w ith

ZN detection of the different bands to isolate the products. No ring-closed bisadduct

could be isolated and thus it is assumed thal ring-opening of the cyclopropylcarbinyl

radical is much faster than trapping. even at very hiph concentrations of TEMPO. Both

the E and Z isomers of the ring-opened bisadduct (En-46) were isolated. as weU as the

products from elimination of TEMPO. the isornenc dienes (EEIEZ-47).

In a crude 'H NMR spscmm, pc& corrcsponding to the dienes wcre not

observed. leading to the assumption that the products decompose on exposure to silica in

an elimination type process as opposed to a radical type mechanism. Reasons why the

bisadducts undergo facile elimination could include i) steric hindrance between phenyl

and TEMPO groups ü) the stabiIity of the highly conjugated diene and iii) the weakness

of the C-O bond. The bisadducts (EIZ-46) were identifiable by the characteristic olefinic

a-hydrogens at 5.80 ppm (2) and 5.70 ppm (E). The rather large coupling constant of

16.5 Hz for the a-hydrogen of the E isomer is consistent with the fact that trans isomers

result in larger coupling constants. Determination of the structures of both isomçric

dienes was more difficdt. but the many chmcteristic oiefinic signals in the 'H NMR

spectmm provided enough information to characterize the two isomeric dienes (EEIEZ-

47).

Phenylcyclopropyiketene (45) was aiso trapped with the isoindolyl radical,

leading only to the two isomeric ring-opened bisadducts (EIZ-18).

___)

OIn

These isomers were purilied using radial chromntography. both as pale white

crystals. in 14% (Z) and 25% (E) yield, respectively. 'H NMR provided the nccessriry

structural information needcd to characterize the two diffcrent isomers. The E isomer

showed a doublet at 6.12 ppm corresponding to the olefinic a-hydrogen, while the a-

hydrogen of the Z isomer appeared as a doublet at 6.06 ppm. Again. the couphg

constants for the a-hydrogens of 14.6 and 10.8 Hz for the E and Z isomers respectively.

provide additional evidence for the correct stereochemical assipnment. The bisadducts

both possess CH2 groups that are clearly diastereotopic, as the hydrogens of the CH2

rnoiety appear as two separate multiplets for both isomers.

Due to the extreme rapidity of the phenyl substituted cyclopropyl ring-opening,

2.2-dimethyl-1-cyclopropylketene (50) was examined as a substrate, as ring-opening of

the dimethylcyclopropylcarbinyl radical has a srnaller rate constant than does 2-

phenylcyclopropylcarbiny~22 When 2.2-dimethyl-1-cyclopropyl diazomethyl h t o n e (49)

was irradiated for four minutes with 254 nm 1ight. a sharp band at 21 19 cm*' was

observed in the IR spectrum and assigned to 2.2-dimethyl-1-cyclopropylk~tene (50).

After trapping the ketene with TEMPO and chromatography. 'H N M R showed many

olefinic periks. including peaks as far downlield as 7.8 ppm. suges t ing these products

were also elhinaring TEMPO. as similar downfield pcaks wcrc seen for the phenyl

substituted dienes.

TO.,

CHN2 4 9 - KC'* 5 O -

Only the bisadducts (E/Z-51) could be observed in the cnide 'H NMR. however

upon chromatography only the dienes (EIZ-52) could be isolated. The dienes (EIZ-52)

were easy to characterize, as it was now anticipated thrit this type of process would occur.

The 'H N M R spectrum of E-52 showed a doublet for the a-hydrogen at 5.80 ppm. while

the p-hydrogen appeared ris a doublet of doublets much funher downtield at 7.60 ppm.

The spectmm of 2-52 showed a doublet at 5.60 ppm assigned to the a-hydrogen. whiIe

the fi and y-hydrogens were poorly resohed and appeared as a multiplet between 6.85-

6.95 ppm. The two methyl groups of the E isomer appeared at 1.88 and 1.91 ppm. while

the methyl groups of the Z isomer appeared at 1.89 and 1.92 ppm. The coupling constant

for the a-hydrogen of E-52 has a value of 15.0 Hz. a rather Iargc value consistent with

tram stercochernistry. The coupling constants for 2-52 could not bc. calculattxi duc a

poorly resolved 'H NMR spectrum.

A product study of 2.2-dimsthyl- 1-cycIopropyketene (50) with TM10 was thcn

examined. Under similar reaction conditions it wrts found that the same type of

elimination products were produced (EIZ-53).

5 3

The chmcterization of the two isorneric dienes (EIZ-53) was again rather facile

a s the spectra were quite similar to those in the reaction with TEMPO. The E isomer

showed a multiplet at 6.10 pprn comsponding to the a and y-hydrogens, while the P-

hydrogen appeared as a doublet of doublets 7.75 pprn. The a and P-hydrogens of the Z

isomer appear as poorly resolved multiplets at 5.80 and 7.2 pprn while the y-hydrogen

appears as a mulitplet between 6.9-7.3 ppm. The mettiyl groups of the E isomer appear

1.93 and 1.95 ppm. while the methyl groups of the Z isomer appear at 1.93 and 1.94 pprn.

The u s e of radical clocks is an important lechnique in studying the kinetics and

mechanisms of rnany chemical and biochemical transformations thought to involve free

radica~s.'~' The formation of carbon centred radicals substitu tcd with a-C02R or a-CN

has been extensively studicd. Reactions such as thc cyclization of 6-cyano-5-hexenyl

radicalsu and the ring opening of 2-carboalkoxy substitutcd cyclopropyl radicals" are

accelerated by factors of lo3 relative to formation of the corrcsponding radictils

substituted by H or alkyl groups. This work hris provided a new method to prcpare

carboxy substituted derivatives (29) of the cycbpropylmethyl radical (21) in a rather

facile way. Future work could expand the numbér of probes examined leading to a

library of kinetic data for these types of radical probcs.

EXPERIMENTAL

Al1 glassware was oven-dried (140 OC) overnight while al1 plastic equipment and

microlitre syringes were kept in a desiccator filled with calcium sulphate. Al1 Iretene

reactions were cmied out under an atmosphere of argon or nitrogen. Ether and toluene

were distilled from Ndbenzophenone just prior to use. Dichloromethane, pentane and

2.2.4-tnmcihylpentane were aii stored over 4A molecular sieves. Deuterated chloroform

was kept over potassium carbonate. Al1 other solvents and religents were not subjccted to

funher purification. Radial chromatography was performed on a Harrison Rrsearch

Chromatotron, mode1 7924. with plates made from Merck TLC grade 7749 silica gel

containine pypsum binder and fluorescent indicator. Bands were dctected with ri short

wave UV lamp or else checked by 'H NMR. Thin layer chromatography wtis pcrformcd

on TLC plates purchwd from Aldrich and bands checked by UV, iodine stain or p-

anisddehyde stain. 'H NMR specrra were obtriined at 200 MHz (Varian Gemini), 3 0

MHz (Varian Gcmini or Mercury) and 400 MHz (Varian Unity). using solvent residue as

internal reference (7.26 ppm tiom TMS in chloroform). "C N M R spectra wcre obtainrd

at 100 MHz or 125 MHz (Varian Uniiy), using solvent residue as internal rekrence (77.0

ppm from TMS for chloroform). IR spectra w m obtaincd on a Perkin-Elmer F ï - I R

Specvum 1ûûû spectrometer. Ultraviolet sprctra and kinetic data were obtained on a

Perkin-Elmer UV/Vis Spectrometer Lambda 12. Dr. Alex Young, using eirher electron

impact or fast atom bombardment as the ionization method, rrin rnass spectra.

S tarting Materials

1 I n-Butvl Diazo Ketons (35)'"

AIL diazo ketoncs were made in an analogous manncr. To 12 ml of di(ethylenc

glycol) ethyl cther. 10 ml of diethyl ether and 3 g of KOH in 4 ml water a 70 OC.

was added dropwise 7.2 g Diazald in 70 ml diethyl rther, This ethereal solution

of diazomethane was stirred for one hour over KOH pellets and filtered. Valzryl

chloride (0.95g. 7.89 rnmol) in 20 ml of dry dicthyl cthcr was thzn added

dropwist: over 20 minutes and then left to stir for 1 hour. Aî'ter evacuririon at the

water pump of excess diazomcthrine. the etht'r w u rvaporatsd and the residue

subjected to radial chromatography with a 3 9 mixture of hexaneslethyl acetate as

the eluent, affording 562 mg (4.46 mmol) of n-butyl diazo ketone as a yellaw

liquid.

2) 2.2-Dirnethvlcvclo~ropvl- 1 -diadietone

Zinc-copper couple"

In a 500 ml Erlenmeyer t l ak with a magnetic stirrer wris added zinc dust (50 g,

0.77 mol) and 40 ml of 3% HCL The mixture was stirred rapidly for one minute

and the supernatant liquid decanted. Sirnilarly, the zinc dust was washed with

three additionai 40 ml portions of 3% HCI, tive 100 ml ponions of distilkd water,

two 75 ml portions of 2% aqueous copper sulphate solution, five 1 0 ml portions

of distilled water, four 100 ml portions of absolute ethanol, and five 1 0 ml

portions of diethyl ether. The zinc-coppcr couplt: was then transfrirrcd ro a

Buchner funnel washed with additional ether and stored overnight in a vacuum

desiccator over phosphorous pentoxide.

2,f-~irneth~lcyclopropanernethanol~~

To a well s t k d mixture of 25 ml anhydrous ether. 4.3 g (0.066 mol) zinc-coppcr

couple and a crystal of iodine, was addrd 13.3 g (0.050 mol) of diiodomcthane.

The reaction mixture w u warrned with a hot watcr bath until the mixture wris

gently rcfluxing on its own. The reaction wris ihen irnrncrsed in a water bath with

a constmt temperature of 35 OC and 1t.f~ IO srir for 30 minutes. To this mixture

was added dropwist: 1.7 g (0.02 mol) 3-methyl-2-buten-1-01 in 2 ml è1ht.r and the

reaciion M t to retlux ovcrnight. The mixture wris coolcd to room temperature

and a saturated ammonium chioride solution was added (20 ml) until most of the

compiex orgiinic salts had precipiiated. The ethereal solution was decrintcd into a

sepriratory funnel and the remaining salts were washed with ether (2 x 25 ml].

The ethereal soiution was extracted with four 15 ml portions of saturated

potassium carbonate and two 15 ml portions of satunted sodium chloride

solution. The ether solution was dried over magnesium sulphate and the ether

evaporated yielding 2.2-dimethyIc yclopropylmethanol as a colourless iiquid (1 -6

g, 0.016 mol, 808).

To 50 ml of distilled water was added 2.2-dimethylcyclopropylmethanol (1.0 g.

0.01 mol). potassium permanganate (6 g. 0.038 mol) and potassium hydroxide

(0.56 g, 0.01 mol). The reaction was allowed to reflux for 2 hours at which point

the hot solution was tiltèred through celite. The aqucous solution was acidified

with conc. HCI to a pH of about 2. The solution was extracted with ether (3 x 50

ml). dried over magnèsium sulphatè and the ethcr evaporated yiélding 2.2-

dimethyl-c yclopropanecarboxylic acid as a colourl~ss liquid (0.9 g, 7.7 mol.

77%).

2,2-Dimethyl-1-cyclopropyl diazornethyl ketone (49)

2.2-Dimethyl-1-cyclopropyl carbonyl chloride and 2.2-dimethyl- 1-cyclopropyl

dirizornethyl ketone were made in the aforementioned tashion. 2.2-Dimethyl-1-

cyclopropyl diazomethyl ketone (49). 'H NMR (CDC13) 6 0.85 (m. IH). 1-16 (S.

3H, CH3), 1.18 (S. 3H. CH3). 1.35 (t. 1H). 1.55 (bm. lH), 5.3 (bs, 1H. CHNt) IR

(CDC13) 2105 cm" (N2 stretch), 1653 cm" (C=O stretch).

Phthalic anhydride (10 g. 67.6 mmol) and knzylamine (7.4 ml. 67.6 mmol)

were mixed in a round bottomed flask and fieatcd with a Bunsen burncr until riIl

of the phthalic anhydride had mélied. DichIoromethane was addcd and the

solution extracted with 2N H2S04. 2N NaOH, bnne and distillcd writer. The

dichiorornethane was evaporated and the N-knzylphthalirnidt. wÿs rcçrystrillizt.d

from pentanddicth y l ether. yielding 12.8 g (53.8 rnmol).

2-Benzyl- 1 ,l,3,3-tetramethylisoindoline

A solution of methyl Grignard Ragent. prepared from 6 g (0.263 mol) of

mapncsium tuminps and 35 g (0.253 mol) iodomethane in 200 ml of dry ether,

was concentrated by slow distillation of ether until the temperature of the residue

mached 80 a ~ . The residue was aiiowèd to cool to 60 OC. at which point 10 g

(42.1 mrnol) of N-benzylphthalimide in 125 ml of dry toluene was added at a rate

to keep the temperature constant, The mixture was then heated to retlux and

allowed to stir at this temperature for 4 hours, rit which point t h mixture was

concentratcd to about 50 ml by distillation. After cooling. the mixture was diluted

with 100 ml of pentane, tlltered through Cclite and washed with three portions of

penrane (25 ml). The combined filtrate was Icft open to the atrnospherc for 7

hours, in which time it turned a dark purple. The filtrate wcts pascd through ri

long column of alumina (basic. Brockmann activity 1). the amine eluting first

yielding 1.2 g (4.5 mmol) of cnide product. which was not puriticd.

2-Bromo- 1,1,3,3-tetrameth yIisoindoline

To a solu~ion of 2-knzyl-1.1.3.3-tetramethylisoindo1ine (1.2 g. 4.5 mmol) in 30

rn1 of CC4 was addcd dropwise Iiquid bromine (4.7 g. 29.4 mmol). Thc reaction

was allowed CO stir for 15 minutes at which point 50 ml of 2N NaOH wris added.

The mixture was extrricted with dichloromethané (3x25 ml), the tiac~ions

combined, driçd over mrignesiurn sulphrite and the solvent evaporated, yielding

0.93 p (3.7 mmol) of crude product.

1,1,3,3-Tetramethylisoindoline

of 2-bromo-1.1.3.3-tctnmethylisoindoline (0.93 g, 3.7 mmol),

NaHCQ (0.5 g, 5.9 mmol) and a catdytic amount of Na2W04* H20 (2 100 mg,

3 1

0.30 mmol) was treated with 30% H201 producine vigorous effervescence. The

solution was immcdiately quenched with 2M NaOH and extracted wirh

dichioromethane. The organic fractions were washed with HIO. dtied over

magncsium sulphate and the solvent removed yielding 0.61 g (3.5 mmol) of white

solid pmduct.

1,1,3,3-Tetramethylisoindolin-2-yloxy l

1 O

To a s t h d solution of 1.1.3.3-tetmcthylisoindoLinc (0.6 1 g. 3-5 mrnol) in 7 ml

of methanol and 1 ml of acetonitrile was addcd iVaHC03 (0.25 g . 3.0 rnmol).

Na2W04- H@ (50 mg. 0.15 mmol) and 1.5 mi 309 H202 ( 12.6 mrnol). The

solution was allowed to stir for 32 h at which point it w u diluted with distilied

water and extracted wiih pentane (2x 20 ml). The organic layers were washed

twice with 2N H2S04 foilowed by brine. Drying over magncsium sulphate and

evaporation of the pentane gave the product (IO) as a bright ydlow solid (0.59 g.

3.1 mmol).

Ceneration of n-butylketene (36) and trapping with TEMPO

A solution OC l-diazo-2-hexanonc (35) (165 mg. 1.31 mmol) in 75 ml of pentane

was irradiated for 10 minutes with 250 nm light. and then TEMPO (2.89 g. 18.5

mmol) was added at room temperature and the soIution s thcd for 20 hours. The

pentane was evaporalcd and the excess TEMPO removed by Kugelrohr

distillation. The product was chrornatographed 4 iimes on silica gel ( 1 % Et3N in

CH2C12) to give the product (37) as an onnge oiI(403 mg. 0.99 mmol. 76%).

1 H NMR (CDCh) 8 0.90 (t, 3H. J=7.2 Hz. CE3CH2), 1 .O- 1.8 (m. (36H. TEMPO),

(4H. 2Ci-l~) ). 1.96 (m. 2H. CWHOT) , 4.46 (t. 1 H. 1 =3.2 Hz. C H a O T ) . I3c

NMR (CDC13) G 13.9. 17.0. 17.1. 20.3. 20.5. 20.6, 20.7, 22.8. 26.6. 32.1, 32.15,

32.2, 33.7, 34.5. 39.2, 39.3, 40.5, 59.6. 59.9. 60.1, 60.6, 83.5 (CHiCHOT). 171.7

(çOzT). One peak unidentified. IR (CDCI,) 1736 cm-' (C=O stretch). EIMS rd..

41 1 (MW. 0.05). 254 (17, M+-TO). 156 (28. TO).

140 (100. ï). HREIMS d z calcd for C2~H.&o3 4 1 1.3587. found 1 1 1.3573.

Ceneration of n-butylketene (36) and trapping with isoindolyl radical

A solution of 1-diazo-2-hexnnone (35) 120.2 mg. 0.16 mmol) in IO ml of degassed

pcntane was irradititcd for IO minutes with 250 nrn light and thcn isoindolyi

radid (85.6 mg. 0.45 mmol) was added at room tcmpcrature and thc solurion left

to stir for 18 hours. The pcntane wris evaparatcd and the residui: subjcctcd to

radial chromatognphy (208 EtOAc in Hex) yiclding the product (38) as pale

white crystals (3 1 mg. 0.067 mmol, 38 Ck). mp. 172- 115 OC.

1 H NMR (CDC13) 6 0.95 (t, 3H. J=5.7Hz. CaCH2). 1.36- 1.70 (m. {24H, TMIO},

(4H, 2CHz)). 1.82-2.04 (m. 2H. C&CHOT). 4.61 (t, 1H. J=4-8Hz. CH2CHOT).

7.1-7.4 {m. 8H, Ar). "C NMR (CDC13) 6 13.9. 14.1. 15.3, 22.6. 72.8. 25.3. 25.7.

(Ar), 121.5 (Ar), 127.2 (Ar), 127.3 (Ar), 137.5 (Ar). 173.2 (çOzT). IR (CDC13)

1776 cm" (C=O stretch). EIMS nt/: 479 (MH'. 0.02). 463 (0.2. M' - CH3) 288

( 16, M+-Oh), 190 (19, Oh), 174 ( 100. In). HREIMS d z cakd for Cjoh3Nz03

479.3274. found 479.3262.

Generation of phenylketene (39) and trapping with isoindolyl radical

A solution of diazoncetophenone (35) (14.8 mg, 0.10 mmol) in 20 ml o f deglissed

penme was irrridiatcd for 15 minutes with 300 nrn and 350 nm light at which

point isoindolyl radical (55.1 mg, 0.29 mmol) w u riddcd at roorn tempcriture and

left to stir for 16 hours. The pentane was evaporrited and the residue subjected to

radial chrornatography (5% EtOAc in Hex) yielding colourlcss crystnls as the

product (40) ( 15.1 mg, 0.030 mmol. 30%).

1 H NMR (CDCI,) G 1-10 (S. 3H. CH3). 1.21 (S. 3H. CH]), 1.33 (S. 3H. CH,). 1.37

(S. 6H, 2Ch). 1.51 (S. 3H. CHd, 1.59 (S. 3H. CH3). 1-64 (S. 3H. CH3), 5.49 (S.

IH, TOCHCO~T), 7.0-7.6 (m. 13H. Ar). "C NMR [CDCl1) 6 25.2. 25.4. 29.9,

30.3, 67.9. 68.2. 86.6 (TwHCO?,T). 121.4 (Ar). 121.6(Ar), 127.2 (Ar), 127.3

(Ar), 127.5 (Ar), 127.6 (Ar), 128.5 (Ar). 128.6 (Ar). 1372 (Ar), 143.9 (Ar), 144.5

(Ar). 145.0 (Ar). 171.4 (TOCHC02T). IR (CDCI3) 1779 cm-' (C=O stretch).

EIMS d z 499 (MW, L), 308 (5. M' -Oh). 190 (100, Oh), 174 (59. In). HREIMS

ml: calcd tor C32H39N24 499.296 1, found 499-2947.

Generation of cyclopropy lketene (28) and trapping with TEMPO

A solution of cyclopropyl-diazoketone (41) (85.6 mg, 0.78 mmol) in 60 ml of

degassed pentane was irradiated for 10 minutes with 250 nm light at which point

TEMPO (265 mg, 1.7 mmol) was added at room temperature and left to stir for 18

hours. The pentane was evaporated and excess TEMPO was removed by

Kugelrohr distillation. The residue was chromatographed on silica gel using

CHzCI2 as the eluent. which ehted the ring closed bisadduct (30) (21.7 mg. 0.06

mmol. 7%) as an orange oil. The eluent was changed (2.5% MeOH in CH2CI2)

which eluted a mixture of EIZ isomers of the ring open bisadduct (EIZ-31) as an

orange oil(32.1.0.08 mmol. 1 1%).

Ring closed bisadfircr: 'H NMR (CDCI,) 6 0.30-0.38 (m. 1 H, c-Pr). 0.52-0.58 (m.

lH, c-Pr), 0.64-0.78 (m. 2H, c-Pr). 1.1- 1.8 (m. (36H. TEMPO), { 1 H, c-Pr}). 3.64

(d, 2H. J=9.4Hz, TOCKGT). "C NMR (CDC13) 6 2.0, 7.9. 14.3. 16.8, 17.0.

19.9, 20.2, 20.4, 20.5. 31.7. 31.8, 33.6. 34.4, 39.0. 40.1, 40.2, 59.6. 59.9, 60.0,

60.5, 89.0 (TOCHC02T). 170.1 ( C o n . IR (CDCl,) 1756 cm-' (C=O stretch).

EIMS d z 395 (MH'. 0.05). 238 (20, M+-TO), 156 (76. TO), 130 (100. T).

HREIMS d z calcd for C3b3N203 395.3274. found 395.3258.

Ring open bisaukhrcts, E isomer: 'H NMR (CDCI,) 6 1.04-1.76 (m. 36H.

TEMPO). 2.40-2.46 (m. 2H. TOCHIC&), 3.82-3.88 (m. 2H, TOCH2CH2). 5.89

(d. lH, J=15.5Hz. HC=WO2T), 7.02-7.10 (m. LH. N=CHCO2T). 13c NMR

(CDCI]) S 17.2. 17.3, 20.3, 20.8. 29.3. 30.4. 32.10, 32.1 1. 33.3. 36.8. 39.2. 39.8.

45.4. 55.8, 59.9. 60.0. 60.3. 73.7 (TOsH2CH2), 121.7 (HC=GHCO2T), 146.5

(HÇ=CHC02T), 166.6 (HC=CHC02T). IR (CDC13) 1732 cm-'. EIMS nd: 395

(MH', 4). 238 (66. M+-TO), 156 (23. TO). 130 (100. T). HREIMS m/,- calcd for

C23&3N203 395.3274. found 395.3277.

Z isomer: 'H NMR (CDC13) 6 1.04-1.76 (m. 36H. TEMPO). 2.88-2.95 (m. 2H.

TOCHzCE). 3.82-3.88 (m. 2H. TOCH2CH2), 5.85-5.95 (d. 1 H. HC=CHCO2T),

6.36-6.42 (m. 1H. HC=CHC02T). 13c NMR (CDCI]) 6 17.2, 17.3. 20.3, 20.8.

29.3, 30.4. 32,10. 32.11, 33.3, 36.8, 39.2. 39.8, 45.4. 55.8. 59.9. 60.0. 60.3, 75.3

(TOÇH2CH2). 1 19.2 (HC=CHC@T). 147.8 (HC=CHC02T), 177.9

(HC=CHC02T). IR (CDC13) 1732 cm" (C=O stretch). EIMS m/= 395 (MH', 4).

238 (66, M'-TOI. 156 (23. TO), 140 ( 100, T). HREIMS m/,- calcd for C2&Nr03

395.3274. found 395.3277. Also availribfe: COSY, HSQC. TOCSY. HMBC ( s e

Appendix D).

Generation of cyclopropy lketene (28) and trapping wi th isoindolyl radical

2InO.= 0111 + I n 0 OIn

A solution of cyclopropyl-diazokctont: (11) (18.0 mg. 0.16 mrnol) in 20 ml of

degassed isooctanc was irradiated for 7 minutes with 250 nm light at which point

isoindolyl radical (62.5 mg. 0.33 mmol) was addcd and left to stir in an oil bath rit

50 OC for 20 hours. After evaporation of the isooçtline the rcsidue was subjected

to radial chrornatogrriphy (5% EtOAç in Hcx) which affordcd the ring closcd

product (42) (21.2 mg. 0.046 mmol, 29%), whilt: a further elution with CHIC12

afforded the trans ring opcned product (E-43) (5.6 mg. 0.012 mmol, 8 96) as ri

coiourless oil, ï h c cis ring opcned product is assumed to have formed but could

never be puriîïed or idcntified. A =action was performed at 25 OC. but the

amount of rinpopened product was too srnall to isohte. and thus the ring-opened

products were isolated from the reaction done at 50 OC. Similarly. a reaction was

performed at 72 OC for HPLC analysis. but no results frorn that exprriment are

included in this report.

1 Ring closed bisa~ircr: H NMR (CDC13) 6 0.54-0.98 (m. 4H, c-Pr). 1.26- 1 . ï O

(m, [24H, InO}, ( IH. c-Pr}). 3.87 (d, IH, J=9.3Hz. InOCHCO21n), - 7.10-7.40 (m.

8H. Ar). ' 3 ~ ~ ~ ~ (CDC13) 62.2, 5.3, 13.7. 25.4, 25.6, 28.7. 29.6, 30.1, 31.4,

68.0, 68.4. 68.7. 87.3 (InOCHC021n), 121.3 (Ar). 121.5 (Ar). 121.6 (Ar). 127.2

(Ar), 137.3 (Ar). 127.5 (Ar). 143.9 (Ar). 143.7 (Ar). 145.3 (Ar), 173.5

(InOCHC021n). IR (CDCI,) 1778 cm" (C=O stretch). EIMS rd: 463 (MH',

0.025), 272 (17, Mt-InO), 190 (50. InO). 173 (100. In). HREIMS nd; calcd for

C29H39NZ03 463.296 1, found 463.2945.

Ring open produci, E isomer: 'H NMR (CDCI,) S 120- 1.64 (m. 2SH. InO), 7.56-

2.68 (m. 2H. InOCHICH2). 4.08 (t, 2H. J=5.7Hz. InOC&X,). 6.18 (d. 1H.

J=l2.OHz, HC=C~C021n). 7.03-7.10 (m. (8H. Ar]. { 1H. HC=CHC021n}). 13c

NMR (CDC13) 8 25.4. 28.8. 32.4. 67.3. 68.3. 75.0 (InOCHtCHi), 121.0. 121.4

121.5. 127.2. 127.6. 133.1. 145.0. 147.2, 167.0 (COIIn). IR (CDCI3) 1744 cm"

(C=O stretch). EIMS ml: 463 (MH", 6). 572 (25. M'-ho). 190 (13. ho), 174

(56, In). HREIMS m/= calcd for C29H39N203 463.2961. found 463.2923.

Generation of 2-phenyl- 1.cyclopropylketene (45) and trapping wi th TEMPO

A solution of 2phenyl- 1-cyclopropyl-diazoketone (41) ( 18-1 mg. 0.097 mmol) in

20 ml of degassed pentane was irradiated for 7 minutes with 250 nm light. at

which point TEMPO (309.7 mg. 2.0 rnmol) was added at room temperature and

left to stir for 18 hours. M e r evaporation of the pentane. excess TEMPO was

removed by Kugelrohr distillation. The residue wris subjected to radial

chromatogcaphy (5% EtOAc in Hex) which eluted the cis decomposed product

(EZ-47) as a white solid and the çis bisadduct (2-46) as an orange oil (6.5 mg,

0.014 mmol. 14.3%). A hrther elution affordcd the tram decomposed product

(EE-47) and the trans bisadduct (E-46) (25.0 mg, 0.053 mmol. 55%).

Bisaddms, E isomer: 'H NMR (CDCl3) G 0.62-0.76 (bs. 3H. CH3). 0.96- 1.82 (m.

33H. TEMPO). 2.64-2.82 (m. lH, - H'H'CC=C). 2.91-3.08 (m. iH. H'&cc=c).

4.81 (dd. 1H. J=5.1, 3.3Hz. TO-CH), 5.70 (d, lH, J=I6.5Hz. HC=WCO2T).

6.76-6.88 (m. IH, HC=CHC02T). 7.2-7.6 (m. 5H. Ph). "C NMR (CDCI3) 5 16.5.

16.7, 20.1. 29.3, 31.4. 38.5, 39.2. 40.0, 59.6. 85.3 (H,COT), 121.7. 126.9, 127.0,

127.6. 142.0, 143.8, IR (CDC13) 173 1 cm-' (C=O stretch). EIMS mk 47 1 (MH'.

0.5). 3 14 (7. M'-TO), 156 (30. TO). 140 (100, T).

Z isonrer: 'H WIR (CDC13) 6 0.62-0.76 [bs. 3H. CH3). 0.96-1.82 (m. 33H.

TEMPO), 3.28-3.81 (m. lH, &H'cc=c), 3.50-3.64 (m, LH. H'&cc=c), 4.83

(dd. 1H. J=7.5. 4.8Hz. TO-CH), 5.70-5.90 (m. IH. HC=CWCO2T), 6.06-6.22 (m.

1H. HC=CHC@T), 7.2-7.6 (m. 5H. Ph). "C NMR (CDCIt) S 16.4, 16.5, 19.8.

20.0, 3f.2, 33.3, 33.9. 35.0. 38.4, 39.8, 59.2. 85.1 (H&OT), 118.4. 126.5. 127.0,

127.3, 129.1. 142.0, 135.7, IR (CDC13) 1742 cm-' [C=O stretch). EIMS mk 471

(W, 3). 3 14 (7. W-TO), 156 (15, TO), 140 (100, T).

Monoadd~tcrs, E-E isomer: 'H NMR (CDC13) 6 1.09 (S. 6H. 2CH3). 1.20 (S. 6H.

?CH3), 1.4- 1.8 (m. 6H. TEMPO). 6.04 (d, 1H. J=11.7Hz. CH=CH-C02T). 6.86-

6.94 (m. 2H. PhCfi=CiJ-CH). 7.3-7.6 (m. [5H, Ph), { 1H. Cfi=CHCOITJ). I3c

NMR (CDC13) 6 17.0. 20.6, 319. 38.0, 60.1. 119.8, 126.0. 127.2, 126.2. 128.8,

129.0. 136.0. 140.4, 133.8. IR (CDCI]) 1728 cm-' (C=O stretch). EIMS ndz 313

(M', 0.1). 157 (100. M'-TO), 156 (TO). HREIMS nd: calcd for Cz0H27NIO2

3 13.2042. tound 3 13.2047.

E-Z isonter: 'H NMR (CDCI,) 6 1.04-1.80 (m. 18H. TEMPO). 5.79 (d. 1H.

J=7.5Hz. CH=WO2T) , 6.76-6.86 (m. 7H. PhC&CH-CH=CH). 7.28-7.36 (m.

3H. Ph), 7.46-7.56 (m. 2H. Ph), 8.22 (dd. lH, I=IO.I, 8.4Hz. PhCH=CH-CH).

13c NMR (CDCl,) 6 17.0. 20.6. 32.0. 39.1. 59.9. 115.6, 125.2. 127.4. 128.7.

128.9. 136.3. 141.1. 145.3. IR (CDCIJ) 1735 cm-' (C=O stretch). EIMS mk 313

(M', 11, 157 (100, M'-TO). HREIMS rd: calcd for C20Hz7N102 3 13.2042. found

3 13.2043.

Ceneration of 2-phenyl-1-cycfopropylketene (45) and trapping with isoindolyl

radical

A solution of 2-phenyl-1-cyclopropyl-diazoketone (44) (20.0 mg. O. 11 mrnol) in

20 ml degassed pentane was irradiated for 7 minutes with 250 nm light at which

point isoindolyl radical (50.6 mg. 0.27 mmol) was added at roorn temperature and

left to stir for 20 hours. Mer evaporation of the pentane, radial chromatogrriphy

(5% EtOAc in Hex) yieldcd the cis isorner (2-48) (8.1 mg, 0.015 mmol. 14%) as

pale white crystals, while eluting with CHzClz afforded the trans isorner (E-48)

(14.8 mg. 0.028 mrnol. 25%) as pale white crystals.

E isomer: 'H NMR (CDC13) 6 0.82 (S. 3H. CH3). 1.24-1.32 (m. 6H. ?CH3). 1.38-

1.54 (m. 12H. JCH?). 1.66 (S. 3H, CH3). 2.68-2.80 (m. 1H. ho-c~H'), 3.04-

3.16 (m. 1H. 1n0-CH'&). 4.90 (t. IH. J=14.6Hz. Ph(In0)CH). 6.12 (d. IH.

J=14.4Hz. HC=WOIT), 6.98-7.52 (m. ( 13H. Ar}, ( IH, w=CHCOzT) ). '-'c

NMR (CDC13) 6 25.2, 25.7, 28.8, 29.4, 30.0. 39.5. 68.3, 86.5 (Ph(1nO)CH).

121.3. 121.5. 121.6. 121.7, 127.6. 127.6. 128.0. 128.2. 142.3. 144.0. 144.7. 145.1,

146.4, 166.8 (C021n). IR (CDC13) 1740 cm" (C=O stretch). EMS nd: 539 (MH'.

0.01). 338 (8, M'-Oh), 190 (40, Oh), 174 (17. In). 157 (100. M+- 2In0) .

HREIMS d.? calcd for C35&3N203 539.3274, found 539.3257.

1 Z isomer: H NMR (CDCI3) 6 0.82 (S. 3H, CH3), 1.23- 1.70 (m. 2 1 H. 7CH3),

3.24-3.36 (m. 1H. ho-c~H'). 3.54-3.70 (m. IH. 1n0-CH'&). 4.94 (bs. IH.

Ph(InO)CHJ, 6.06 (d. 1 H. J=10.8Hz. HC=CHCO2In). 6.36-6.46 (m. I H.

HCSHCQJn), 6.8-7.4 (m. 13H. Ph). I3c NMR (CDC13) 6 25.3. 25.4. 25.7. - 28.8.29.5. 30.0. 35.7.68.1. 86.6 (Ph(InO)ÇH), 119.0. 121.3. 121.5. 121.6, 127.1,

127.2. 127.5, 127.9. 128.1. 144.0. 147.7. 166.7 W2In). IR (CDCIt) 1741 cm-'

(C=O stretch). EIMS d: 539 (MH'. 0.05). 348 (4, M'-Oh). 190 (21. Oh). 174

(16. In), 157 (100. M'- 21110) . HREIMS nu: calcd for C35i&3N@~ 539.3274.

found 539.3294.

Ceneration of 2,2-dimethyl-1-cyclopropyl ketene (50) and trapping with TEMPO

2.2-Dimethyl-1-cyclopropyl diazomethyl ketone (49) (32.1 mg. 0.23 mmol) in 40

ml of degassed pentane was irradiated for 4 min with 250 nm light and TEMPO

(908.8 mg. 5.83 mmol) was added at room temperature and the solution stirred for

24 hours. The pentane wiis evaporated and excess TEMPO removed by

Kugelrohr distillation. The residue was subjected to radial chromatography (10%

EtOAc in Hex) yielding first the cis diene (Z-52) (3.9 mg. 0.015 mmol, 6.3%) as

white needles (mp 105-108 OC) and then the tram diene (E-52) (10.9 mg. 0.041

mmol. 17.7%) as white crystais (mp 68-7 1 OC).

Monoaclrluct, E-isomer: 'H NMR (CDC13) 6 1.06 (S. 6H. CH3), 1.17 (S. 6H,

2Ch). 1.4- 1.8 (m. 6H. C&C&CH,), 1.88 (S. 3H, CH3), 1.90 (S. 3H. CH3), 5.80

(d. lH, J=iS.OHz. C=CH-HC=m@T), 6.01 (d, lH, J=ll.IHz, C=CH-

HCSCHCQT). 7.62 (dd, lH, J=13.2. L1.4Hz, C=CH-HC=CHC02T). 13c NMR

(CDC13) 6 16.9, 18.9. 20.4, 26.4, 31.7. 38.8, 59.9. 116.8. 123.7, 141.3, 146.2,

167.8. IR (CDCS) 1731.7 cm-' (C=O strerch). EIMS ndz 265 iM', 1.5). 156 (5 ,

TO). 109 (100. M'- TO). 81 (31. M*- COrï ) . HREIMS ml,- cdcd for C16E-i2+i02

265.2042. found 265.2047.

1 2-isomer: H NMR ICDCIJ 8 1.06 (S. 6H. CH3), 1.16 (S. 6H. ?CH3). 1.2-l.7 (m.

6H. C&C&CE2), 1-85 (S. 3H. CH3), 1.9 (S. 3H. CHJ), 5.55-5.65 (bd. IH. C=CH-

HC=CHC@T). - 6.85-6.95 (m. {lH. C=CiJ-HC=CHC02T}. [ l H . C=CH-

HC=CHC02T)). N?v~R (CDCl3) 6 17.3. 18.5. 20.9, 27.2. 32.2, 39.3, 60.1, - 1 13.2. 122.6. 141.2, 146.3, 180.4. LR (CDCI!) 1733.2 cm" (C=O stretch). EIMS

W'Z 266 (MW. 9). 156 (20. TO). 110 (36. T). 109 (100. MT- TO), 81 ( 1 0 , M+-

C02T). HREIMS d: calcd t'or C16H27N01 265.2042, round 265.2050.

Ceneration of 2,f-dimeihyi-l-cyclopropyl ketene (50) and trapping with isoindolyl

radical j

2.2-Dirnethyl-l-cyclopropyl diazorncthyl kecone (49) (30.2 mg, 0.22 mmol) in 40

ml of degassed pentane was irradiated for 4 min with 250 nm light and TM10

(IO4 mg, 0.55 mrnoi) was added at room temperature and the solution stirred for

24 hours. After evapotation of the pentrine the residue was subjectcd to radial

chromatography (15% EtOAc in Hex) yielding kkst the cis dime (2-53) (4.5 mg,

0.015 mmol, 6.9%) as a pale white solid (rnp 87-90 OC) and then the tram dicne

(E-53) (34.3 mg, O. 12 mmol. 53%) as a pale white solid (mp 75-77 OC).

Monoadducts, E-isomer: 'H NMR (CDCI,) 8 1.46 (bs, 6H, 2CH3), 1.52 (bs. 6H.

2CH3). 1.93 (S. 3H, CH3). 1.95 (S. 3H, CH3). 6.02-6.14 (m. 2H, C S H - - HC=CWO2ln), 7.12-7.2(1 (m. 2H. Ph). 7.26-7.36 (m. 2H. Ph). 7.73 (dd. IH,

J=14.1, 11.4Hz C=CH-HC=CHCOtIn). I3c NMR (CDC13) 6 18.8. 25.2. 26.4,

28.6. 68.0. 115.8. 121.3, 123.7, 127.4, 142.1. 143.9. 146.8. 168.6. IR (CDC13)

1731.8 cm" (C=O stretch). EIMS d z 299 (M'. 0.5). 190 (5. ho). 104 (l(I0,

MW- InO). 8 1 (35. MH'- C021n). HREIMS m.4 caicd for CisHisNO2 299.1885,

found 299.1882.

2-isomec Cis diene 'H NMR (CMZ13) S 1.41 (bs, 6H, 2CH3), 1.49 (bs. 6H.

X H d , 1.88 (S. 3H. CH,). 1.92 (S. 3H, CH3), 5.8 (d. 1H. C=CH-HC=CHC021n), - 6.9-7.0 (dd, IH. C=CH-HC=CHC021n), 7.08-7.16 (m. 4H. Ph). 7.2-7.3 (d, lH,

C=CH-HC=CHC02In). 13c NMR (CDC13) 6 18.5, 25.1, 25.7. 27.1. 29.2, 29.9.

68.4. 112.4 121.8, 122.6. 127.8. 141.8. 144.5. 147.5, 167.6. IR (CDCI,) 1739.5

cm-' (C=O stretch). EIMS m4 300 (MH'. 1). 190 (19, InO). 109 (100. MH'-

InO). 8 1 (29, MH'- COzIn). HREIMS rd: calcd for CI9Ht6No2 300.1964. found

300.1972.

Kinetics of n-butylketene (36) and isoindolyl radical

A 0.250 ml sample of a 19.0 mm01 solution of the diazo ketone (35) in isooctane

was irradiated in a UV ce11 for 4 minutes at 250 nm. This was pipetted into a 1.2

ml UV ceIl containing 0.5 ml (0.4, 0.3, 0.2') of a 106 mmot radical solution.

adding pure isooctane to have consistent volumes. Observing the decrease in

absorption at 355 nm led to good first order rates.

*0.167 ml of the diazo kctone solution was uwd dur: to Iow concentrarion ratios

of the ketcnc and radical.

Kinetics of phenylketene (39) and isoindolyl radical

A 0.020 ml sampl: of a 0.0848 mm01 ketene solution (39) (irradiated 5 min with

300 and 350 nm Iight) was injected into 1.2 ml of a 1.12 mm01 (1.01, 0.896,

0.758. 0.503. 0.33) isoindolyl radical solution. Observing the absorption

dccrcase at 249 nm Ied to good first order rates.

REFERENCES 1) Staudinger. H. Chem Ber. 1905.38, 1739.

2) Staudinger. H.; Klever, H.W. Chem Ber. 1906,39,968.

3) Staudinger, H.; Klever, H.W. Chem Ber. 1906,39,3062.

4) Staudinger, H.; Dyckerhoff, K.; KIever, H.W.; Ruzicka, L. Chem Ber. 1925. 58.

1079.

5) Lillford, P.J.; Satcheil. D.P.N. J. Chem. Soc. (8). 1970. 1303.

6) Singer. L.S.; Lewis. I.C. J. Am. Chem Soc. 19h8.90.3211.

7) Huang. W.; Henry-Riyad. H.; Tidwell. T.T. J. Am. Chenr. Soc. 1999. 12 1.

3939-3943.

8) a) Carter, J.; Fenwick. M.H.; Huang, W.; Popik. V.V.; Tidwell. T.T.

Cm. J. Chem. 1999.77.806.

b) Allen, A.D.; Cheng, B.; Fenwick. M.H.; Huang, W.; Missiha, S.

Tahrnassebi D.; Tidwell. T.T. Org. Lert. 1999, 1.693.

C) Allen, AD.; Cheng, B.; Fenwick. M.H.; Givchchi, B.; Henry-Riyad, H.;

Nikolaev. V.A.; Shikhovri, E.A; Tahmassebi. D.; Tidwell, T.T.

Wang, S. J. Org. Chem. 201.66.26 1 1.

9) Sung, K.; Tidwell, T.T. J. Org. Chem. 1998.63.9690-9697.

10) Bauld, Nathan L. Ratiicais, Ion Radicals and Triplets. Wile y-VCH: Toronto,

1997. pp 11-12.

11) Griffiths. P.G.; Moad, G.; Rizzardo, E.; Solornon, D.H. Ausr. J. Chem. 1983, 36.

397.

12) Micallef, AS.; Bott. R.C.; Bot&. S.E.; Smith, G.; White, J.M.; Matsuda, K.;

iwamura. H. J. Chent. Soc. Perkin Trans. 2. 2000.7, 1285.

13) M e n , AD.; Tidwell. T.T. Unpublished results.

14) Lowry. T.H.; Richardson. K.S. Medianism and Theop in Orgonic Chnirisrry: 3d

Edition. Hirper and Row: New York, 1987. pp 807.

15) a) Griller, D.; Ingold, KU. Acc. Chem Res. 1980, 13.3 17.

b) Bowry. V.W.; Lusztyk, J.; Ingold. KU. J. Am Chenr. Soc. 1991, 113.5687.

C ) Beckwith, A.L.J.; Bowry, B.W. J. Alit. Chem. Soc. 1994. 116.27 10.

16) Newcomb. M.; Johnson, C.C.; Manek, M.B. Varick, T.R. J. Am Chenz. Soc.

1992, 114. 10915.

17) Mathew, L.; Warkentin, J. J. A m Chem Soc. 1986. 108,7981.

18) Forrester, A.R.; Hay, J.M.; Thomson. R.H. Organic Chernisr? of Stable Frer

Rodicals. Academic Press. Ncw York: 1968. pp 39.

19) Chateauneuf, I.; Lusztyk. I.; Inpold. K.U. J. Org. Chuin. IY98.53, 1629.

20) Agosta. W.C.; Smith III. A.B. J. Am Chem. Soc. 1971.93.5513.

2 1) Atkinson. J.K.; Ingold. KU. Biochemistry 1993.32,9209.

22) Beckwith, AL-J.; Bowry. V.W. J. Org. Chem. 1989,54268 1 .

23) Newcomb. M.; Varick, T.R.: Ha. C.; Manck, M.B.; Yuc. X. J. Amer. Chem. Soc.

1992, 114.8158.

24) Nikolaev, V A ; Uikin. P.YU.; Korobitsya, I.K. J. Org. Chem USSR. 1989. 25,

1059.

25) Shank, R.S.; Shechter, H. J. Org. Chem. 1959.24. 1825.

26) Daukn, W.G.; Berezin. G.H. J. Am. Chem Soc. 1963.85.2130-

27) b g , J.; et al. J. Org. Chem. 1995.60.564.

APPENDIX A

SELECTED IR SPECTRA OF OBSERVED KETELIES

APPENDIX B

SELECTED 'H NMR SPECTRA OF ISOLATED COWOUNDS

- l 7 - ,

i 0 - ; - .

- i 7.177

- 1

#

9

-

,- 7.163

-7.155 , !

- :

f - 7 . 2 4 1 'u>

L W : 4 - r

I ' - 7 . u i I

i d l - j '-7.091

,I 1 P - d

1i -- - 4.610 m ' , i I

1.4 1 t t

i O . 9 6 9

P u l m Smquencm: m2pUl

Bolvont I CLIC13 T e . 2 5 . 0 C 1 298.1 K VNITT-500 "ultraSOOœ

PClLBS SSQUmNCE I a l u . do ley 5.000 i m c Pulse 00.7 dmgrosm Aau. t h n i 3.001 moc Width 3038.8 t ïs 4 rapot î t iona

OBssRva Hl, 499.11462753 m r DATA PROC1ISSINû

Lino btomîening 0 . 1 Hz IT d r e 65536 Total tirno O m i n , 32 s e c

N .-' L U *

l . ~ , 1 ,.J t . l., I , 1 . -,-.l 1. . . - . r - . I l . . !-J

0 . 3 0 8.95 36.29 0.18 2.36 lO.U2 1 .13 0 . 59

O I n

w : 1 t a

r a ' P t " J

0

n O

y-e E n N '3

<

C

\ l t

2- In0 . -- 2-0~~ E-43 c

0 o r - v - -

- - - rr ' u t - L P =

APPENDIX C

APPENDIX D

SELECTED 2D NMR SPE- OF ISOLXTED COlMPOüNDS

CHAPTER 2

Generation of Highly Conjugated Ketenes with Proton Sponge

Ketenes are extremely versatile synthetic reagents that have k e n employed in

many syntheieses. Whik ketenes readily undergo nucieophilic rtttrick by water. alcohols

and amines to Eorm carbxylic acids. esters and amides. respectivçly.' there art: usually

more facile routes to rhese types of compounds.' The most distinctive and synthrtically

usefui ceaction of ketenes is the [2+7-1 cycloaddition to form a four-membered ring. This

cycloaddition constitutes one of the most useful methods in the preparation of these

cyclic cornpounds.

Of the many differenr [2+2] cycloadditions of ketenes, the one that is the most

syntheticaliy useful. especiaily in the phmaceuticd sciences, is that of a ketene and an

imine resulting in a P-hctarn.

The P-hctam skeleton is the key componeni of the most widely emplo yed famil y

of antibiotics. Included in this family are the penams (l), cepherns (2) and monobactams

Due to the importance of this farnily of antibiotics. rnany methods to synthzsize

the p-lactarn ring have k e n ernployed. including 1) hydroxamatt: cyclization 2)

isocyanate alkene addition and 3) ketene-imine cycloaddition. also known as the

Staudinger reaction? The Staudinger cycloaddition has received much attention due to

the availability of imines and ketenes, as well as it k ing the most direct route to the P-

lactam nucleus. ' Many different ketenes and imines have been used to effect the cycloaddition

leading to B-lactams. For exarnple. in 1997 Gunda found thrit the iminc (1) rcacted with

azido ketene, resulting in the P-iacram (5) with a rather large diastèreomcric ratio of

Keienes produçed from Wolff rearrangernents can also be employed in these

cycloaddition reactions as seen in a synthesis of the p-lactam 8 in 1997.' The use of

ketenes generaied from a-diazo ketones in cycloadditions is of importance because the

cycloaddition usually proceeds with trans stereochemistry. which can ofren difficult to

achieve. whereas ketenes generated from acid chlorides usually Ieads to cis

stereochemistry.' Podlech employed the diazo ketone (6). which upon rnixing with the

irnine (7) and irradiation. resulted in the B-Iactam (8) and its diastercorner in a 93:7 ratio.'

However. the production of ketsnes from Wolff rerinangernents and

dehydrochlorination reactions from acid chlorides has drawbaçks. a-Diazo ktxones.

while not difficult to make, often require the hazadrirous dirizomethane as ri reagent and

thus can be only be synihesizrd in srnül1 quantities. Further. a-dirizo lieiones are

sparinply soluble in organic solvents. requiring ~üct ions to be pcrformed an a fairly

small scale. Alternatively. while dehydrochlorination of acid chlorides by triethylamine

can be run on a rnacroscale, the iesultant triethylamint: hydrochloride is known to

catdyze the dimerization of ketenesm6 Moreover. residual tricthylamine catalyzrs the loss

of stereoselectivity in the p-lactam ~~cioaddit ion.~

To this end. Leckta. et al, have recently published a procedure for

dehydrochlorination~ that avoids this problem of catalysis of dimerization by

triethylammoniurn ~hloride.~ When the strong thermodynarnic base

bis(N,N-dimethy1arnino)-1.8-naphthalene (Proton Spongeb) (9) is used as the proton

acceptor, the hydrochloride salt of Proton Sponge precipitatrs out of solution when the

reaction is performed in toluene. As the sait no longer remains in solution. dimerizrition

is avoided.

Howevcr. mixing ont: equivalent of Proton Spongc and one equivalent of acid

chloride does not normrilly produce detecrriblt. Iimounis of ketent.. Evcn though Proton

Sponge is a vcry strong thermodynrimic b u . its largt stcric b u k results in it k ing a

rather slow 'kinetic base'. Addition of rrietnylamine as ri 'shuttlc base' Icads ro

formation of the ketene in quantitative amounts as triethylamine effttcts ketenr formation

and subsequently Proton Sponge deprotonaies the rricthylammonium hydrochloridtt. and

precipitates out of so~ution.~

Leckta employs this procedure to produce P-Iactams in very high enrintiorneric

excesses with modest yields. In his procedure. Leckta employs a chiral alkaloid to act as

the 'shuttle base', which results in the luge stereoselcctivity. kckta speculritcs thrit the

high stereoselcctivity of these acid chlonde reactions is due to the chiral amine

complexing with the keiene Ieading to a stsnoseIective reriction with the imine6

proton II

sponge + chi r a l ami ne ICC)

base

The goal of this projtxt was to attempt ketenc production with Proton Sponge and

a cataiytic arnount of triethylarninr as the 'shuttlt. base'. Spsçifically. highly conjugriled

ketenes would bt: penerited in this fashion in toluene. and thcir stsbility and reactiviry

assessed. Observation of the ketene IR bands and trapping with TEMPO would permit

the identification of these conjugatcd ketenes. The ketenes sought by this method; (10).

(11). (12). (13). and (14). are al1 of theoretical and practical interest. and their trripping

with TEMPO is expected to lead to unusual products.

Vinyiketene (11) hris k e n employed in numerous [2+2] cycloadditions with

imines generating p-lactams.' Vinyl substitutcd p-lactams are of synthetic interest due to

the number of chemical transformations that can be carried out on the vinyl group. For

example. in 1977 Manhas reacted vinylketene with the imine (15). giving the fi-lactam

(16) in fairly high enantiomeric excess. Subsequent ozonoiysis of the vinyl group

produced the keto-fi-liictarn (17)~'

Only recendy has butadienylketene (12) kgun to k utilizcd ris an unobserved

intermediate in the synthesis of p-~actams.~"~.' The synthetic possibilities offered by a

butadienyi functionalized P-lactam has spurred interest into the generation of

butadienyketene (12). as numerous chemical transformations can be performed on the

diene. including Diels-Alder cycloadditions. In 1996. Mahajan generated

butadienylketene (12) from sorbyl chloride (18) at elevated temperature with in siru

irapping by the imine (19) to synthesize the dienyl substituted p-lactam (20)."

The butadienyl substituied P-Iactam W~IS rhen utilized to psrform Di&-Aldcr rype

reactions leading to rather unusual fi-lac~ams as seen when (20) is used in a [Jc?]

cycloaddition with dimcrhyI acztylenedicrirboxyirice (21). leriding to the P-lactarn (22):

1 t was suggested that an initia11 y formed 1.4-c yclohexadirnt isomerized to 22.

RESULTS AND DISCUSSION

Five higtiiy conjupated ketenes were prepared and trapped ernploying the

dehydrochlorination method wilh Proton Sponge and a caralytic amount of triethylamine.

When 1.3.5-cyclohexatriene-7-carbonyl chloride (23) was rnixed with Proton Sponge and

triethylamine at O OC, a pale yellow solution resulted with a white precipitate assurned to

be the hydrochloride salt of the Proton Sponpe.

Until this point. heptafulvenone (10) had only k e n observed by IR analysis on

one occasion in an argon matrix as indicated by a band ai ? 103

The formation of heptafulvenone (10) was toliowcd by IR andysis and it was

determined that under thc reaction conditions employed (10% mol Et3N) the ketene was

not beinp formed in appreciable amounts. as only a small ketene peak at 3101 cm" was

k i n g obsewed. An explanation for the slow rate of ketene formation is that the a-proton

of the acid chloride is relatively non-acidic since accumulrition of negative charge at the

a-carbon would Ierid [O an eight electron x systern (24).11

Upon addition of one equivalent of triethylamine. the keiene formed as the

predominanc product as the IR band of the ketene ai 2101 cm-' kcamr very sharp while

a concomiiant decrem in the intcnsity of the acid chloride band occurred. This IR value

of 2101 cm-' is in good agreement with litrrarure value.

Addition of TEMPO to the reacrion mixture and separrition by chromatography

gave rather unexpected and initiaIly puzzling products. Radial chrornatography nsulted

in three distinct bands. each of which was collecied and analyzed. The first two bands

when analyzed by 'H NMR clearly displaycd aldehydic protons. aromatic protons. and

TEMPO protons. Further speciroscopic mrthods rmplo yed includcd Nb1 R. mass

spectroscopy, IR and numerous 2D NMR techniques. With al1 of this spectroscopie data

md some ihought. it was eventually possible to determine the struciure of the aldehydic

products. It was finally concluded that the three products were piperidinyi o. m. and p-

iormylbenzoates (25). (2@ and (27). based on a cornparison to known spectri of the thrre

isomers of rnethyi f~rm~lbenzoate . '~

The frs t band collected by radial chromatography cleanly separated as the o-

isomer (25) in 9% yield, while the second band was an unseparated mixture of the m and

p isomers (26, 27) in 10% yield in an isomeric ratio of 1 5 . The 'H NMR characteristic

aldehyde hydrogens for the O, m. and p-isomers absorbed at 10.7, 10.105. iind 10.1 17

ppm, respectively.

The third band collected from radial chromatography contained a major product

which proved dirficult to identify, and an unknown product. perhaps an isomer. was also

present. 'H NMR analysis. while displaying many peaks in the olethic rcgion, provided

little structural information as the spectrum was too complex to interpret, Similixly, IR.

13c NMR and 2D NMR did not provide enough information to cont-rn the structure.

Good evidence for formation of a dimer (28) of a monoadduct was afforded by the mass

spectmm. A molecular ion peak was observed at 549 m/,-, the mass for the dimer. while

no peak was observed at 430 d. where the molccular ion for a bisadduct would be

found. Funher, two rather intense periks that would result from the decornposition of the

dimer were observed at 392 ndz which results from loss of one TEMPO from the dimer

and at 274 d. which is the monomeric form of the dimer, Conclusive evidence for

formation of the dimer was found when a cornparison to the known corresponding methyl

ester dimer was made.13 A multiplet at 6 2-0.2.1 was found to be very similar for the

hydrogen atoms attached to the bridging carbons of the dimer.13

The formation of the ring contracted formyl knzoates cm be rationalized &y a

mechanism involving the known tautornerization of cycloheptatriene to norcaradiene-[A

As shown in Scheme 1, radical attrick on the ketene (10) would occur at the carbonyl

carbon generating a seven-electron R system (29). Allylic tearrangement and

recombination of the carbon radical with another equivalent of TEMPO leads to the

bisadduct (30). Tautornerkation of the bisadduct leads to the substituted norcaradiene

(31). Loss of tetrarnethylpiperidinyi radical leads to the formation of the oxygen based

radical which rearrangcs to the aldehyde (32). perhaps in a concened process to provide

the driving force for cleavnge of the N-O band. A subsequcnt hydrogen atarn abstraction

restores arornaticity resulting in pan-formyl benzoate (27). The other isomers would be

produced in a similar fashion.

TO. -

I

CHO

2 7

The dimer is easily formed by combination of (29) with itself. The dimer was not

obtained as a completely pue product, but its structural assignment was unequivocal

based on the compatison of the 'H NMR to that of the corresponding rnethyl ester. It is

believed chat one or more isometic dimers arc prexnt based on the analogy to the methyl

ester, but these were not positively identified due to the complexity of the NMR spectra.

The same procedure utilizing Proton Sponge w u employed for other highly

conjugated ketenes. Vinylketene (11) was generated from the corresponding acid

chloride (33) and Proton Sponge. immediately forrning a deep ydlow solution without

the addition of triethylarnine. A band observrd at 21 18 cm" in the IR speçtrum was

assigned to vinylketene.

Formation of the ketene without the need for a catalyric amount of triethyhmine

stands in contrast for the need of an equivalent of tnethylamine for heptafulvenone

formation. This cm be rationalized by the fact the a-hydrogens of 3-butenoyl chloride

are expecied to be much more acidiç compared to the a-hydrogcn of 1 .33

cycloheptatriene-7-cxbonyl chloride. dur: to the antiaromaticity of the cycloheptatrienyl

anion. In addition, the a-hydrogens of 3-butenoyl chloride are more sterically accessible

for Proton Sponge than the corresponding teniary a-hydrogen of 1.3.5-cycloheptatnene-

7-carbonyl chloride.

After addition of TEMPO to the ketene solution, chromatography gave the

isorneric olefinic bisadducts (E/Z-34) in a combined 49% yield.

The E isomer was easy to identify by its charactcristic olelïnic signals in 'H

NMR. A broad doublet at 6.10 ppm was assigned to the a-hydrogen. while a doublet of

triplets at 6.95 ppm was assigncd [O ihe P-hydrogen. The hydrogcns at the carbon

bearing the TEMPO group were observed as a doublet of doublets at 4.37 ppm. while the

TEMPO protons absorbed as a typical multiplet at 1.0-1.8 ppm. The 'H NMR spectrum

of the minor Z isorner was poorly resolved because the amount of purified Z isomer

obtained was rather srnall. Howcver. a poorly resolved doublet at 5.8 1 ppm corresponded

to the a-hydrogen. while the P-hydrogen absorbed as a multiplet at 6.42 ppm. Similar

sipnals were observed for the hydrogens at the carbon bearing the TEMPO group as well

as the TEMPO hydrogens. The coupling constants for the a-hydrogens of 15.7 and 12.8

Hz for the E and Z isomers respectively, provide additional evidence for the correct

stereochemical assignment.

Sorbyi chloride (18) hris k e n utilized in ptevious syntheses to generate

butadienylketene (12). usine triethylamint: and elevated temperatures. However. it was

found with this procedure using Proton Sponge without hearing that butadienyketene

(12) was not generated in appreciable arnounts.

It was assumed that the terminal rnethyl group of sorbyi chloride was not acidic

enough to gencrate bu tadienylketene (12) under the reac tion conditions uxd. A solution

to this problem w u to isomerizc the double bonds of sorbic acid (35) by treatment with

two equivalents of LDA.'*

The enoliite dianion (36) is generated by proton abstraction from the terminal

methyl group and upon reprotonation, the kinetic product, E-3.5-hexadienoic acid (37) is

obsewed, as the highest negative charge density resides on the a-carbon.

When E-3.5-hexadienoyl chloride (38) was treated with Proton Sponge at -78 OC,

there was formation of a deep ydlow colour and copious amounts of a white precipitate.

A very sharp pedc at 2 1 1 L cm" in the IR spectrum wrts rissigned to butadienylketene (12).

and it was determined that the cataiytic amount of triethylamine was not necessary as the

acid chloride peak at 17% cm" had disappeated. It is interesting to note, however, that

when drops of' triethyhmine were added to the solurion at -78 OC. thew was formîtion of

a brilIiant, but transient red colour. While no evidènce wris gathered to determine the

origin of this red colour, it was suggested that it was due to the zwitterionic species (39)

of triethylamine adding to the ketene.

While it is rare for a teniary amine to add to ii kerzne. it has k e n observed

previously by UV spectroscopy in the addition of pyridine to che ketene (JO), forrning the

zwitterionic species (41 ).16

@ + Q C - q I C-O -

% O

4 0 4 1

Addition of TEMPO to the butadienylketene solution, and chromatographie

separation of the pmducts gave the bisadduct (42). as a yellow solid in 37% yield.

Idenification of the bisadduct was rather facile as four olèfinic peaks were quite

characteristic and the integration proved that rhe ptadienyl radical had been captured ai

the prirnary carbon. Cornparison of the spectra of the bisadduct (42) with those of the

conespondinp 6-hydroxy methyl ester confirmed the structure." A broad doublet a 5.93

ppm was assigned to the a-hydrogen, while a doubler of triplets at 6.14 was assigned to

the Ghydrogen. A multipIct between 6.35-6.50 ppm was asigned to the y-hydrogen and

finally a doublet of doublcts at 7.33 pm was assigned [O the P-hydrogen, Only the EE-

bisaddduct could be purificd and chnracterized, and u no other praks in the crude 'H

NMR were observed, it was thought thrit the EE isomer was the only isomer produced in

detectable amounts.

Tb, II TQ-C,OT

Allenyketene (13) wris generated and obscrved in the same fashion t'rom the

corresponding acid chloride (43). Allenylketene w u identified by the IR band at 2 127

cm-', while a characteristic ailene streich was seen at 1955 cm-'. However. it was

impossible to discern whether the peak at 1955 cm-' was dur to dlenyketene or residual

acid chloride. Upon addition of TEMPO, chromritography resulted in the two isorneric

bisaddducts (EU-44). formed by trapping of the radical at the vinylic position.

9 * 4' // //

The E isorner, isolated as colourless crystals in 60% yield, was rather easy to

identify. The terminal olefinic protons absorb quite differently at 4.54 and 5.23 ppm, but

with 'H NMR the assignrnent of which hydrogen is cis or trans to the vinylic TEMPO

group was not made. Assignment of the a and B hydrogens was rather simple as they

both absorbed as doublets, at 6.20 and 7.02 ppm. respectiveIy. The Z isomer, which was

present in much smallcr quantities, was isolated as an orange oil in 3% yield. A sirnilx

'H NMR spectrum was =en as the terminal olefinic hydrogèns absorbed at 4.75 and 5.22

ppm. while the a and B hydrogcns both absorbcd as doublets. at 5.22 and 5.86 ppm.

respectively. The coupling conslanîs t'or lhe a-hydrogens of the E and Z isomers. 14.8

and 12.4 Hz respectively, prove that the correct stereochcmical assignment was made.

The 'H chernical shifts of the E and Z isomers are rather different. but the 2.3-

pentadienoote structure of both is confmed by ihc "C and IR spectra.

Finally, the highly conjugated bisketene (14) was gcncratcd from the

corresponding acid çhloride (45) and Proton Sponge. Upon treating E-3- hèxendio y1

chloride with Proton Sponge at O OC, a decp orange solution was observed and upon IR

analysis a band at 21 17 cm*' was observed and assigned to the bisketene (II).

This novel bisketene had never been observed previously and so was first trapped

with methanol forming the dimethyl ester (46). The dester was characterized by

comparing it to known literature spectra.18

MeOH &'",ir/,K OMe

O// O

Formation of (46) by methanol reaction with the acid chloride giving the diester.

is excluded, as formation of the ketenr: is rapid and it was observed by IR prior to the

addition of methanol.

Bisketene (14) was ako uapped with TEMPO and after chrornatography resulted

in the rather unusual isomenc bisadducts (EEIEZ-43). formed by a, oaddition. O

Addition of one molecule of TEMPO to one end of the bisketene leads to the

carbon radical (47a). for which a resonance structure can be drawn (47b). Capture of the

delocalized radical by a second equivalent of TEMPO pives the bisadduct (EEIEZ-48).

While aoaddi t ion to a bisketenc is unusual it is not without preccdent. as it has k e n

observed in the addition of Br;! to a bisketene.19

Chromatography resulted in a mixture of the EE and EZ isorners in a 9:I ratio

with a combined yield of 378. The EZ isorner was never isolated but was characterized

as a mixture with the EE isomer. The EE was obtained in pure form by recrystallization

from methanol. 'H NMR provided conclusive evidence that the bisadduct, rather than the

tetra(adduct) had formed based on the peak integmtions. The EE isorner was rather easy

to identify as the symmetrical molecule had onIy two olefinic peaks. The a-hydrogen

was assigned as a doublet at 6.26 ppm, while the p-hydrogen was assigned to a multiplet

between 7.3-7.5 ppm. The EZ isomer proved to be more difficult to identify because of

the small quantities present in the sample, A broad doublet at 6.15 ppm was assigned to

the a-hydrogen of the E okfin. while the a-hydrogen of the Z olefin appeared as a broad

doublet at 6.30 ppm. The P-hydrogen of the Z oletin absorbed at 6.69 pprn. while a

doublet of doublets at 8.44 ppm was attnbuted to the B-hydrogen of the E olefin.

Coupiing constants of the EZ isomer aided in the stereochemical assignment. Values of

15.9 and 10.4 Hz for the a-hydrogens of the E and Z olefins respectively, are consistent

with the fact that trans isomers result in larger coupling constants.

While it could be speculated that the ketene band at 21 18 cm-' in the IR spectrum

is due to the monoketene (49). this is excluded by the results of TEMPO addition to the

bisketene. Formation of the bisTEMP0 diester as obsemed in the reaction could only be

generated by a meçhanism in which there is presencc of the bisketene. The awaddition

proves that the bisketene is in fact produced in the course of the reaction.

4 9

Generating ketenes with Leckta's procedure provides a new method to produce

ketenes in high yieids without dimenation, Due to the high versatility of ketenes in

cycloadditions and their imponance to the pharmaccutical sciences, this proves to be an

important step. In this work. it ha been shown that this procedure can be applied to

highly conjugated ketenes. In future work these conjugated ketenes could be employed

in the synthesis of P-lactams,6 as weU as in ceactions with other enophiles. and with

various electrophiles and nucleophiles.

EXPERIMENTAL

All glassware was oven-dried (140 OC) overnight while ail plastic equipment and

microlitre syringes were kept in a desiccator filled with ca1cium sulphate. Al1 ketene

reactions were carried out under an atrnosphcre of argon or nitrogen. Ether and toluene

were distilled €rom Naknzophenone just prior to use. Dichloromcthane, pentane and

2.2.4-tnmethylpen~ant: wcre d l stored over 4A molecular sieves. Deuterated chloroform

was kept over potassium carbonate. All other solvents and reagents were not subjected to

further purification. Radial chromatography was pcrtormed on a Harrison Research

Chromatotron. mode1 7924. with plates made from Merck TLC grade 7749 silica gel

containing gypsum binder and tluorescent indicator, Bands were detected with a short

wave UV lamp or e k checked by 'H NMR. Thin layer chromatography was pcrformcd

on TLC plates pu rchad from Aldrich and bands checked by UV. iodine stain or p-

l anisaldehyde stain. H NMR spectra were obtained at 200 MHz (Varian Gemini). 300

MHz (Varian Gemini or Mercury) and 400 MHz (Varian Unity), using solvent residue as

internal reference (7.26 ppm h m TMS in chloroform). "C NMR spectra were obtained

at 100 MHz (Varian Unity) or 125 MHz. using solvent residue as internal reference (77.0

ppm from TMS for chloroform). IR spectra were obtained on a Perkin-Elmer Fi'-IR

Spectrum 1000 spectrometer. Ultraviolet spectra and kinetic data were obtained on a

Perkin-Elmer UVNis Spectromcter Lambda 12. Dr. Alex Young. using either electron

impact or fast atom bombardment as the ionization method. ran mass spectra,

Starting Materials

To a stirring solution of benzene (10 ml) and rhodium tri!Iuoroacetate dimer (13

mg, 0.02 mrnoi) was added dropwisè by syringc: rthyl diazoacetate (0.624 g. 5.5

rnmol) over ri period of two hours. Afier confirmation of tht: absence or ri diuo

signal by IR, the knzene was removed by water aspirator and the residue

subjected to Kugelrohr distillation yiclding a clear oil as the desired ester (0.830g.

5.4 mmol. 92%).

l$$-Cycloheptatriene-7-carbonyl chloride"

A solution of ethyl 1.3.5-cycIoheptatriene-7-carboxylate (1 .O g. 6.7 mmol) in 8 ml

of methano1 was added to ii solution of NaHC03 (0.80 g, 9.5 mmol) in 10 ml of

water. The solution was refluxed for 2 hours and then poured into water (30 ml).

ï h e basic solution was washed with pentue (2 x 25 ml) to remove unreacted

ester, acidified (pH=l) with 304 HzS04 and extracted with diethyl ether (3 x 25

ml). The ether layer was dried river magnesium sulphatc. the ether removed

under reduced pressure and the residue subjected to Kugelrohr distillation

afîording the acid as pure crystals (0.59 g, 4.3 mmol. 64%). The x i d chloride

was synthesized in the same fashion as in Chnpter 1.

1 ) 2 LDA ___)

3 8

To 10 ml of frcshly distilled THF and 15 ml of 2M LDA (30 mmol) was added

dropwise by syrirtge a 1.8M solution of sorbic acid (35) (1.0 g. 8.9 mmol) in dry

THF at -10°C. The dxk brown soluiion irnmediately forms a white prccipitate

and gradually tums orange. The white precipitate begins to dissolve as the

waction is warmed to room temperature and left to stir for one hour. A reflux

condenser is attached to the flask as 20 ml of 3M HC1 is added to quench the

reaction. The reaction is worked up with chree 30 ml portions of ether, one brine

wash and dried over magnesium sulphate to yield a yellow oil as the carboxylic

acid (0.85 g, 7.6 mmol. 85%). The acid chloride was synthesized in the same

fashion as in Chapter 1.

A solution of 3-butyn-1-01 (4.0 g, 0.057 mol). diisopropylamine (23.9 g. 0.25

mol) and paraformaldehyde (4.5 g, 0.15 mol) were stirred in 120 ml of dry THE

Cuprous iodide (5.6 g. 0.03 mol) was then added in small portions turning the

solution a bright green. The stirring solution was thcn brought to reflux and

allowed to stir overnight. The brown solution was allowed to warm to room

temperature, filtered through cclite and concentrated in vacuo. The residue was

diluted with 40 ml of watcr and 50 ml of diethyl ether then aciditkd with 3M

HCl. The solution wu filtered to remove precipitate and the aqueous layer

extracted with four 25 ml portions of ether. The combined organic layers were

washed with 25 ml of water and 50 ml of a saturated sait solution, dried over

MgSOJ and concentrated under vacuum, yielding the ailenic alcohol (2.5 g, 0.03

mol) as a clear liquid.

3,4Pentadienoic Acid

A solution of 3.4-pcntadièn-1-01 (1.4 g, 0.017 mol) in 100 ml of rcrigent grade

acetone was placed in a round bottom flask and immersed in an ice-salt bath at

-10 O C . An addition funnel was charged with 10 ml of Jones rèrigenc which was

added dropwise ovcr 30 minutes. The solution was allowed to stir t'or an

additional 90 minutes at this temperature before warming to roorn temperature.

Isopropanol was added to quench any unreacred Jones reagent. The mixture wris

ixtered and the green solution was concentrated in vacuo. The residue w u

diluted with 100 ml of water and extracted with thrw 50 ml portions of ether.

The combined organic layers were dried over MpSOJ and concentrated with a

rotary evaporator. Kugeirohr distillation yielded the pure acid as a yellow liquid

( 1.2 g, 0.0 12 mol). The acid chlondè was then synthesized in a sirnilar tàshion as

Ln Chapter 1.

Ceneration of heptafulvenone (10) and trapping with TEMPO

1.3.5-Cyclohcptatriene-7-cubonyl chloride (23) (78.5 mg, 0.51 mmol) and 1.8-

bis(dimethylamino)naphthalene (9) (120 mg, 0.56 mmol) were sthed in 3 ml of

dry toluene at 0°C for 30 minutes, gradualiy tuming the solution a pale yellow

with a srnall amount of white precipitate. A cataiytic amount of triethylamine

(0.0029 mg. 0.029 mmol) was t k n added to the solution immediately tuming it

red, at which point TEMPO (800 mg. 5.12 mmol) was added and the solution

allowed to stir for 18 hours. After filterhg through celite and removal of solvent.

excess TEMPO was sublimed off by Kugekohr distillation. The residue was then

subjected to radial chromatopaphy (10% EtOAdHex) elutinp first the O-formyl

benzoate (25) (13.4 mg, 0.046 mmoI, 98). second a mixture of m,p-formyl

benzoates (26,27) (14.9 mg, 0.051 mmol, 10%) in a 15 ratio and finally a mixture

of isomeric dimcrs (28) (34 mg. 0.062 mmol. 24%) which could not bt. assigned

individual structures.

N-piperidinyl O-Formyl benzoate: 'H NMR (CDCb) 6 1.21 (S. 6H. 2CH3). 1.30

(S. 6H. 2CH3). 1.4-1.8 (m. 6H. TEMPO-ring), 7.69-7.72 (m, 2H. Ar). 7.99-8.04

{m. 2H. Ar). 10.7 (S. 1H. C m ) . I3c NMR (CDC13) 6 17.2.20.9. 32.1, 38.5. 60.9.

128.4 (Ar), 129.8 (Ar), 132.4 (Ar). 133.5 (Ar). 137.5 (Ar), 166.2 (COIT ). 192.0

EHO). IR (CDCl3) 1741.9 cm-' (C=O stretch), 1697.4 cm-' (HC=O stretch).

EIMS d z 290 (MHt, 0.1). 274 (MH'-O. 2). 156 (TO, 100). 133 (M'-TO, 5 1).

HREIMS nd: calcd for Ci7HwN03 290.1756, found 290.1762.

N-piperidinyl m-Formyl benzoate: 'H NMR (CDC13) 6 1.13 (S. 6H, 2CH3). 1 .?Y

(S. 6H. 2CH3), 1.4-1.9 (m. 6H, TEMPO-ring), 7.61-7.78 (dd. IH. Ar). 8. 10-8.12

(dm. IH. Ar), 8.31-8.35 (dm, 1H. Ar). 8.54 (m. 1H. Ar), 10.1 (S. 1H. C m ) . 13c

NMR (CDCI3) 6 17.2. 21.1. 32.2. 39.4, 60.9, 129.5 (Ar), 131.5 (Ar). 133.3 (Ar),

135.4 (Ar), 165.6 (ÇO-T), 191.6 (CHO). IR (CDC13) 1744.8 cm-' (C=O stretch).

1705.7 cm" (HC=O stretch). EIMS nt/= 290 (MH'. 6). 289 (M'. 3). 274 (MH'-O,

84). 156 (TO. 39). 133 (Mt-TO. 100). HREIMS m k calcd for C17H3N03

289.1678, found 289.1680.

1 N-piperidinul p-Forrnyl benzoare: H NMR (CDC13) 6 1.13 (S. 6H. 2CH3). 1.29

(S. 6H, 2CH3). 1.4-1.9 (m. 6H. TEMPO-ring), 7.96-7.99 (dm, 2H. Ar), 8.21-

8.24 (dm. 2H. Ar), 10.1 (S. 1H. Cm). I3c NMR (CDCI!) 6 17.2, 21.1. 32.3.

39.4.60.9, 129.9 (Ar), 130.4 (Ar), 135.1 (Ar), 139.4 (Ar). 165.7 (C02T ). 191.9

(ÇHO). IR (CDC13) 1744.8 cm-' (C=O stretch). 1705.7 cm-' (HC=O stretch).

EIMS d; 290 (MH', 6), 289 (M', 3). 274 (MH'-O. 84). 156 (TO. 39). 133 (M*-

TO, 100). HREIMS d. calcd for C17H3N03 289.1678, found 289.1680. (IR and

MS taken as a mixture of both isomers)

Dimers: 'H NMR (CDC13) 6 1.0-1.3 (m. 24H. 8CH3). 1.4-1.8 (m. 12H. TEMPO-

ring), 2.0-2.16 (m. 2H). 5.3-5.4 (m). 5.55-5.65 (m). 6.3-6.4 (m), 6.8-6.9 (m), 7.25-

7.35 (m), 7.8 (d). "C NMR (CDC1,) 6 14.4. 17.1, 20.9. 21.1. 21.1. 32.9. 25.5,

31.8.32.1.32-3, 39.3, 32.0,42.1, 42.2,60.5.60.6,60.6, 77.5. 124.6, 124.8, 124.8.

124.9. 125.9, 126.0. 127.3. 127.4, 127.5. 127.6. 128.7. 128.8, 128.9, 129.2, 129.2,

129.3. 129.4, I30.2. 130.2, 131.9. 132.0. 132.3, 132.4, 132.4, 132.5. 132.8. 132.8,

137.1. 137.3. 166.5. 166.6. 167 S. IR (CDCI,) 1734.9 cm*' ( C S strctch). EIMS

mk 549 (MU', 0.2). 392 (M*-TO 5). 274 (dimerl2. 27). 156 (TO. 25). 140 (T.

100). HREIMS d: calcd for C34b9Nz04 549.3692. found 549.3690.

Generation of vinylketene (11) and trapping with TEMPO

3-Butenoyl chloride (33) (69.0 mg. 0.66 mmo1) and 1.8-

bis(dimethy1amino)naphthaiene (9) (158.0 mg, 0.74 mmol) were added to 3 ml of

dry toluene at OOC immediately tuming the solution a dark orange. To this

solution TEMPO (261.5 mg, 1.7 rnmol) was added and allowed to stir t'or 20

hours. The solution was filtered through celite. solvent evaporated and the

residue su bjected to radial chromatography ( 108 EtOAc in Hex) yielding the first

the cis bisadduct (2-34) as a colourless oil (12.0 mg. 0.032 mrnol, 5%) and then

the trans bisadduct (En34 (109.9 mg. 0.29 rnmol. 44%) as pale white needles (mp

110-1 1 1 OC).

E-isomer: 'H NMR (CDCI,) S 1.M (S. 6H, 2CH3), 1.13 (S . 12H. C H I ) , 1.17 ( S .

6H. 2CH3). 1.2-1.8 (m. 12H. TEMPO-ring). 4.47 (dd, 2H. J = N . 2.1Hz.

TOC&), 6.10 (bd, IH, k15.7Hz. C=a-C&T), 6.95 (dt, 1H. J=15.9. 3.8Hz.

TOCH2C&). 13c NMR (CDCI3) 6 17.0, 17.1. 20.2. 20.6, 3 1.9. 32.9, 39.1. 39.7.

60.0. 60.2, 75.9 (TO-CH2), 118.8 (C4-C02T). 134.3 (TOCH2-C=C), - 166.6

(COLT ). IR (CDCI,) 1732.3 cm-' ( C S stretch), 1657.6 cm" (C=C stretch).

EIMS d~ 380 (M', 0.01). 240 (W-T. 1). 224 (M+-TO, 1). 156 (TO. 100).

HREIMS d: calcd for C2t&lNZ03 38 l.3L 17. found 38 1.3 113.

Z-isomcr: 'H NMR (CDC13) 6 1.0- 1.2 (m. 24H. CH3), 1.2-1.8 (m. 12H.

TEMPO-ring), 4.89 (dd. 2H, J=6.8, 3.2Hz. TOCFI-), 5.8 1 (bd. lH, J=12.8Hz.

C = a - C a T ) . 6.47 (m. 1 H. T O C H a = ) . I3c NMR (CDQ) 6 17.9. 17.4. 20.3,

20.9, 21.1, 29.9, 32.1, 33.3, 39.3, 39.8, 39.9. 59.8, 60.1, 60.3. 76.3 00-CH2),

117.4 (C=Ç-C02T). 147.9 (TOCH2-ÇK), 167.6 (CqT ). IR (CDCI,) 1741.1

cm" (C=O stretch), EIMS d z 381 (MH', 0.1). 224 (M'-TO, 1). 156 (TO, LOO),

140 (T, 58). HREIMS d z calcd for CZZ&lN203 381.31 17. found 38 l.3109.

Generation of 1,3,5-hexatnenone (12) and trapping with TEMPO

E-3.5-Hexadienoyl chloride (38) (30.4 mg. 0.23 mmol) and 1.8-

bis(dimethylamino)naphthalene (9) (57.4 mg, 0.29 mmol) wère added to 1 ml of

dry toluene at O*C . A k r s i i ing for 30 minutes the solutian turned a pale orange

with a white precipitnte at the bottom. To this solution TEMPO ( 1 11.1 mg, 0.71

mmol) was added and the solution allowed to stir for 16 hours. Thc solution was

filtered through celite. solvent evriporated and the midue subjected to radiai

chromatography (10% EiOAc in Hex) yielding the bisadduct (EE-34) (44.2 mg,

0.1 1 mmol, 47%) as a paie yellow soiid (mp 114-1 17 OC).

'H NMR (CDC13) 8 1.06 (S. 6H, 2CH3), 1.12 (S. 6H. 2CH3), 1-15 (S. 6H, 2CH3).

1.17 (S. 6H. 2CH3). 1.3- 1.8 (m. 12H. TEMPO-ring). 4-41 (m. 2H. TOC&), 5.93

(d. lH, J=lS.OHz, CSH-Cal ' ) , 6.14 (di, 1H. J=15.0. 4,IHz. TOCH2CH=).

6.35-6.50 (rn, 1H. TOCH2CH=CH), 7.34 (dd, IH, J=lS.O. 4.1Hz. HC=CH-

C02T). I3c NMR (CDCld G 17.2, 17.3. 20.4, 20.8, 32.1, 33.1, 39.2, 39.8. 60.1,

60-3.77.0 (TO-ÇH2). 119.7 ( C s - C m , 128.4 (TOCHTC=ç), 138.7 (TOCH2-

c=C). 144.8 (C=C-Con, 167.3 tç02T ). IR (CDC13) 1730.0 cm-' (C=O

stretch), 1643.8 cm-'. 1627.0 cm-'. EMS d z 407 (MH*, l), 251 (MH'-TO, 2),

156 (TO, LM)). 140 (T, 35). HREIMS nd: calcd for Cub3N203 407.3274. tound

407.3287.

Generation of allenylketene (13) and trapping with TEMPO

E/Z- 4 4

3.4-Pcntadienoyl chloride (43) (59.8 mg, 0.52 mmol). TEMPO (804.6 mg, 5.16

mmol). 1.8-bis(dimethyIamino)naphtha1cne (9) (134.3 mg. 0.63 mmol) and

tricthylamine (5.0 mg, 0.049 mmol) were stirred in 5 ml of dry toluene at 0°C.

The solution was allowed to warm slowly to room temperature and stirrinp was

continued for 16 hours. After filtering through celite and removal of solvent.

excess TEMPO was sublimed off by Kugelrohr distillation. The residut: was then

was cluted through a plue of silica gel to remove unreacted proton sponge, the

solution evaporated and this residue was subjected to radial chromatography (5%

EtOAcMex) eluting first the cis isomer (2-44) (5.6 mg, 0.014 mmol, 38) as an

orange oil. and second the trans isomer (E-44) (121.8 mg, 0.31 mmol, 60%) as

colourless crystals (mp 168- 170 OC).

E-isomer: 'H NMR (CDCld 8 1.03 (S. 6H. 2CH3). 1.08 (s, 6H, ?CH3), 1.20 (S.

12H. 4CH3). 1.36- 1.8 (m. 12H. TEMPO-ring) 4.54 (S. lH, bC=C), 5.24 (S. 1 H.

&CS) , 6.20 (d, IH, kL4.8Hz HC-C02T), 7.02 (d, 1H. J=16.5H~.

HCSHC02T). I3c NMR (CDCI3) 6 16.9, 20.6, 20.7. 3 1.9. 32.2. 39.0, 39.6, - 60.2, 60.5. 98.6 (H&=C), 115.8 (HC=CHC&T). 139.2 (HC=C(OT). 159.1

(HC=CHCO2T), 167.1 W 2 T ). IR (CH2CIz) 1731.8 cm-' (C=O stretch). 1636.9

cm*' (C=C stretch), 1596.9 cm-' (C=C stretch). EIMS DI/: 392 (M', 6). 236 (M'-

TO. 28). 156 (TO, 341, 140 (T, IO). HREIMS ni: calcd for C23h0N203

392.3039, found 392.3033.

2-isomec 'H NMR (CDC13) 6 0.9-1.8 (m. 36H. TEMPO), 3.75 (s, 1H. H2C=C).

5.22 (S. IH. H2C=C). 5.86 (d. LH. J=l2.4Hz. HC-CO-). 6.20 (d. lH, kl3.2Hz.

HC=CHC02T). 13c NMR (CDC13) 6 17.2, 17.3. 20.8. 2 1.0, 32.3. 32.6. 39.3. - 40.1.60.3. 60.6.95.6 (H,C=C). 1 18.6 (HC=CHCOtT), 135.9 (HC=C(OT). 159.3

(HC=ÇHC02T). IR (CH$&) 1750.4 cm-' (C=O stretch). 1634.9 cm" (C=C

stretch), 1590.0 cm-' (C=C strerch). ElMS ndc 392 (MH', 0.5). 236 (M'-TO, 3,

156 (TO. 28). 140 (T, 100). HREIMS m/= calcd t'or C23&1N203 393.3 1 17, t'ound

393.3 103.

Generation of E-l,6-dioxo-l,3,5-hexatriene (14) and trapping with methanol

E-3-Hexadienoyl chloride (45) (42.4 mg. 0.24 mmol) and 1,s-

bis(dimethylamino)naprhalene (9) (161.2 mg. 0.75 mmol) were xided to 2rnl of

dry toluene at O OC immediately turning the solution orange. Triethylaminz ( 14.5

mg, 0.14 mmol) was then added formine a brown precipitate. The soiurion was

allowrd ta stir for 5min kfore the addition of 1.5 ml of anhydrous merhanol. The

solution wris allowed to warm slowly ro room temperature and stirring was

dowcd to continue for 2 hours. Aftsr filtering through d i t e and evriporation of

the solvent, the rcsidul: was extracred Crom 1N HCI (3 ml) with dierhyl ether

(2x5ml). After drying of the ether lriyer with MgS04. the ether wu waporated

and the residue suhjzcted CO Kugclrohr distillation yit'lding the dièster (46) as a

colourless oil(35 mg, 0.20 mmol. 8 19).

'H NMR ICDCII) 6 3.09-3.1 1 (m. 4H, Cb). 3.68 (S. 6H. XI&, 5.67-5.74 (m.

2H. CH).

Ceneration of E-1,6-diox~1,3,5-hexatriene (14) and trapping with TEMPO

E-3-Hexadienoyl chloride ( 5 (33.7 mg. 0.19 mmol), 1.8-

bis(dimethy1amino)napthaIene (9) (122.5 mg. 0.57 mmol) and TEMPO (419.5

mg, 2.69 mmol) were added to 2ml of dry toluene at O OC. Triethylamine (2.2 mg,

0.022 mmol) was then added Corming a brown precipitate. The solution was

allowed to warm slowly to room temperature and stirring was allowed to continue

for 18 hours. After filtering through celitr, the solvent was evaporitèd, and the

residue was subjcctcd to Kugelrohr distillation to remove cxcess TEMPO. Radial

chromatography (10% EtOAcIHex) affordcd the bis(TEMP0) adducts as a

mixture of EE and EZ isorncrs (EEIEZ-48) (28.4 mg, 0.068 mmol. 36%) in a 911

ratio which upon recrystaIlization from MeOH yielded the EE isomer (EE-48) as

a white solid (mp 218-221 OC).

EE-isomer: 'H NMR (CDCI3) 6 1.06 (S. 12H. 4CH3). 1.18 (S. 12H. 4CH3). 1.4-

1.8 (m. 12H). 6.27 (M. 2H. I=12.OHz. T02CCH=CH). 7.35-7.50 (m. 2H.

T q C C H = a ) . I3c NMR (CDC13) 6 16.7. 20.4. 31.7. 38.8. 60.1. 126.9. 141.1.

165.99 IR (CDC13) 1736.9 cm-' ( C a strerch). 161 1.9 cm" ( C S stretch), EIMS

d: 421 (MH', 5). 405 (M'-CH3. 15). 156 (TO. 100). 140 (T, 92). HREIMS dz

calcd for C z ~ t t ~ N ~ O j 421.3M6. found 421.3066.

1 EZ-isomer: H NMR (CDCI3) 8 1.M (S. 12H. 4CE3), 1.18 (S. 12H. 3C&), 1.4-

1.8 (m. EH), 6.03 (bd. 1H. J=10.4Hz, T&CCH=CH(Z)), 6.15 (bd, IH, 1=15.9

HZ, TOiCCH=CH(E)), 6.69 (t. lH, . k11.4Hz. T02CCH=CE(Z}). 8-44 (dd.

1H. J=13.9, 12.4Hz. T&CCH=m[E]). 'Ic NMR (CDC13) 6 20.5. 31.1. 37.9.

59.3. 128.0. 138.4. 166.0 IR (CDC13) 1736.9 cm" (C=O stretch). 1611.9 cm-'

(C=C stretch). EIMS d z 421 (MH'. 5). 405 (M+-CH3.15). 156 (TO. 100), 140

(T. 92). HREIMS ndz calcd for Cl4hlN2O4 421.3046, found 421.3066. (IR and

MS taken as a mixture of EE and EZ)

REFERENCES 1) Brady, W.T. The Chenrisr- of Kerenes, Allrnes and Relared Compounds.

John Wiley and Sons, Toronto: 1980. pp 279.

2 ) Tidwell, T.T. Ketenes. John Wiley and Sons, New York: 1995.

3) Palorno, C.; Aizpunia. J.M.; Ganboa, 1.; Oiarbide, M. Errr. J. Org. Chern.

1999,3223.

4) Gunda. T.E.; Sztaricskai. F. Tetrahedron. 1997.53.7985.

5 ) Podlcch, J.; Li~dcr. M.R. J. Org. Chem. 1997.62.5873.

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J. Am Chem Soc. 2000, 122.783 1.

7) a) Bose, A.K.; Spiegelman, G.; Manhas, M.S. Tetrahedron Lett. 1971.3167.

b) Zamboni. R.; Just. G. Can J. Chem. 1979.57, 1945.

8) Manhas, M.S.; Ghosh, M.; Bose, AK. J. Org. Chem. 1Y90,55, 575.

9) a) Sharma. AK.; Mazumdar. SN.; Mahajan, M.P. J. Org. Chem. 1996.61,

5506.

b) Sharma, A.K.; Jayakumar. S.; Mahajan. M.P. Tetrahedron Leu. 1998,7205.

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1984, L 17.809.

14) Lowry, T.H.; Richardson, K.S. Mechanism and Theoq in Organic Chemistry:

3& Edirian. Harper and Row. New York: 1987. pp 907.

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16) Barra, M.; Fisher. T A ; Cernigliaro. G.J.; Sinta. R.; Scaiano, T.C.

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19) Brown, R.S.; Christl. M.; Lough, AJ.; Ma. J.; Petcrs, E.M.; Peters. K.;

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APPENDIX A

SELECTED IR OF OBSEVRED KETEIWS

APPENDIX B

SELECED 'H IWIR OF ISOLATED COMPOWDS

APPENDIX C

SELECTED "C NMR OF ISOLATED COMPOLNTIS

TO- 2.

APPENDIX D

SELECTED 2D NMR OF ISOLATED COMPOLWDS

PULSE S I Q M N C 8 t p11SQC

I a l u . d e l a y 1 . 0 0 0 mmo Acq . t l m o O . 1 0 0 i s c width s 4 6 0 . 0 A r

I D ~ l d t h 2 1 3 6 7 . 5 Rz a r s p m t l t î o n i I % 2 5 6 i n c r n m s n t r

ObBBRV8 RI. 4 9 9 . l b 6 1 7 6 0 M x

DIS COUP^.^ ~ 1 3 , 12s . 6 9 5 0 4 1 6 nn+ P o w i r 30 dB on durina ncqulrltlon off during dslay W 4 O - V r r l a n P M l w a d u l o t s d UATA PROC1188INO

Orumi rpodlratlon 0 . 0 8 7 i m c rl DATA PROC8GBIm

O a u i r a ~ e d î r a t i o n 0 . 0 1 1 m s c F l ' m i r a 30a8 n l O 4 E T o t a l t i m a 1 h ~ , 27 m i n , 4 imc

nlkr lrenwlck U r 1 dl273

No* 15 2000

PULBB ENQUBNClti TOCBY

nslar. delmy 1.000 m i a

iilninu 0 . 0 2 5 nec AC^. tims O.18fi ime W l d t h 5460.0 Ri a b width 5466.7 Ar 1 repatltioni 1 r 356 lnarmsnti

OBBERVR ni . 4 9 9 . 8 4 6 2 1 6 0 DATI PROCESSXWO

Qauim rpoditition 0 .087 8œc

Fi DATA FROCKSSIHO t h u m r rpodiiitiun 0.016 mie

* rr aIss 201b >( 2041 Total tlma 4 1 mln. 24 mec

p y t S 8 BIIQMNCBi CIOAR n ~ l u . delsy 1.000 mec ACQ. t h e 0.188 mec WLdth 5460.0 Ar ID Wldth 30165.9 AS 32 re~etltlonw 511 lncrementm

oI)BSRM Al, 499~8462760 DATA VROC.BSINO #p. rine bel1 0.094 wac

Il DRTA PllOCIIBSIW Sine bel1 0.008 smc

CT slxs 2048 x 4096 a Total trime 6 hr, 7 min, 46 mec

solvrnti CDC13 Temp. 25.0 C 1 790.1 K

UNITY-500 wultra500*

PULSE SBQUUNCBr 9COSY Relax. delry 1.000 mec Acq. tirne 0.138 mec Wldth 3703.7 Hr

ID Width 3705.4 H X

Slnple mcan PS6 lncrements

ODBBRVE HI, 499. maa~760 ml2 DATA PROCEBBINO sine bel1 0.069 sec

fL DATA PROCKBSXNO

Bq. alne bel1 0.034 sec rr .Ica PO48 x IO48 Total time 5 mln, 12 mec

nlke rnnwlck HF1 62785 Nov 27 1000

PULSE 6EQUBHCEi C I Q A R ~ ~ ~ ~

n e f u . dblay 1.000 i a c

Acq. tlme 0.138 sec ,

Width 3703.7 Hz 2D Width 30165.9 Hz 16 rapetit iona 512 incramsnts

08s~nwI Hl. 199.8462160 Hffr D I T A PROCEBSINO gins bell 0.069 mec

Fl DATA PROCIESSIHO

s i n o bell 0.017 sec FT dte 1011 x roPi

a Total t l m m 2 hr, 57 m i n , 30 roc

( '

APPENDIX E

SELECTED MASS SPECTRA OF ISOL.4TED COSIPOUNDS