Studies Directed Towards the Synthesis of Novel Naturally Occurring Alkaloids

i l STUDIES DIRECTED TOWARDS THE SYNTHESIS

NOVEL NATURALLY OCCURRING ALKALOIDS

I .tI

I I

i A THESIS I i PRESENTED FOR THE DEGREE OF

I ,I DOCTOR OF PHILOSOPHY

i L

THE UNIVERSITY OF ADELAIDE

fi,.7,,.¡¿,¡p{<-./ iç ' 'l - ¡Î :'

BRUNO KASUM, B,Sc.

DepRRrmeNT oF OnsRtruc CHEmISTRy 1984 CONTENTS

Page

SUMMARY (i)

STATEMENT (Íii)

ACKN0I¡ILEDGEMENTS (iv)

CHAPTER 1 A CLASSICAL APPROACH TO THE SYNTHESIS OF PERLOLINE

I NTRODUCTION I

DISCUSS ION 7

1.1 Synthesis of the Diphenyìamine Synthon (4) 7 1.1.1 Reamangement of 3-Al kyl -3-aryl -L-(2' o carboxyphenyl ) tri azenes J 1.1.2 Reanrangement of a,N-Diphenylnitrones t4 7.2 Synthesis of the 4-bromo-2-oxo-1,2-

di hydropyri di ne-3-carboxy] i c aci d synthon ( 5) 23

CHAPTER 2

2.L Attempts to form the Tertiary Amide (a2) 31 2.2 Metallation of Diphenyìamine (4) and reaction with Ethyl 3-chloro-2-cyanobut-2-enoate (34) 36 2.3 Alternative Routes to Dehydroperloline from

2- ( 3 ,4-Dimethoxypheny'l ami no ) acetophenone 43

CHAPTER 3 SYNTHETIC ROUTES TO A NOVEL MARINE SPONGE ALKALOID INTRODUCTION 47

DISCUSSION 55 Page

3.1 Approaches from Hagemann's Ester 55 ac A Procedure from 2-Nitrodimedone 60

3.3 Routes based on the Cyclisation of Intermediates derived from 5,S-Dimethyl -3-

( 2-dimethyì ami noethenyl ) -2-cycl ohexen-1-

one (47) 63

CHAPTER 4 4.L Synthesis of the 7.0x0-4,5,6,7-tetrahydroindole

precursor and Attempted Ring Expansion 7T

4.2 An Alternative Route from 2,3-Epoxy-3-

methyl cyc'l ohexanone oxime 88 4.3 A Final Approach from 4-Methyl-Z,5,6,7-

tetrahydro-lH-azepi n-2-one ( 13) 92 4.4 Synthesis of the Pyrro'loazepindione precursor

(3) from 3-N-(2-pyrrolylcarbonyl )amino-

propanoic Acid (17) 96

CHAPTER 5 EXPERIMENTAL 702

5.1 l'lork described in Chapter I 105

5.2 l^lork described in Chapter 2 I23

5.3 l^lork described in Chapter 3 L42

5.4 l¡Jork described in Chapter 4 151

REFERENCES 18t

PUBL I CATIONS 198 (i )

SUMMARY

Chapters I and 2 describe a convergent approach to the synthesis of dehydroperloìine, a precursor of the naturalìy occurring alkaloid perloline. Chapter 1 deals with the preparation

of N-(2-bromophenyì ) (3,4-djmethoxyphenyl )amine and 4-methoxy- 2-oxo-1,2-dihydropyridine-3-carbox_v'l ic acid. The diphenyla¡nine was prepared by thermal rearrangement of N-(2-bromophenyì)-2- (3,4-dimethoxyphenyì )oxaziridine derived from the appropriate nitrone. The synthesis of various 4-substituted-2-oxo-I,2- dihydropyridine-3-carboxy'lic acids in high yields from 3-halo or alkoxy-2-cyanobut-2-enoates is also described.

Chapter 2 deals wjth various uirsuccessful attempts at

coupling the above two synthons by formation of a tertiary amide. The bulkiness of the diphenyìamine apparent'ly precluded the synthesis of the required arnide. This chapter also includes the reaction of the dilithiated diphenylamine vrith ethyl 3-chloro-2- cyanobut-2-enoate. The final ring closure to form the tertiary amide could not be accompìished. An alternative unsuccessful

strategy based on the Knoevenagel reaction of ethyl cyanoacetate with 2-(3,4-dimethoxyphenyiamino)acetophenone is aìso discussed. (ii)

Chapters 3 and 4 describe synthetic routes to a novel marine sponge alkaloid containing a fused pyrrote-azepinone ring system linked to a glycocyamidine moiety. chapter 3 discusses a variety of approaches to one precursor from substituted methylcyclohexenones such as isophorone and Hagemann's ester. Although unsuccessful these approaches yie]ded interesting results.

chapter 4 descrÍbes a successful route to an arternative precursor, 7-oxo- I -phenyl methy'l -4, 5,6, 7-tetrahydroi ndol e based upon the heteroannelation of 2-amino-3-methyl -2-cyclohexen-1-ones with dimethyìformamide dimethyì acetal. However, ring expansion of the ketone could not be achieved. Alternative routes such as the attempted heteroannelation of 4-methyl-3-pheny]methylamino- 2,5,6,7-tetrahydro-(lH)-azepin-2-one and the oxime of 3-methyl-z- phenylmethylamino-2-cyclohexen-1-one are described also.

A successful synthesis of pyrrolo[4,5]azepin-6,10-(lH)-dione is presented in the last section of chapter 4. This precursor was amived at by the cycl ization of 3-N-(2-pyrrolytcarbony'l)aminopropanoic acid in po'lyphosphoric acid. The condensation of the precursor dione with gìycocyamidine proceeded aLbeit in very poor yieìd. The final dehydration of this aldol product to the naturaìly occurring compound has not yet been achieved. (iii)

STATEMENT

This thesis contains no material previously submitted for a degree or diploma in any University and to the best of my knowledge and belief, contains no material previously published or written by another person, except where due reference is made in the text.

BRUNO KASUM (iv)

ACKNO}ILEDGEMENTS

I would sincere'ly ìike to thank my supervisor, Dr. R.H. Prager, for his guidance, encouragement and enthusiasm during the course of this work. The helpful assistance. and suggestions from other members of the Department, particularly Dr. A.D. hlard are also acknowledged.

This research was conducted during the tenure of a

Commonwealth Postgraduate Award, for which I am grateful.

Finally, I would like to thank my parents for their understanding and support during the course of my studies. INTRODUCTION I

INTRODUCTION

The alkaloid perlolinel (1) found in perenniat r"yu grurr* (zoLiun perenne L. ) and tall fescue (Festuca arundinacnù? nu, recently become of great interest both as a synthetic target and because of its pharmaco'logica'l propenuies.3

OMe

H H

(1) (2)

Perìolidine (2), a minor alkaloidaì component of rye grass, has also been isolated4 from 2,. perewrc, and to date four syntheses have been published.5-7 The synthesis of perloline has been reportedS as well as mild oxidations which have produced a colourless non basic material, dehydroperloline9 (3), the subject of the synthetic work described in the first part of this thesis.

* Also called New Zealand rye grass or Engìish rye grass in

Chem.Abstr. 2

(3)

Perloline has been linkedlO with the condition known as "rye grass staggers"ll observed in sheep and cattle grazing pastures consisting soìe'ly of rye grass seedlings or new shoots.10 Rye grass from these pastures contains a much higher alkaloid content (0.15-0.25%) than more mature grass (0.02-0.06%) which contains most'ly per'loìine.

Parenteral administration of perìoline to guinea pigs and sheep at dose levels similar to those found in sheep grazing on rye grass, produces effects resembling symptoms of rye grass staggers. However, ora'l administration of perloline (1C0-200 mg/kg) produces the symptoms in guinea pigs but not in ,h..p.10

Recent work has shown that corynetoxins, formed in gaìled seeds of noLim rìgidwn (annual rye grass) a related species, by a bacteri um Corynebacteriun rathayi and a nematode , Anguina agrostis, are responsibìe for annual rye grass toxicity.12'13 However it is still unclear whether similar toxins are responsible for the staggers condition associated with perennial rye grass. 3

Since perloline occurs only in small quantities in rye grass, an efficient synthesis would encourage further research into its physioìogical activity. Although dehydroperloline has been recently synthesizedS'14 in this department it was the aim of this work to develop a highly convergent route to this compound and hopefuìly open some new areas of chemistry in the process. Dehydropertoline v,,as chosefas a more suitable target because of its greater stability and the fact that reduction under very mild conditions leads to the naturally occurring alkatoi¿8 (f). 4

A hypothetical dissection of the dehydroperloline molecule, shown in Scheme 1, suggested that a convergent synthesis was plausible from two relativeìy smaller fragments: the substituted diphenylamine (4) and 2-oxopyridinecarboxylate (5Ifhese 2 compounds

Me (3)

OMe ET

N H H Br

(4) (5)

SCHEME 1

r¡,ere accordingly chosen as the next most suitable sub-targets.

Compounds (+) and (5) coutd theoretically be reunited in three

di sti nct !,,ays: 5

1) simultaneous formation of amide and aryl-aryl bonds

2) formation of aryl-aryl bond prior to amide bond 3) formation of amide bond then aryl-aryl bond. All three methods were investigated during the course of this work.

Although a variety of methods exist in the literature for the formation of amides,15 methods for aryl-ary'l bond formation are not as common. The first approach considered was that of 3) above. Thus if the amide bond was constructed first, compound (6) should be formed.

OMe

(6)

SCHEME 2

An Ulìmann type coupling reaction uti'lizing one of the many coup'ling reagents known16 was expected to produce dehydroperloline (3) (Scheme 2). Ullmann coupling reactions of 4-halopyridines with other 4-halopyridines have been reported,lT'18 as has the intramolecular coup'ling of aryì halides.l9

An interesting alternative to the Ulìmann reaction could be the reductive coupling of (7) with lithium aluminium hydride, although 6

the relative rates of amide reduction versus aryl halide reduction remain to be determined.

OMe

( c I tl o

H (7)

An analogy to this type of coupling has been reported with z-Z..chlorostilbene to give phenanthnene.20 D I SCUSS ION 7

1.1 Synthesis of the Diphenvlamine Svnthon (4)

Aìthough there are several routes to diphenylamines available in the ìiterature, the most widely used are the Chapman rearrangement?l-z4 and the Ullmann condensation?S'26 The Chapmun2T ,.urrangement involves the thermal rearrangement of N-ary'lbenzimidates (8) to N-aroyldi- pheny'lami nes (9) ( Scheme 3) .

A A¡2 N N A 3 \ Ar \ rl Ar o,, (B) (e)

OH -t HrO

2 SCHEME 3 Í HN ,/o Arl

This procedure is, however, limited by the availability of the aryl imidates (8).

The Ullmann condensation29'29a relies on the reaction of aniline or a substituted aniline with an o-chlorobenzoic acid (Scheme 4). B

The resulting N-phenylanthranilic acid is then made to undergo thermal decarboxylation to the required diphenylamine.

co2H + Cu A

co2H A

SCHEME 4 This method too, is limited in that reductive dehalogenation may sometimes become the major reaction.29b This method has very rarely been used to make ha'logenodiphenylamines. Thus it was decided that some new methods for the preparation of diphenylamines shouìd be investigated. 9

1.1.1 The rearranqement of 3-al kyl -3-ar.yt -1-(2-carbox.yphenyl )triazenes

Nakayama and Yoshida30 synthesized a variety of N-atkyì- diarylamines (11) bV heating 3-alkyl-3-aryl -1-(2-carboxyphenyì )- triazenes (10) in chlorobenzene (Scheme 5). The reaction was shown to proceed uia a benzyne3l jnt.rrediate which was subsequentìy trapped by the N-a'lkylarylamine formed ín situ from the decomposit'ion of the triazene. This reaction has not been extended to include substituents on the ring bearing the carboxyl group, nor have steric

1 N -R -N\ N/ A H N ( + \_, A rCl H /\,

( l0)

2 R1 R %yietd

Me Ph 96 c

PhcHz Ph 94 I

czHs p-MePh 93 \*z PhcH2 p-ClPh 68 (11)

SCHEME 5 and electronic effects of ortho substituents of R2 been investigated. Thus it might be possible to achieve a general synthesis of diphenylamines if Rl could be selected so as to be readily removable. 10

The 3,4-dimethoxybenzy'l group appeared to be a good choice since the cleavage of this moiety has been documented .32-34 In order to synthesize the diphenylamine (4), triazene (12) would be required to undergo thermal rearrangement as depicted in Equation 1.

B Me

A Phcl

(12) ( 13 )

Equation 1

Nakayama et aL prepared triazenes (10) bV the addition of the appropriate N-alkylary'lamìnes to diazotized anthranilic acid.30 Accordingly, the required starting materials were 2-bromo-N-(3'4- d'imethoxybenzyl )aniline (14) and 6-amino-3,4-dimethoxybenzoic acid (17). The acid (17) was prepared as shown below by modifjcation of a literature procedure.35'36 11

H Me K MnOa I OH Hzo A Noz I tn o2 (15)

EtOAc H, /pto2 2so 1 atm.

Me H 2 ( 17 )

The N-benzylarylamine (14) was synthesized in 93% yield by reduction of the corresponding Schiff base (16) with sodium borohydride in methanol3T lfquation 2).

Several trial reactions uJere conducted in order to ascertain whether or not the amine (14) would add to the diazonium carboxylate derived from (17) but these were not promising: the conditions of Nakayama et aL 1ed only to the recovery of amine (14). The acid (17) was not recovered from extraction of the aqueous phase but instead an acidic material was isolated in 'low yield. Its L2

NaBHa / c MeOH N l Br

o/Y\e (16) ( 14) o/\Àe o/v\e Equation 2

structure couìd not be determined but it did not exhibit an absorbance in the infra-red spectrum which indicated the presence of a tri azene ( -tl-trt=tt¡ moi ety ( 1575 cm-l) .

In order to increase the so'lubiìity of the amine (14) in the reaction mixture, methanol/acetone was used but although (14) was completely soluble in this medium, still no reaction ensued with the diazotized acid (17). Attempted reaction of (la) with benzenediazonium carboxylate resulted in the partia'l recovery (50%) of the amine and also in the fúration of a compìex mixture of À products. The unreactivity of the amine may have been due primariìy to the presence of the ortho bromine subst,ituent. Presumabìy the inductive and steric effects of this group on the

nitrogen atom lowered the nucleophilicity of the amine considerab'ly.

Nakayama aìso reported3o that weakìy basicamines such as diphenylamine gave none of the expected triazenes when treated with 13 benzenediazonium carboxylate, however N-(4-chlorobenzyl )anil ine was successful. Although a permutation of this route, shown below was possible in theory it was not considered a practical approach. A more direct route was clearly required.

Br OMe Nr* + e H o2

OMe

Br OMe

co2H

M T4 l.L.? Rearranqement of o,N-diphen.yl nitrones

Spìitter and Caluin3B'39 found that irradiation of the o,N- disubstituted nitrone (18) in ethanolic solution led to the formation of formamide (20) in 86% yield.

o NMe,

I rll + hv Ethanol I H MerN

( 18) (1e)

hv Benzene A

Y H

( 21) NMe2 ( 20)

SCHEME 6 15

The rearrangement of cr,N-diphenylnitrones33 hu, been shown to proceed uia an oxaziridine intermediute40'41'42 1eg. (19)) formed photochemically, and its subsequent rearrangement to the formamide (Scheme 6).

The rearrangement of the relatively unstabìe 2,3-diaryì- oxaziridines involves N-0 bond cleavage which can be heterolytic or homolytic depending on the conditions and substituents.33 l,,lith electron releasing substituents on the cr ring as in oxaziridine (19), aryl migration resulted in polar solvents (ethano]), while in apo'lar sol vents hydrogen mi grati on v',as found to be competi ti ve , gi vi ng ri se to benzanilide (21) (Scheme 6).

Hence if oxaziridine (22) could be thermally rearranged in ethanol (Equation 3), the expected product would be the formamide (23). Hydroìysis of (23) with aqueous alkali33 should then liberate the free

Br % A.

Ethanol Br

(22) (23)

Equation 3 amine (4) required fo.r the synthesis of dehydroperloline. 16

The oxidation of certain imines to the corresponding oxaziridines hás been documented in the literature.39'43,49,50 Thus it was anticipated that oxidation of (16) might lead to the oxaziridine (22) (Equation 4).

m-CPBA I

(16) (22')

Equation 4

using simiìar conditions as described by pe*s44 but employing m-chloroperbenzoic acid instead of peracetic, the results of the attempted oxidation of (16) were disappointing. Although a variety of solvents and conditions was employed, none yielded the desired oxaziridine (22) or any of the rearrangement products expected to arise from it. These compounds were the benzanilide (24) and the formamide (23).

(24) H

¡ 77

In most cases the oxidation proceeded too far, to give complex mixtures of products. A slow addition of the peracid to (16) in dichloromethane at 0o gave, after flash chromatography, three major fractions, one of which was identified and assigned the structure (25). A possible mechanism for the formation of (25), which was isoìated in only 15% yield, is shown in Scheme 7.

) Ar r

Me "f

(25)

SCHEME 7

The i.r. spectrum of the product exhibited absorbances at 3300 (0-H stretching) and 1660 cm-1 (hytlroxamic acid C=0 stretching) consistent with structure (25). The mass spectrum showed the lH expected M-l peaks at m/e 335, 337 and the n.r.r. spectrum showed the presence of one exchangeable hydrogen (0-H), seven aromatic hydrogens and two methoxyì groups. The other two fractions 18

from the chromatogram could not be identified. Attempts to prepare an authentic sample of the hydroxamic acid (25) by condensation of hydroxylamine (26) (prepared by the reduction45 of

2-bromonitrobenzene with zinc and ammonium chloride in aqueous ethanol) with 3,4-dimethoxybenzoyl chloride46 under a variety of conditions5l gave no trace of the required product. Attempted oxidati on47 of the N-trimethylsiìyl amide (27) with diperoxo- oxohexamethyl phosphoramidomolybdenum (\/I)48 in dichloromethane was also unsuccessful, returning the starting amide (2a) (scheme g).

ct H \oH M Et2o

(?6) (25)

siMe3 MoOu. HMPT I CHtCla , r.t. several days I (27)

SCHEME 8 19

Splitter and Calvin reported39 that they also were unable to oxidize aromatic Schiff bases to the corresponding oxaziridines unless the aldehyde component contained strongly electron-withdrawing groups or the substituent on nitrogen was altyl.52 When the experimental conclitions of Davis and String..53 were used, who prepared 2-sulphonyìoxaziridines from sulphonimines, a cleaner reaction u,as obtained. Unfortunately, the maior product was the benzanilide (2a) with onìy a small amount of the required formamide (2¡). Presumably the oxaziridine (22) was formed and rearranged in situ to give the product resuìting from hydrogen migration as expected in dichloromethane. The failure of these methods led to the consideration that the nitrone (28) would serve as a more suitable starting material. This nitrone had not been reported in the available literature nor had there been prepared any nitrones bearing ortho-halogen substituents on the N-phenyì ring.

An appìication of .the procedure used by l^lheeler and Gor.54 to prepare nitrone (29) was used in synthesizing (28). Thus

N-(Z-bromophenyì )hydroxylamine (26) when condensedss with 3,4-dimethoxybenza'ldehyde in ethanol afforded the nitrone (28) in

80% yield. Irradiations6'57 of the nitrone in ethanol at 350 nm or in sunlight through pyrex, at a concentration of I S/litre, led to the formation of the oxaziridine (22). The reaction course t{as conveniently followed using U.V. spectroscopy by observing the disappearance of the nitrone absorbance at 330 nm. The oxazirjdine lH intermediate (22) was detected ¡y n.m.r. spectroscopy; the proton on the carbon of the oxaziridine ring was observed at ô 4.67 20

\ -o R2

I 2 ( 28) R= Me R =Br

1 2 (2e) R=R =H

as a sharp singlet. l,Jhen the ethanolic solution was refluxed for one hour thermal reamangement of (22) occurred to give the formamide (23). The singlet at ô 4.67 slow'ly diminished in size, with the appearance of two new singlets at ð 8.5 and 8.2 corresponding to the formyl proton of (23). (Restricted rotation5S about the amide bond may account for the presence of two formyì resonances i.e. conformers). The best yieìd of the formamide which could be realized was 70% but only if the nitrone was purified and the solution stirred during irradiation. The free diphenylamine (4) was easiìy obtained by hydrolysis of the formamide with potassium hydroxide in ethanolic solution.

The photochemical rearrangement of oxaziridines in the singlet state has been studied by 0livero$'12 und has been shown to be 2L governed by stereoelectronic factors. Thus in the singlet excited state of the oxaziridine, migration of the group anti to the lone pair eìectrons on nitrogen occurs. Hence oxaziridine (22) rvould require the less stable Z-stereochemistry (Fig. 1) if it were to rearrange in this manner.

H. //r, k),

Figure t However it was apparent by n.m.r. analysis that the oxaziridine (22) was a single stereoisomer and the precursor nitrone was the Z-isomer (28). Although the stereochemical consequence of the isomerization of a nitrone to an oxaziridine has not been investigated, this would appear to be the wrong stereoisomer to allow the migration of the dimethoxyphenyl group to occur. Since no product resulting from hydrogen migration v'ras observed the mechanism is most likeìy non-concerted. The most probable mechanism appears to be that suggested by Calvin,38 viz. that in a polar solvent the rearrangement occurs via the zwitterjon (30), resulting in the migration to nitrogen of the most electron-rich group. 22

o I HC-N + f

( 30)

l^lhen the photolysis vlas conducted in benzene, the exclusive product was the benzanilide (24), while in dichloromethane a 2:1 ratio of (2a) and (23) resulted. This suggests that in non-polar solvents either the concerted hydride rearrangement occurs or the intermediacy of a diradicul52 ,p..ies such as shown below,although the required hydrogen atom transfer would not be expected to be i ntramol ecul ar.

o _N 23

1.2 Synthesis of the 2-Pyridinone Synthon

The synthesis which was proposed for the 2-pyridinone ( 5) is outlined in Scheme 9.

I cozEr il CO2Er

CN N

(31) (sz ¡

¡¡¡ \ /

Ef ET ¡Y \ N MerN l{ (s) (33)

Key ¡ Kzcot/n"rO ¡¡ Pøru / Benzene ¡¡¡ DMF dimethyl acetal iv HzSo4 / rro

SCHEME 9 24

The hydroxybutenoate (31) was considered a suitable starting material since its preparatjon had already been documented in the literature.59 Treatment of (31) with phosphorus pentabromide was expected to g'ive the bromo compound (32). 2-Cyanobutenoates have been reported to produce enamin.r60 when treated with DMFÌ dimethyt acetal and by anaìogy (32) was expected to furnish the enamine (33) upon reaction with this acetal. Cycìization of (33) in aqueous acid should then give rise to the2ayridinone (5), cyclizations of this type having been reported with similarly substituted enamin.r.S'61

Hydroxybutenoates9 (31) was prepared by a Knoevenagel condensation of ethyl cyanoacetate with acetic anhydride in 70% yietd but this compound failed to react with phosphorus pentabromide in benzene to give (321. The alternative 3-chlorobutenoate62 (¡+) was easiìy prepared in 60% yie'ld by refluxing a so'lution of (31) in benzene with phosphorus pentachloride. Treatment of the chlorobutenoate (g+) wlth only one equivalent of DMF dimethyl aceta'l in DMF failed to give the required enamine, giving instead a substitution product63 (35). A possible mechanism for the formation of the 3-dimethylaminobutenoate (35) is shown in

Scheme 10. ReflUxing a so'lution of (35) in DMF with excess of the acetal gave the bisenamine (36). At this stage it was hoped that the dimethylamino group could be eventually replaced by a halogen and so (eO) was cyc'lized to the 2-bromopyridine (37) with hydrogen

t otulF i s dimethyl formami de. (25)

\¡t MeO a.,NMe, CN

( 34)

ct Me \4 co2Ef

M"z CN

(35)

SCHEME 10

bromide in acetic aciU60 lS.heme 11). The 2-bromopyridine (37) proved to'be more readily available than the corresponding

2-pyridinone since the conditions for the latter had not yet been

optimized; it was envisaged that (37) could be hydrolysed by potassium hydroxide in methanol to give the Z-pyridinone (38) or the corresponding carboxyìic acid. 26

DMF dimethyl acetal f ET DMF CN

(¡o)

HBr AcOH

\ /

NM"z N M"z

Et roH /nneoH Et

(37) ( 38)

SCHEME 11

The hydrolysis of 2- and 4-alkylaminopyridines containing a strongly activating group (such as nitro) has been documented,64'65 however sodium hydroxide in aqueous ethanol faited to hydrolyse

(37) even after extensive reflux. It seemed possible that demethyìation of (37) to give the unsubstituted amino derivative would be a better approach. The amino compound could then be diazotir.d66'77 and hence substituted more readily. However, (37) failed to undergo demethylation in refluxing hydrobromic acid,68 while neat hydrogen iodide69 only led to extensive decomposition of (37). 27

An alternative approach which involved the reaction of

3-hydroxybutenoate (31) with DMF dimethy'l acetal was then considered (scheme 12). unfortunately reaction of (31) with thjs acetal under a variety of conditions gave none of the desired enamine. The isolated product was instead, a colourless,

crystalline and moisture sensitive compound assigned structure (41) primari]y on the basis of spectral data derived from it. Further evidence for the structure was obtained when it was found that treatment of (41) with water regenerated the initial hydroxy-

OH OH

c02Ef O2Et AcOH \ Ef Hzo / CN CN H (31) (3e) (40) DMF acetal

POCt 3 Meo,

ET ET

CN N (41) H

SCHEME 12 28

butenoate (31). since neither (41) nor the trimethytsi'lyì enol

ether of (31) couìd be encouraged to react with DMF dimethy'l acetal to give enamines, this route was not pursued any further.

The resistance of the dimethylamino group of (37) to

substitution led to the idea that an alkoxy'l group wourd be a more suitable substituent. Hence a method would be required to affect the final bond forming reaction for amide (42).

OMe

(42)

Recent reports of the successful displacement of activated methoxy'l groups by organomagnesium and organolithium reagents by

M.y.rr7O suggested that a methoxyl group would be ideal. shourd this approach fail then this group could be hydrolysed and repìaced by a halog.n,71,72 thus allowing an Ullmann coupling to be investigated. 29

The 3-methoxybutenoate (43) was prepared in 90"/" yield by the reaction of ethyl cyanoacetate with trimethyl orthoacetate.T3

Refluxing a soìution of (a3) with DMF dimethyl acetal gave the desired enamÍne (44) in 85% yield after chromatography.

The enamine (44) was found to cyclize smoothìy in hydrogen bromide/acetic aci d\j'74 to give the 2-bromopyridine (45) or in aqueous acetic acidB to the 2-pyridinone (47). Hydroìysis of the esters to the corresponding acids (46) and (49) was achieved by refluxing each compound for a short period (30-45 min) in aqueous sodium hydroxide solution. Further hydroìysis of (4g) to the 4-hydroxy-2-pyridinoneTs (+n) was observed when ronger reaction times were used. This compound however was extremely water soluble and consequently did not interfere with the isolation of the desired acid (48) .L.+ Schc^<- ,rl 30 Me

DMF 02Er acetal

CN CN M (+r ¡ ( 44) nconf n2o Br OMe

EI COzEr

r H (4s) (47)

_t o 20 oH f H2o

H (a6a ) R,= H<, ( 48) (,¿¡) L,et

further hvd rolys ¡S v

(+s¡ H SCHEME 13 Z U]IdVH] 31

2.L Attempts to form the Tertiary Amide (42)

Initial'ly, the coupling of the two synthons appeared to be straightforward. The bromopyridine acid (46a) was converted to the acid chloride with oxa'lyì chlorid.T6 brt the diphenylamine (4) failed to react with it under a variety of conditions. The addition of equivalent amounts of pyridine or 4-dimethylaminopyridineTT to form the more reactive acyl pyridinium species did not succeed in producing any of the desired amide. Dicyc'lohexylcarbodiimideTS'79 (DCC) coupling of the acids (46a),(46b) (4-0Et) and (48) with the diphenylamine in tetrahydrofuran or acetonitrile was unsuccessful, even with the addition of catalytic amounts of 4-dimethylamino- pyridin..80 Attempted condensation of the 2-pyridinone acid (48) with (4) in polyphosphoric acid8l'82 again led to the recovery of both materials. Even the addition of sodium ethoxide to a mixture of the amine and ester (45) in order to generate the unionS3 of (a) failed to induce the required condensation. This type of approach has been documented for relatively hindered amines. 0ther coupling reactions and conditions tried are summarized in the experimental section. Further reactions using the 4-hydroxy-Z-pyridinone acid

(49) were not attempted due to its insolubility in many of the usual organic solvents.

A molecular model of the diphenylamine (4) showed that the nitrogen centre was particu'larly hindered due to the presence of the 'large bromine substituent. In addition, the inductive effect caused by the bromine atom wouìd have decreased the nucìeophilicity. The low basicity exhibited by the amine (4) seemed to imply that it was 32

an even poorer nucleophile than diphenylamine (ttre latter was soluble in concentrated hydroch'loric acid whereas (4) was not).

Certain other factors which may have been responsible for the lack of reactivity between (4) and the acid chlorides of (46a) and (46b) i ncl ude i 1) The 4-alkoxyì group of the acid chlorides increasing electron density on the carbonyl carbon,

and 2') the two ortho substituents flanking the acid chloride moieties of (46a) and (46b) hindering the approach of amine (4). The rather ìong reaction times and forcing conditions required for dìphenylamine to undergo simp'le acetylationS9 and 2,2'-dibromo- di pheny'lami ne to undergo a'l kyt ati on85 exempì i fy the rel ati veìy poor nucìeophil icity of diphenylamines.

Although not attempted, the reaction of diphenylamine (a) with the 2-oxodihydropyridine carboxylate (47) might prove successful owing to the possible intramo'lecular catalysis by the 2-hydroxypyridine 36 tautomer. .

A second approach with modeì compounds is summarized in Scheme 14. Diphenyìamine was found to condense with cyanoacetic acid in ether in the presence of DCC to form the amide (S0)87 in 90% yie'ld and this was elaborated to compound (53). Although this type of approach was not as convergent as the originaì one, all the steps outlined proceeded in excellent yields. Unfortunately a1ì attempts to prepare the required cyanoacetamide (5a) by the DCC coupling reaction between cyanoacetic acid and amine (4) met with no success. 33 H A NH Dccf Ether N 2 N

Et ArrNH ( 50) A AcOH nrec (ove),

o DMF r2 dimethyl acetal f2 \ N MerN (sz¡ ( 51)

nar f AcoH

4,,

( s3)

SCHEME 14 34

OMe

( 54)

An alternative method gave acceptable yields of the model compound (50) but could not be repeated with the required amine (4).

At this stage it was obvious that the poor nucleophilicity of amine (4) would have to be overcome before this compound could be utilized. Thus, the lithium amide (5S) was prepared.

OMe OMe MeLi EtÀ; ' oo H Br [i+ (4) Br (55)

o Ether

OMe

OMe Br

( s6)

SCHEME 15 35

Treatment of this species with a more reactive substrate such as chloroacetyl chloride could then give the amide (56). (scheme 15) Cyanoacetyl chlorideSS was not used due to its instability,Sg especially as it was felt that chlorine moiety of (56) could easiìy be replaced by cyanide at a latter stage.

When chloroacetyì chloride was added to a suspension of (55) jn

ether, the salt redissolved to gíve a clear solution. Upon work

up the amine (4) was recovered quantitativeìy. Presumabìy an

acid-base reaction had occurred in which the amide anion served to remove one of the acidic methylene hydrogens of the acid

chloride. This approach was not investigated further as a more

successful route was developed. 36

2.2 Metallation of Diphenylamine (4) and reaction with Ethyl

3-ch I oro-2 -c.yanobut-2-enoate ( 34 ) .

After many fruitless attempts to utilize diphenyìam'ine (4) as a nucleophile it was proposed that metallation of (a) might render it far more reactive.35 Thus if the dianion (52) could be generated

it might be made to react with 3-chlorobutenoate (34) in the manner

shown in Scheme 16. The resultant quinolone (58) should be readiìy

OMe OMe

N N OMe H Br

(4) (57 )

ct co2 Et

N (s¿) \

Me OMe DMF dimethyl acetal e

N N M"z ( 58) HrOf o"on (5e) DEHYDROPERLOLINE (3)

SCHEME 16 37 convertible to dehydroperloline by completion of the Z-pyridinone ring using some previous'ly developed chemistry.

When a solution of the diphenylamine in ether was treated with one equivaìent of methyìlithium at 0o the amide salt precipitated. Reaction with a further equivalent of n-butyllithium at 0o gave the dilithiated species as a pale lemon suspension.

Add'ition of two equivalents of (3a) caused the solution to become blood red in colour. t^lork up of the mixture showed that none of the desired quinolone (58) was present. Instead, a low yield (26%) 1H of compound (60) identified on the basis of n.m.r., i.r. and mass spectra'l evidence, was obtained. This compound was isolated

H Et

( 60) N onìy after extensive chromatography as a mixture of geometric lH isomers about the double bond, as clearly seen in the n.r.". spectrum. Two separate resonances for the methyl group could be seen at ô 2.45 and 2.26. The major product however (40%) was the reduced diphenylamine (61).

OMe I

ET OMe N

( 61) (62], 38

The low yield of compound (60) may have been due to acidity of the methyl hydrogens of (3a) which were most probably removed by the strong base (57). Unfortunately, attempts to improve the yi e'l d by usi ng ì ower temperatur.r9o or I ess pol ar sol vents9! '92 '93 to decrease the basicity of (57) were unsuccessful. Formation of the ary'l cuprate reagent by reaction of (SZ) with the ether soluble tetrakisIiodo(tri-n-butylphosphine)copper ( I)] compl ex did not significantly enhance the amount of 1,4-addition92,94 u, expected. The 3-methoxybutenoate (a3) failed to react at all with the aryl cuprate while the 3-iodobutenoate (62), prepared from

(34), was found to be insoluble in the reaction medÍum and consequently did not react at all with the cuprate. Since (57) was also insoluble in ether it was feìt that this may have contributed to its low reactivÍty with the chlorobutenoate (34), but in THF, where (57) was completely in solution, no reaction at all was observed with (3a). The reduced amine (61) was always the on'ly product. Again, the basicity of (57) in THF93 might have increased to such an extent that only an acid-base reaction occurred with (34) at 0'.

During the course of some related work it was discovered that phenyllithium added very efficiently to the enamíne (4a) to give the phenyl substituted compound (63)14 (Equation 5). 39

Ether

Et I o 2E¡ N MC (++¡ MerN (63)

Equation 5

Enamine (44) possessed no acidic hydrogens and so appeared to be an ideal choice for reaction with (57). !,lhen a solution of the enamine in ether was added to a suspension of (57) also in ether, the familiar blood red colour was produced. Work up gave the expected product (64), but again the yie'ld was low (I7%).

Repetition of the reaction under identical conditions but in THF led to isolation of (65) as the major product, formed by

Me OMe

02Er 02Er

CN N

( 64) (65 )

N-a'lkylation of the dianion (57). Although reactions of dianions are considered to occur uía the more reactive centre, carbon rather 40 than nitrogen in this case, exampìes of preferential N-aìkylation have been reported elsewhere in the literature.95

Compounds (64) and (65), aìthough structural isomers, exhibited quite different spectral characteristics. The enamine

(65) was also isolated as a mixture of isomers which could not be separated. Consequentìy satisfactory microanaìytical sampìes of (64), (65) and (60) proved difficult to obtain.

Conversion of (60) to the enamine (64) was achieved by refluxing a so'lution in neat DMF dimethy'l acetal for three hours. This product was also found to consist of a mixture of double bond isomers. Cyclization of (64) in refìuxing 80% aqueous acetic acid gave the 2-pyridinone (67) as the major product. Chromatography of crude (67) showed it to be contaminated with small amounts of a second product. This material proved to have properties and spectroscopic data identical with those of enamine (65) although it was only one isomer. Presumably reaction of the dianion (57) with 3-chlorobutenoate (34) gave also a small amount of nitrogen alkylated material (66) which was subsequently carried through the next two

OMe

Et (66)

steps with (60) to give the enamine (65), but which failed to cyclìze 4l to the Z-pyridinone derivative.

Several attempts to affect the final ring closure of (67) to give dehydroper'loline met with unexpected failure. Refluxing a solution of (67) in toluene overnight or heating a so'lution (67)

OMe Me

N H H

(3) (67) R = OEt

(68) fl= OH

and methyllithium in THF gave no detectable amount of dehydroperloline by t.l.c. anaìysis (dehydroperloline exhibits an intense fluorescence 'light under U.V. at 366 nm).

The Z-pyridinone ester (67) was hydrolysed to the acid (68) but cyc'lization could still not be induced. Attempted dehydration of (68) utilizing DCC, phosphorus pentoxide or concentrated su'lphuric acid gave none of the desired product. Attempted sublimation of (68) at 150'in order to eìiminate water and sublime out dehydroperloline again was unsuccessful. An interesting point noticed about the mass spectrum of the acid (68) was that at 70eV 42

no molecular ion was evident. Instead, the base peak was a fragment of m/e 348 corresponding to the loss of eighteen mass units. The mass spectrum was tótally different to that of the hoped-for dehydroperìolin..96 The loss of water may have occurred as shown in

Equation 6.

- Hzo

m/e 366 m e 348 ( 68) Equation 6

Since only limited quantities of the 2-pyridinones (67) and (68) were availabìe by the previous synthesis and it was hoped that cyclizations using the acid chloride of (6S) could be invest'igated, a more efficjent route to (68) was clearly required. 43

2.3 Alternative routes to Dehydroperloline from 2-(3,4,-dimethoxy-

I ami no ace none 69

A more promising route to (60) which would avoid the tedious preparation of amine (4) and its subsequent metallation is shown in

Scheme 17. An Ullmann reaction between 2-bromoacetophenone and

OMe Cu

I NH2 N H

(6e)

Base

Me OMe

N e l{ H R, <_+

H (60)

(67) R= OEt

( 68) R= OH SCHEME 17 44

3,4-dimethoxyaniline to give the amino ketone (Og),9/ foìlowed by

a Knoevenagel reaction of (69) with ethyl cyanoacetate was

expected to furnish (60). This compound could be produced only in

low yie'lds by the previous synthesis. The Uìlmann reaction was found to proceed best in refluxing l-butanol93 *ith two equivaìents of veratrylamine. The presence of I% copper and I% cuprous iodide9S was found to be vital. Even with these cataìysts the best yield of (69), after chromatography on alumina , was 26%. Decomposition93 of the veratrylamine during the reaction was probabìy responsibìe for the low yield. Purifjcation of the amino ketone (69) proved difficult at first, since chromatography on very active neutral alumina using dichloromethane aìways resulted in the formation of

the acridine (70) (Scheme 18). Fortunateìy when the alumina was

deactivated, (addition of 3% water) the amino ketone (69) could be isolated. The synthesis of acridines from diphenylamine ketones has been reported in the literature.99

Me M

Me Me H (os¡ Al2o3 -H2 o

(70)

SCHEME 18 45

OH ruaoey' EtOH ET

CN N

7s%

(71 )

SCHEME 19

Disappointingly, at this stage the Knoevenagel reaction of

(69) with ethyl cyanoacètate could not be achieved, even though analogous reactions have been reported in the literature;5a'100 for^ example the condensation of 2-hydroxyacetophenone with ethyì cyanoacetate gives the .orru.in101 (71) (Scheme 19). A refluxing solution of the amino ketone (69) in benzene or toìuene with various catalysts such as ammonium acetat.,102 pentylamine acetatelo3 and ammonium acetate/acetic acid gave none of the required product (60) or the cyclized material (58). Treatment with stronger bases such as sodium ethoxide in ethanoì succeeded only in inducing a base cataìysed cyclization of (69) to acridine (70). A final attempt was made to utiìize the more reactive malononitrile to give the 46 OMe OMe CN base N OMe H H

(6e) (72)

CN OMe

( 60)

co2Er

SCHEME 20 dinitrile (72), partial hydroìysis of which would lead to (60) (Scheme 20). The hydrolysis of analogous dinitrile compounds to the mono carboxyìic acids has been achjeved.S However, the amino ketone (69) failed to condense with malononitrile under simiìar conditions to those using ethyl cyanoacetate. The reluctance of

(69) to undergo the Knoevenagel reaction may have been due to the: 1) bulkiness of (69), which sterica'lly hindered the approach of ethyt cyanoacetate 2) increase in electron density on the carbony'l carbon of (68) from delocalization of the nitrogen 'lone pair. Since the reaction failed with malononitrile which is considerably smaller than ethy'l cyanoacetate, electronic factors seemed more 'like'ly. This was supported by the bright yeìlow coìour of (69).

0n account of the fai I ure of the Knoevenage'l approach to provide usefu.l quantities of the 2-pyridinone carboxylic acid (68), the synthesis of dehydroperloline9T was regretfully abandoned. t ulldvHl 47

INTRODUCTION

In 1980 Sharma and co-workersl'2 described the isolation and characterization of a novel marine sponge alkaloid (1).

H,N 14 13 H (t) R= H ( hydrochloride) 15 (2) R= Br 9 4 3 I

5 H R, H ,tt///

The structure of a related compound Hymenialdisin.3-5 (Z) found in the Mediterranean sponge AnineLLa oevryacosa and in

Hymeniacidon ALdis has since been determined4 on the basis of

X-ray analysis and spectraì evidence. Alkaìoid (1) was discovered in the Great Barrier Reef sponge PhakeLLia fLabeLLataL which also contains a host of other natural products, some possessing antimicrobial activity while others are intriguing because of their unìque structure

A'lthough the ye'l'low compound (1) does not exhibit any antibacterial properties, it is believed that (1) and the phakellins,6 another class of phannacologically active substances present in the sponge, ffiêV have a common biosynthetic precurror.l

Examination of the structure of (1) shows that the possibitity of geometrical isomerism exists at the 10, L1 double bond. However, 48 it was concludedl that the isomer shown is the correct one on the basis of the large downfield shift of the 9-methylene hydrogens in

1 the rH n.m.r. spectrum, produced by the anisotropy of the amide carbonyì at C-12.

Chemical degradationl of the free base (1) with aqueous potassium permanganate led to the formation of (3), itself recentìy

(3) H H

isolatedT fron H¡meniaeidon aLdis (de LaubenfeLs) but possibìy an artefact. Structures (1), (2) and (3) are unique, and as such present interesting synthetic chal'lenges. It was hoped that analogues of (1) such as (2) could be synthesized and tested for any bioìogical activity. In the development of a synthesis for (1) the pyrroloazepine (3) would also be taken into consideration as a "stepping stone" to (1).

A logical precursor to (1) appeared to be the ester (4) since it was felt that condensation with guanidine would be like'ly 49

co2Ef

(4)

H H

to give the free base (1). Compound (4) could in principìe be derived from the ester (5) as shown in Scheme 1.

ET EtrOC Et

H H H H

(5) 1. OH- I 2. H3O'

(4)

H H

SCHEME 1 50

An aìternative progenitor to (l) could be the pyrroloazepindione (3) which might be prepared by oxidation of the pyrro'loazepinone (6) using reagents such as selenium dioxideS or DDQ.9 The condensation of gìycocyamidine (7) with indole-3-carboxaldehydel0 und substituted benzaldehyde5ll'12 in the presence of sodium acetate has been documented and proceeds uia attack from the methylene carbon of (7). A'lthough the reaction of (7) with ketones has not been reported it was

[o]

H H H H

(6)

Base H

(7)

H,N HN H H

OH ...-\' - Hzo (B)

H H H H

(r)

SCHEME 2 51 envisaged that condensation with (3) might give rise to the aldot product (8). Dehydration of this atcohol would give the free

base (1) presumably as a mixture of isomers which could then be

separated. No generaì syntheses for compounds of the type (6) have been reported so a study was undertaken to investigate this. Three separate routes were clearìy evident in principle:-

1) heteroannelation of a suitably functjonalized cyclohexenone, followed by ring expansion - R

H H H

(e) R= H (tt) n=n (6) R=H

(10) R=COzEt (rz) R=Co2Et (5) R = COrEt

Equation 1

2) heteroannelation of a suitably functionalized caprolactam

(6)

(13) R=H

( 14) R =CO2EI

Equation 2 52

3) annelation of a suitably functionaìized pyrro'le

ET + ozH H H H

( 15 ) (16) ( 17 )

(s) Equation 3

The chemistry depicted in Equation 1, which would hopefully 'lead to a synthesis of the precursor molecule (5), clearly required the ring expansion of the 7-oxotetrahydroindoles (11) or (12) to occur in a predictable manner. AccordinglJ, in the Beckmann rearrangement of the corresponding oximes (18) and (19) the migration of bond "a" rather than bond "b" would be necessary as shown in Scheme 3, and the same is true in the Schmidt reaction of ketones (11) and (12).

bond 'a' H H

Beckmann (6) R=H rearrangement (5) R= COrEt

H ,lrr4OH bond 'b' (18) R= H (19) R= COzEt H H SCHEME 3 (20) R=H (21) R= COzEt 53

N H H

+ (23) Hso

I -rNMe H (22) .H

(24)

SCHEME 4

It has been reportedl3 that both the syn and onti oximes of 2-acetylpyrrole (221 undergo facile Beckmann rearrangement to give only N-methyl-2-pyrrolecarboxamide (2a) and none of the alternative reamangement product (23) (Scheme 4). 54

HNs

Í H H (25) (26) Equation 4

rln^oTs

base

I R R

27 ) R=H Equation 5 (28) R=H

29 ) R= Me (30) R=Me

To understand these facts it was suggested that the syn oxime, the thermodynamically more stable isomer due to hydrogen bonding (as depicted in Scheme 4), was formed upon pro'longed heating of the mixture. The rearrangement of this isomer then produced only (24) as would be expected. Thus a paraìlel could be drawn between the rearrangement of (22) and that of the oximes (18) and (19) in which simiìar hydrogen bonding could exist. The Beckmann rearrangement of Z-cyclohexen-l-one oximes reported in the literature show that the migrating bond tends to be the one possessing the least double bond character.14 0n the basis of this evidence the oximes (18) and (19) should rearrange to give the desired pyrroloazepine systems (6) and (5) respectively.

A few examples which support this are shown above in Equations

415 and 516'17 DISCUSSION 55

3.1 The most direct approach to ester (I2), the progenitor of the pyrroloazepine subtarget (5) (see Equation 1), was considered to be that shown in Scheme 5.

o2Er co zEt MerN t

ll (31) ( 10) o2Er

orN l¡r

(32) zÊl cOrEt

H (33) (12)

Key ¡ DMF dimethyl acetal ¡¡ Base, NO2-X !t¡ nrl edfc iv Base, NH2-X

SCHEME 5 56

Starting with the readily available Hagemann's ester (10),

reaction with dimethyìformamide dimethyl aceta'l b,as expected to give the enamino-ketone (31).18 The anionl9 d..ived from

Hagemann's ester, by treatment with sodium. ethoxide i,n ethanol, has been reported to undergo aìky'latíon at the 3-position with reactive alkylating agents .19'20 By anaìogy, one might expect enamine (31) to be aminated using a suitable reagent to g'ive the

intermediate amino compound (33). Reagents such as

o-tosyì hydroxyl uri ne21 and 0- (2,4-dini trophenyl ) hydroxyl ami ne22 as well as otherr23 huu. been used to successfuììy aminate resonance stabilized carbanions. A possible variation of this approach would be the nitration24(0. nitrosationzs)ot the anion

derived from (10) to give the nitro-enamine (32), folìowed by reduction directly to the 7-oxotetrahydroindole (12). This type from of methodo'logy has been used in the synthesìs of indol.r26-28 enamines such as (34), as illustrated in Scheme 6.

Unfortunately, refluxing a mixture of Hagemann's ester

with DMF dimethyl acetal failed to produce any of the required

enamine (31) giving instead the isomeric compound (35).

Et cO2Et co 2

MerN

(35) (36) 57

M"z MetN eafc \- H2 o2

(34)

- HNMe 2

SCHEME 6

In order to circumvent this problem Hagemann's ester was converted to the ketal2n (go). It was hoped that the most acidic and easily

accessible protons would now be those of the methyl group. However,

the ketal failed to react with Dl'lF dimethyl acetal under a variety of conditions 53

Bredereck's reagent3o (bis(dimethy'lamino)-t-butoxymethane), a much more reactive equivalent which has been used in cases where

DMF dimethyì acetal will not react, also failed to form the required enamine, returning instead the ketal. It is known that the reactivity of DMF acetals and aminals is related to-the pKar3l'32 of the reactants. Perhaps formation of the anion at the methyì carbon of (36) is not favoured due to the cisoid nature of this species, which would prohibit fulì conjugation.

At this stage it appeared from experimenta'l evidence that alkyìation of Hagemann's ester lvas not possible at the methyl carbon.S5Thm it was decided to reorder the reaction sequence shown previously in Scheme 5. Formation of the nitro compound

(37) was firstìy necessary, followed then by reaction with DMF dimethyl acetal to give the required enamine (32) (Scheme 7).

o2Er co2Er

Base 7 NO¡X ozN

(37) ( 10) DMF dimethyl acetal

EI c ozEr M.z t'l \ N orN H SCHEME 7 (12) (32) 59

Unfortunately, using a variety of nitrating agents and conditions, only small amounts (ca. <5%) of (37), which was found to oxidize upon work up, could be detected. The anion of Hagemann's ester (generated with sodium ethoxide in ethanol) failed to react with conventional nitrating agents such as ethy'l nitrate24 and iso-amyl nitrate24 even after extensive reflux.

When potassium t-butoxide in THF was used to generate the anion, a procedure which has been reported to substantially improve the yi e'l ds of cr-ni trati on of cycl ohexanones ,31 fol I owed by treatment

'i wi th so-amy'l ni trate, no such improvement i n the yì eld of (37 ) was evident. Subjecting Hagemann's ester to a mixture of acetyl nitrate32 and sodium acetate (to generate equiìibrium amounts of the anion) at 'low temperatures or even room temperature again resulted in no reaction. In all cases the maiority of the ester uras recovered unchanged. 60

3.2 A less adventurous synthesis of the alternative nitro compound (39) presented itself (Scheme 8). It was expected that

R R

(38a) R= H (3ea) (aOa) (3Bb) R= Me (3eb) (4ob)

R <_ 4 orN

(11) R= H (ala) (42) R= Me (41b)

SCHEME 8 treatment of the model compound nitrodimedone (39b)33 with either phosphorus trichlorid.34 or oxalyl chloride35 would convert it to

3-chloro-2-nitrodimedone (40b). However with these and many other 61

reagents the sole product was always a dimeric species containing no chlorine atoms. This adduct was tentatively assigned the structure (43) on the basis of the available spectral data. Although it was clear from observing molecular models of (43)

o-I (43)

that a C. axis of symmetry was inherent, the "doubling up" of the three expected resonances for the methyl, methylene and viny]ic protons couìd not be explained.

The methoxy derivative (44) was chosen as a substitute for (40b) and prepared by heating (39b) with potassium carbonate and dimethyl sulfate in acetone. Although a preparation of this

MeO

(44) o 62

compound has been reported,36 b, treating 2-nitrodimedone (39b) with diazomethane in ether, this procedure was felt to be less amenable to ìarge scaìe work.

Preliminary experiments with the methoxy compound (44) indicated that the addition of dimethyìcuprate3T proceeded extremeìy rapidìy but resulted in the formation of the tetramethy'l compound (45). Although this was unexpected,it can with hindsight

(4s) o

be understood since the initial product (41b) would be an avid Michael acceptor. This information and the difficulty experienced in reproducing the synthesis reported for 2-nitrocyclohexane- l,3-dione (gga)38 led to the abandonment of this as a pathway to the 7-oxotetrahydroindole system. 63

3.3 Following on from this, it v'¡as conceivable that if the ethoxycarbonyl group of Hagemann's ester was removed,then this might facilitate reaction with dimethylformamide dÍmethyì acetal, by destabilizing the three possible anions (Equation 6).

R \ R+ - @

(e) R=H

(46) R= Me

Equation 6

The 3-methyl hydrogens were nou, expected to be comparable in

acidity to the 4-methy'lene hydrogens. Hence on treatment with

DMF dimethyl acetal, a mixture of enamines was expected.

Although 3-methyì-2-cyclohexen-1-one (9), ca.n be prepared from Hagemann', .ster39'40 it was decided that isophorone (46)

wouìd serve as a modeì compound because of its ready availability.

Indee4 when a mixture of isophorone and 1.5 equ'ivalents of

DMF dimethyl acetal was refluxed for 3 hours, a dark red viscous oil was formed. Fractional distillation of the crude mixture

gave two products: the required enamine (47) (73%) and the isomer

(48) (2A/"). The structure of compound (47) was determined by 1'H n.m.r. spectroscopy; the splitting pattern of the two adjacent

vinyìic protons of the enamine double bond was diagnostic. 64

Mez

o Me

(+l'¡ ( 48)

It was thought that compound (47) might be used to arrive at the oxime

of the appropriate 7-oxotetrahydroindole (a9) as outlined in Scheme 9.

H MerN NH2OH excess

H 6 \on

(471

Base

+ Hgo

( H Beckmann ) H H !^on

(50) (4e)

SCHEME 9 65

Substitution of the dimethylamino residue of similar

compounds such as enamino esters4l und conjugated amidines42

has been reported and proceeds in good yield. When the enamino- ketone (+Z) was treated with excess hydroxy'lamine hydrochloride

in refluxing ethanol with sodium acetate, the orange colour of (47) disappeared within a few minutes. l^lork up of the solution gave a colourless crystalline solid as the onìy product (95%),

which was identified as the spiro-oxime (51). A 'likely mechanism

for its formation is shown in Scheme 10.

H M HON

Nr-LoH

(47)

NH2OH 2 \x

(51)

SCHEME 10 66

Repetition of this reaction using onìy one equivalent of

hydroxylamine gave a 50% yield of (51). This suggested that

the intramolecular conjugate addition occurred first and was followed by the trapping of the saturated ketone to give the

oxime (51). l,'lhen acetic acid was used instead of sodium acetate

a complex mixture of products resulted, with only a small amount of (51) evident by 'H1 n.m.r. spectroscopy. In order to prevent the intramolecular 1,4-addition an 0-substituted

hydroxylamine was clearly required. Methoxyamine was chosen as a suitable reagent,and under similar conditions the bismethy'l- oxime (52) was unexpectedly formed in nearly quantitative yield as a mixture of isomers.

ruaH/rHr Me o PPA 11 o th HMPTA n'uotne (s2)

UNKNOWN (dimeric species) Meod ^ %ott" (53)

Hso +

H q,rOMe ( 54)

SCHEME 11 67

Attempts to cyc'lize (52) (Scheme 11) in order to prepare the methyloxÍ¡he (54) were to no avail. Applying the experimental conditions of Storkf3 who regiose'lectiveìy aìkylated the N,N-dimethylhydrazone of isophorone (55) (Scheme 12), succeeded onìy in the decomposition of (52).

ruaH/rHr 1. R.X + HMPTA 2. H3O R

\1 NMe2 NM%

(55)

SCHEME 12

However, the initial red colour of the solution indicated that the anion (53) may have been formed.

When (52) was heated in po'lyphosphoric acid at 110o decomposition of the starting material was the prominent reaction. A small amount of an unidentifíed compound was isolated, the spectraì data of which indicated that it was a dimeric species.

This was probably formed in a Diels-Alder type reaction as will be discussed for the enamine (47).

The enamine (47) was also treated with other N-substituted amines in order to ascertain whether the reaction suggested in

Equation 7 was a viable method for the preparation of a

7-oxotetrahydroindole. system and these reactions are summarized in Table I following. 68

Base

H H

(42)

Equation 7

Table 1

Reactions of enamine (47) with va.rious N-substituted amines.

Ami ne Sol vent Condi ti ons Resul t

refl ux Starting material recovered NH2-0-S02H Benzene

refl ux +KotBu

room Starting material temp. recovered overni ght NHz-NMez Ethanol

refl ux unidentified mixture of 2Èh products.

An extension of this work which appeared promising was the possible conversion of enamine (47) to the vinyl azide (56) (Equation 8). 69

M"z N3-

¡+t) ( so) Equation I

It was conceivable that (56) might be induced to cyclize to (42)

by loss of nitrogen as suggested in Equation 7 (X=Nr). A

precedent in the literature u,as the cycìization of certain styryì

azides, either thermaì'ly or photochemicaììy to render indoles as the major products .44'45 Attempts to substitute the dimethyìamino group of (a7) with sodium azide in ref'luxing dimethylformamide, methanol or tetrahydrofuran were surprisingly unproductive. Stirring a two phase mixture of the enamine in chloroform and a saturated aqueous solution of sodium azide

containing methyltri'n-octyl ammonium chloride also failed.

The use of excess tetra-n- butylammonium azid.46 'in chloroform

similarly gave no substitution product with (47). When an acetic

acid solution of the enamine and sodium azide was heated for a short time, no pyrrole-like material was formed, but instead the

aromatized compound (57) was isolated.

Mass spectraì data suggested the formation of a dimeric lH species white the n.r... spectrum indicated resonances characteristic of isophorone and a trisubstituted aromatic ring.

The same product was obtained when (47) was heated alone in acetic 70

acid which indicated that a vinyl azide was not an intermediate.

A probable mechanism is shown in Scheme 13.

tn H Me.N .1 H+ )

* Me, ilt"t H

(57)

SCHEME 13 U]IdVH] ' 7T

4.1

A more successful route to the 7-oxotetrahydroindole system was finaì1y developed. It was strongly expected that enamines of the type (59) might be heteroannelated by heating

with dimethyìformamide dimethyl acetal (Scheme 14). A'lthough no precedent existed in the literature for the formation of pyrroìe

systems in this fashion, similar methodology had been empìoyed in the synthesis of Z-pyridinones.4T Formation of the intermediate shown would render the electron deficient methine carbon of the

mixed acetal function susceptible to attack by an anion formed at the methyl carbon. This would lead, after elimination of methyl- amine , to the required aromatic system.

Enamines such as (59) have been prepared by reacting substituted 2,3-epoxycyclohexanones with the required primary amines49'5lb'51c or secondary amines.48-51u Although (sga)a9

and (Sgc)48 have been prepared by this route (59b) and (59e) have

not been documented. It was hoped that the benzyl moiety m'ight be used as a protecting group for the completed pyrrole ring

system because of the notorious instability of the free amines.

The removal of benzyì protecting groups from pyrroles has been accompìished by hydrogenation. 52 ,53

Should this method fai'1, the unsubstituted pyrro'le could alternatively be obtained by utilizing the reaction of the primary amines (59a) or (59c) with dimethylformamide dimethyl

acetal. The corresponding cyc'lized compounds were expected to

have some stabiìity conferred upon them by the adjacent carbonyl group. 72

1 1

2 RNH 2

1 R-H (58a) (sga) Rl= R2= H d= ue (sau¡ (5eb) C= H , R2= Bz (ssc) C= Me, R2= H (5ed) Rî= Me, R2= Bz (r1o-; Q' - lr! ., &'. + lt"o&r.

DMF dimethyl acetal

I c I

(tr) nl= R2= H (42) Rî= Mê, R2= H (s0a)R1= H ,R2=Bz (OOU) nt= Mê, R2= Bz

SCHEME 14 73

Isophorone epoxide (58b) was used as a model compound but when treated with benzylamine in aqueous methanol at room temperaturg,50 none of the expected enamine (59d) was formed. Instead, the jmjne (Ot) could be isolated in nearìy quantitative yield. Upon continued heating of this compound rearrangement occurred to produce the desired product (59d) the maximum yie'ld being 58%. A possible mechanism is suggested in Scheme 15.

H^O¿\ H t H OH

\8, I Bz Bz (ot¡ 1t

<_ HO

Bz o (sed)

SCHEME 15

Altering the amount of benzylamine had no significant effect

on the outcome of the reaction. No reaction was observed in the absence of water. The use of higher boiling solvents such as 1-propanol markedly decreased the reaction time required, from 16h (in methanol) to 4åh. contrary to this, the reaction 74 of isophorone epoxide with secondary amines, for examp'le morpholine, was very rapid even in methanol and gave the morpholino-enamine (62) in 90% after overnight refìux. Compounds of this type have been documented.49'50

N (62)

Enamine (59d) cyclized as expected when heated with excess dimethy'lformamide dimethy'l acetal at L50o overnight. A 70% yieìd of the 7-oxotetrahydroindole (60b) could thus be obtained.

Repetition of this sequence with the required epoxide (58a) furnished enamine (SgO) in 70% yie'ld, cyclization of which produced the

7-oxotetrahydroi ndol e ( 60a) .

The formation of the N-unsubstituted derivatives (11) and (a2) by this methodology proved impossible. Firstly the model substrate, enamine (59c),could not be synthesized from isophorone epoxide. Indeed, the epox'ide could not be made to react with

ammonia under a variety of conditions (summarized in Table 2 of the experimentaì section). Chemical equivalents of ammonia such as dial'lylamine and hexamethyldisilazane, the protecting groups of which can be removed,54'55 proved unreactive with isophorone epoxide even

when heated neat. However if an emulsion of isophorone epoxide

in excess concentrated ammonia was sonicated for 6h, a L9% yieìd 75

of the enamine (59c) could be achieved after 6 hours. In contrast to this, epoxide (S8a) reacted smooth'ly in concentrated aqueous ammonia at 35" to give the enamine (59a) in 39% yieìd.

Unfortunately,when this compound was heated with dimethylformamide dimethy'l acetal, annelation to the 7-oxotetrahydroindole did not take place. The sole product from this reaction vÀ,as identified as the amidine (63) which proved most resistant to any attempts at cyclization as summarized in Scheme 16.

DMF dimethyl acetal

o 150 Me 2

(5ea) (63)

1 excess acetal ,15oor15h or z NaHf THF , 8oo, 6h or s polyphosphoric acid, tzsl gn or 4 DMF , tsoo, l5h or s CFTCOTH , rooo, I h

(11) SCHEME 16 76

The reluctance of (63) to undergo cyclization under basic conditions may be due to the fact that the predominant pathway would be'uia the non-concerted S-endn'trigonal ring cìosure' contrary to Baldwin's rules.56'57 (Figure 1).

+ Me 2 H

5 - Endo -Trig 5- Exo-Trig

Figure 1

However, under acid catalysis the expected mode of cyc'lization would be the 5-eæo-trigona'l process, an allowed reaction. Since no cyclization was observed in PPA or trifluoroacetic acid, other factors are also responsible.

It is interestìng to note that anaìogous aromatic systems have been cyc'lized to indoles, but only when the methyì group is suffjcientìy activated by an electron-withdrawing substituent such as nitrile or ethoxycarbonyl. In these cases, longer reaction times are still necessary. For example, the imine (64) could not be induced to cycljze even in the presence of strong bases, whereas (65) required only five hours heating with tithium t-butoxide to produce the indole (66)58 (Scheme 17). 77 t c Er

H (64 )

ET orEt tBroH 1. LrotBu/ f a5h \ 2. hydrolysis Me

(65 ) (66 )

SCHEME 17

A few alternative routes to the N-unsubstituted 7-oxotetrahydro-

indote (11) seemed p'lausible using the epoxide (58a) as the starting materia'1. Literature precedence for the reaction of

cycìic epoxides with azide59-61 suggested that this ion could be

made to react with (58a) to give an intermediate azido-alcohol. Subsequent dehydration might then furnish the vinyì azide (67). Similarìy reaction with nitrite ion, although not documented' might be expected to give the nitro compound (69) (Scheme 18). Both (67) and (69) would then have a sufficientìy activated methyì group to permit facile reaction with dimethyìformamide 78

(58a) Hp No; I ,ro

o2 (67) (os¡

DMF acetal DMF acetal

\ I \ M M

a2 (68) ( 70)

['] [']

(11)

SCHEME 18 79 dimethyl acetal. Reductjon of the corresponding vinyl azide (68)60'62 and enamine (70) should then yield the desired product (11).

However, when the epoxide (58a) was treated with various azide sources utilizing a range of conditions, (Table3 in experimental section) no evidence could be obtained for the formation of vinyl azide (67). Aìthough reaction occurred jn refluxing d'ioxane/water with sodium azid.,59 the product, whose i.r. spectrum exhibited no azide absorbance, decomposed before it could be characterized.

The epoxìde (5Ba) behaved as expected with nitrite jon to give the nitro compound (0g) albeit in mediocre yìeld. This was achieved by reìuxing a two phase mixture of saturated potassium nitrite and dioxane containing (58a). The identity of the

¡6^nn,NMe 2

(71)

product (71) from the reaction of (69) with dimethy'lformamide dimethyl a6etaì v,,as unexpected as it was derived by reaction of the anion formed at the methyìene carbon. The increased acidjty of these hydrogens probably resulted from the greater stabilization offered by the anion (due to its transoid relationship with the nitro group). Alternative attempts to prepare the model N-unsubstituted-7-oxotetrahydroindole (a2) by reaction of the 80

epoxide (58b) with various equivalents of the aminomethyìene synthon were also fruitless. These are summarized in Scheme 19.

The carbamate (74) could be prepared by treatment of the enamine (59a) with ethyl chloroformate but it could not be induced to cycìize when heated with dimethylformamide dimethyl acetal or bis(dimethyìamino)-t-butoxymethane.63 The ethoxycarbony'l group was expected to be cleaved under mild conditions, for example with trimethyìsilyl íodide.64 Treatment of the carbamate with base could in theory ìnduce cyclization onto the carbonyl carbon, but (77) cou'ld easily be converted to the desired (ll ) as shown in Scheme 19.65 Also, the formamide (73) could not be prepared by refluxing a solution of the enamine (Sgc) in formic ac'id nor with the mixed anhydride of formic acid/acetic anhydrid..66 The reactions of isophorone epoxide with formaldoxime6T and formamidinium acetate did not give rise to the expected intermediates (75) and (72) nor was there any evidence to suggest cycìization of these to

(42). The structures of the resultant products could not be determined from the available data. In addition, attempted heteroannelation of the enamine (59a) with trimethylorthoformate or bis(dimethy'lam'ino)-t-butoxymethane once again gave none of the desired product (11) (Equation 9). 8l

(s8b)

OH \ N:CH2 eton H2 f F\^, NHZ -OAc

+ x (75 )

/NHz {- N-CH (72)

f,= N-CHO (73 ) H

(74)

N Et H

DMF acetal Base OR

(76) (77)

E ,'. TMSI [H] z' -Hro

H (11)

SCHEME 19 82

1. Hc(oMe)r,rooo,15h or 2. (NMe)2cH deu

(5ea) (11)

Equation I

sjnce the free pyrroìe (11) could not be obtained directly by cyclization of the unsubstituted enamine (59a), hydrogenolysis of the benzyl group from the substituted compound (60b) was investigated (Equation 10). Even this course of action proved fruitless as the benzyl group proved extremely resistant to hydrogenolysis; for example hydrogenation of (60b) in methanol or ethanot at 1 atmosphere using freshly prepared L0% palìadium on charcoal catalyst68 returned the material quantitatively. The addition of a few drops of concentrated hydrochloric acid69

t',l

Þt I, ( 6ob) (42)

Equation 10

had no effect. Simitar difficulties have been encountered with 1-benzyl-4-oxotetrahydroindoles .70'7L For these compounds the 83 removal of the benzyl group can be accomplished by brief treatment with sodium in I iquid arnrnonia solution .72'73 lJhen this procedure was app'lied to (60a), a mixture of two compounds resulted but unfortunateìy both oxidized extreme'ly rapidìy and could not be lH characterized. However, the n.t.r. spectrum of the crude mixture confirmed that the benzy'l group had been cleaved.

It was felt that the 4-methoxybenzyì group might be more readily remove¿74 ay hydrogenoìysis and so the enam'ine (5ge)

(Rr=¡, R2=4-Me0Bz) was prepared utilizing the reaction of 4-methoxybenzy'lamine with the epoxide (58a). Surprisingìy the enamine could not be induced to react with dimethylformamide dimethyl acetal to give the corresponding 7-oxotetrahydroindole under any conditions; a dark intractible material was formed i nstead.

The results of this work suggested that removal of the benzyl group by reduction would be best accomplished after the ring expansion of the ketones (60a) and (60b) to the pyrroloazepinone systems (see Equation 1). Reduction of the amide functionality with sodium in l iquid ammonia uJas not expected to 0..u.,75 since a dianion would presumab'ly be formed on cleavage of the benzyì group. During the preparation of a related 7-oxotetrahydroindole (80) from the appropriate enamine (79) it was noted that this compound could not be cycìized under the usual conditions (Scheme 20). Presumably under the basic cyclization conditions, removal of the proton adiacent to the ethoxycarbonyl group generated a stabilized anion which could not react any further. 84

o2Ei 02Et cqEr

BzNH, DMF

1-PrOH /uro I Bz

( za¡ (7e ) ( 80)

SCHEME 20

Fol I owi ng the strategy outl i ned previ ousìy 'in Equat'ion 1 , the preparation of the oximes of ketones (60a) and (60b) was attempted but disappointing results were obtained.

l Bz \ox

(ooa) R=H (81a) R=H

(6ob) R= Me (81b) R= Me

Neither of the ketones afforded the corresponding oximes under the more usual conditions .r7 '72'76 It seemed most likety that

extensive conjugati on77 '78 of the nitrogen ìone pair electrons into the carbonyl function was prohibiting nucleophilic attack by hydroxyìamine. In an attempt to overcome this probìem more 85 acidic conditions were used. Refluxing an ethanolic soìution of (60a) with excess hydroxyìamine hydrochloride overnigntTS ted onìy to compìete recovery of the starting material. Stirring a solution of (OOa) in acetic acid78 with hydroxylamine hydrochloride overnight gave the same results, while heating led on'ly to decomposition of (60a). When a methanol solutjon of (60a) containing excess hydroxylam'ine chloride was heated overnight, a new set of resonances, corresponding to the two pyrrole aromatic lH protons was observed in the n.t.r. spectrum of the mixture. Although the yield appeared reasonable (50%), attempted isolation led to poor recovery of the oxime, its presence, however, being confirmed subsequently by accurate mass measurement. Adding cata'lytic amounts of hydrochloric aciil led to rapid decomposition lH of the ketone (60a). There vlas no suggestion by n.t.r. spectroscopy that rearrangement of oxime (81a) was occurring in sítu which had been reported for similar reactionr.TS Although oximes of 4-oxotetrahydroindoles, e.g. (82)78 have been prepared it is plausible that in these cases less coniugation of the carbonyl group with the nitrogen lone pair exists. It is welì known that alkylation, arylation and nitration of pyrrole is preferred at the 2-position with little at the 3-position. In addition, the benzyl group in the case of interest may have presented steric problems. 86

l Me

(82)

0n account of the fa'ilure of ketones (OOa) and (60b) to form oximes in quantities amenable to large scale work, it was decided to examine the Schmidt reaction of these compounds. Once again, even under the most acidic and forcing conditions only a trace of the rearrangement product could be obtained. Heating the ketone (60b) in polyphosphoric acid with excess sodium az'ide at 80o for 2h onìy led to its recovery unchanged. Trace amounts of the rearrangement product (83b) v,,ere isolated from the same reactjon carried out at 100o for 4h. Higher temperatures led to debenzyìation of the starting material to give (42) (Scheme 21) and several other unidentified products. The use of systems Such as concentrated hydrochloric acid/sodium azideTg and concentrated su'lphuric acid/ether/sod'ium azideS0 gave no rearranged material. Similar'ly heat'ing ketone (60a) with one equivalent of hydroxyì - amine-Q-sulphonic acid in formìc acid81 fo. several hours led on'ly to its recovery unchanged. 87

(s3b) H

I ruar.ry' ePn Bz

I o Bz 120

(6ob) H

(42)

SCHEME 21

Due to the unwillingness of the carbony'l functions of ketones (60a) and (60b) to undergo nucleophilic attack, a variation of this route which involves the chemistry presented earlier in Equation 1, will be discussed in the next section. The ready availabitity of the 7-oxotetrahydroindole system by this route could however lead to a synthesis of difficuìtly substituted indol.r.82 88

4.2 In view of the failure of the ketones (60a) and (60b) to undergo ring expansion an early incorporation of the oxime

functionality was investigated as shown in Scheme 22. Thus reaction of the epoxy-oxime (8aa) with benzylamine folìowed by heteroannelation of the product (85a) was hoped to give the oxime (81a).

R R .-

H \ \" L 'oH

R= H (s8a) (Baa) (8sa ) R= Me (58b) (84b) (8sb)

I l Bz Bz H

R=H (B2a ) (8la) R= Me (ezu¡ (81b)

SCHEME 22 89

Utilizing isophorone epoxide as a model compound, reaction with hydroxyìamine in aqueous ethanol gave the epoxy-oxime (g+u).83'84

Refluxing a solution of this compound and benzylamine in methanol gave the hydroxyamine (86b) in 74% as well as a small amount of the regioisomer (87b) (tlT).

R/ H BZ Nrttttt H

*ttttn" HO " I B z \o" \o"

(86b) R,--tl. (87b) (tL ø) Rt{

13C The n.m.r. spectrum of (B6b) clearìy showed it to be the required isomer due to the doublet resonance centred at 65.7 ppm for C-2 in the off-resonance spectrum (Diagram 1). Dehydration of (86b) pnoved to be more difficult than expected considering the fact that this compound was a tertiary alcohol. The more usual methods summarized in Table 4 of the experimentaì section returned on'ly the starting material. Vacuum pyroìysis of (B6b) at 0.3 mm through a heated silica tube at temperaturesbelow 350o gave the same result. At 550' some dehydrated material was

1 evident by 'H n.m.r. spectroscopy a'lthough much decomposition had occurred. Fortunately, heating a mixture of either (B6a) or (86b) with powdered lithium hydroxide led to dehydration and a clean

conversion to the enamines (gSa) or (85b). 13c 2o.1 MHz nmr spectrum

H HNttttt"'

a 6 q",on

5 1

Off- resonance

C-4,5; 3xMe N-C H2 c-3 c-2 c-2'-o' c-6 c-1 c-1' Decoupled

160 150 140 130 120 1f0 100 90 80 70 60 50 40 30 20 10 0 ppm (o O

Diagram 1 91

Unfortunately, neither of lhe enamines could be induced to cyclize when heated with dimethylfo.rmamide dimethyl acetal. Methylation of the oximeS6 function appeared to have occurred firstn but the methyloximes could not be made to react further.

Al though bi s ( di methyl ami no) -t-butoxymethaneST o. tri s ( di methyl ami no ) - methaneSS are more reactive alternatives to dimethylformamide dimethyl acetal, their use was not tried. 92

4.3 The final alternative strategy which could be used to arrive at the pyrroloazepinone system, b,as that suggested in Equation 2. This required the formation of the azepinone first, then annelation to form the pyrrole ring (Scheme 23). The starting caproìactam (13) was obtained by the Schmidt reaction of

3-methyì -2-cyclohexen-1-0n..79 Epoxidation of (13) cou'ld not be achieved by reaction with alkaline hydrogen peroxideSg or by using m-chloroperbenzoic acid.90 However (88) could be prepared indirectly via the bromohydrìn (89) with aqueous sodium hydroxide9l at room temperature. A small amount of the unreactiYê còs bromohydrin was recovered from this reaction upon bulb to bulb distillation. Treatment of the crude epoxide with benzylamine in refluxing aqueous 1 -propanoì gave a mixture of products. Bulb to bulb distitlation of the crude reaction mixture over potassium bisulphategz under reduced pressure, in order to affect dehydration, gave the starting epoxide (2O%) as well as some of the eis hydroxyamine (90a). This was unexpected but might be explained by the initial formation of the trans isomer foì1owed by isomerization to the thermodynamic product (90a) The extensive

hydrogen bonding possible in this compound was clearly evident from the observation of molecular models. This was supported by the

1 'H n.m.r. spectrum which showed the benzy'lic methylene hydrogens

of (90a) to ue diastefttopic in nature giving rise to a clear AB quartet (Diagram 2). A superior method was later found which involved heating the trans bromohydrin (89) with benzylamine in

aqueous methanol. A quantitative yield of the pure cis 93

OH I H2 o2

H H

(13) (88)

2 rrres/Hro Hzo

BzNH2 Hol t tt" ]10\t"

H r,neory'nrof Hco3- H Br H ñ,ut'

I Bz

(89) rnans (90a) cts (90b) rRANS

DMF dimethyl acetal

H t{ H

Bz z

(83a) ( e1)

SCHEME 23 H tH 60 MHz ntl. spectrum

,,r/// N __ s H (90a) H_c_H

I A t

(o Þ

ppm Diagram 2 95

hydroxyamine was obtained in this manner.

Attempted dehydration of (90a) by vacuum distillation over powdered potassium bisulphate was only partiaìly successful, whereas lithium hydroxide gave the corresponding enamine (91) in 80% yield. Unfortunately, as was experienced with the enamino- oximes (85) previously, the azepinone (91) could not be heteroannelated with dimethylformamide dimethyl acetal. No lH cycì'ized material was ever observed utilizing n.*.r- spectroscopy. The use of the more reactive bis(dimethyìamino)- t-butoxymethane was also unsuccessful. A possible reason for this lack of reactivity might be attributed to the removal of the acidic amide hydrogen to form an anion. This wouìd make formation of a second anion at the required methyl carbon less likely. 0n the other hand the amide (g2) has been reacted with bis(dimethylamino)- t-butoxymethane to give the enamine (93) with no complications (Equation 11).

(rr¡e 2 N)2cHdeu

H 1600, 4-24h H Mgl'l 57% (e2) (e3)

Equation 11

The failure to arrive at a fused pyrrole/caprolactam system by any of the previous methodology led to an elegant and more direct approach which is discussed in the next chapter. 96

4.4

The most successful and perhaps the simpìest approach to the pyrroloazepine system was that depicted previousìy in Equation 3 and represented in Scheme 24. This type of methodology had been documented in the 'literature as a convenient method for the preparation of two reìated compounds (g+)94an¿ (95)95.

H H H

( e4) (e5 )

Ihus it was hoped that pyrrole-2-carboxylic acid (15) might be condensed with either ethyl 3-aminopropionate (tO)96 or 3-aminopropionitrile (96) to give the amides (98) and (97) respectively. Hydrolysis of either to the corresponding acid (17) and cycìization using polyphsophoric acid (which was used in the preparation of (94)) would presumably give the required pyrro'loazep'indione (3). The amides (97) and (98) were formed in excellent yields (90-100%) by the use of dicyclohexylcarbodiimideeT in acetonitriìe. Attempted hydroìysis of the nitrile (97) to the acid was unsatisfactory under any conditions including refìuxing in aqueous methanol with potassium hydroxi¿e.94 The nitrile was usually recovered unchanged but in low yield. Contrary to this, the ester (98) underwent smooth hydrolysis to the acid (17) which 97

H H (15) Et N (e6) (ro)

N c o2E¡

H H

(sz¡ ( eB) oH/H2O

"o\

(17)

PPA

(3) H

SCHEME 24 98

proved to be extremely water soluble. This factor ìowered the yield to 53% and could also account for the low recovery of the nitrile on attempted hydrolysis. Cyctization of the acid (17) in po'lyphosphoric acid was best achieved (40%) when the mixture was vigorously stirred at 95o for 30 min. At 50-60" no cyclization was observed and temperatures higher than 100o led to rapid decomposition of the starting material. The pyrroìoazepindione (3) had identical spectraì data reported for this compound while 9B a mixture melting point with an authentic sample showed no depressi on .

Due to the ease with which the acid decomposed upon heating, milder conditions were sought for the cyclization. Attempted cyclization of the mixed anhydride (99) at room temperature or at 50" with tin tetrachloride95 returned (99) unchanged. (Scheme 25). /,co2E¡

H Et3N ' Oo H H cH2ct2

(17) (ee)

snct4f CH|C|2 ¡ RT 15h reflux 2h

(3)

SCHEME 25 99

When Eaton's reagent,99 a mixture of methanesu'lphonic acid and phosphorus pentoxide, was used instead of PPA, cyclization of (17) could be induced at 60" but the yield was low (10%) and much decomposition resulted. The nitrile (97) was recovered unchanged after an attempted cycìizatjon with PPA.95 In addition, when a solution of (97) in dioxane containìng anhydrous zinc chlorìde was saturated with dry hydrogen chloridel00'101 ¡^upid decomposition ensued. None of the cyc'lized prnoduct could be detected.

The failure of the substituted pyrroles (96), (17) and (99) to cycìize efficientìy could be partia'lly understood since the ability of pyrrole to be acyìated or nitrated at C-3 is very poor.

This and removal of some electron density from the aromatic ring by the amide carbonyl may have been contributing factors. A few preìiminary experiments were conducted at this stage to test the feasibility of the condensation reaction of the pyrroloazepindione

(¡) and glycocyamidine (7). When (3) was heated with gìycocyamidine hydrochloride in the presence of excess sodium acetatell in acetic acid for 3h a small amount of the amide (100) was isolated (Equation 12).

(101) 100

AcOH/NaOAc

H H H

(3) (7) (8) R=H

( 100) R= COMe

Equation 12

An accurate mass measurement of this compound proved impossible to

obtain due to the ease with which it decomposed at temperatures greater than 200o. Lower temperatures (180") and ion currents (18eV) gave rise to a retro-aldol reaction and the pyrroìoazepindione molecular ion was always the base peak. However daughter ions at

n/e 220, ZO5 could have been derived from loss of various fragments either from the glycocyamidine ring or the 7-membered ring of (100). The addition of small amounts of acetic anhydride to the reaction mixture to catalyse dehydration had no observable effect.

The acetyl derivative (101) was prepared in situ by repìacing the acetic acid with acetic anhydride. It was envisaged

that in this compound the carbonyl carbon would be more prone to nucleophilic attack bV (7). However, the maior product was the amide 101

o-¿L derivative (103¡1 was produced' (101)Ànone of the expected diacetyl

Rl- H

2 ( 102) R=H d=CoMe

(103) C= R'= CoMe

Only a few attempts to dehydrate ( 100) were attempted due to lack of material, and were unsuccessful. These were firstìy, treatment with acetic anhydride and pyridine and secondly, sublimation under reduced pressure. The first gave the amide (101) presumabìy uia a retro-aldol reaction while the second succeeded onìy 'in purifying the starting material .

In conclusion, although trial reactions suggested that dehydration of (100) to the natural product derivatives (102) or (103) could not be carried out, further work in this area is needed to verify this. This is currently being investigated. CHAPTER 5

EXPERIMENTAL 702

GENERAL

Melting points (m.p.) were measured on a Reichert hot stage microscope. Melting points and boiling points (b.p.) are uncorrected.

Microanalyses were performed by the Australian

Microanalytical Service, Melbourne.

Infrared spectra were recorded on either a Perkin-Elmer 397 infrared spectrophotometer or a Jasco IRA-1-grating infrared spectrophotometer using the 1603 cm-l band of polystyrene as a reference. Samples Were prepared as nuiol mulls unless otherwise stated. Solution spectra were determined in chloroform (CHCI3) with 0.2mm cells. 0n1y significant bands are quoted.

proton nuclear magnetic resonanc. (lH n.m.r.) spectra were recorded on a Varian T60 spectrometer or a Jeol JNM-PMX60 spectrometer both operating at 60 MHz, a Bruker WPBQ pulse Fourier Transform spectrometer operating at 80 MHz, or a Bruker CXP 300 pu'lse Fourier

Transform Spectrometer operating at 300 MHz. Samples !{ere dissolved in deuteriochloroform (CDCI¡) and spectra were calibrated using tetramethyls'ilane aS an internal standard unless otherwise stated. Samp'les dissolved in hexadeuterioacetone (CD3C0CD3) or hexadeuterlodimethyìsulphoxide (CDgSOCDg) were also calibrated with tetramethylsiìane. Data are presented as chem'ical shift (O) in parts per million (p.p.m.); multiplicity as sing]et (s), doubìet (d), triplet (t), quartet (q), doublet of doublets (dd), doublet of tripìets (dt), doublet of quartets (dq), AB quartet (ABq)' 103

complex multiplet (m); coupling constants (J) are expressed in Hz; relative intensities of resonances are expressed in whole proton units.

Carbon-l3 nuclear magnetic resonan.. (13C n.m.r.) spectra were determined using a Bruker WPBO spectrometer operating at

20.1 MHz. Samples were dissolved in CDCIs urìless otherwise stated and calibrated using TMS as an internal standard. Samp'les dissolved in CD.3C0CD3 or CD3S0CD3 were also calibrated using TMS. Spectra are quoted as o chemical shift downfield from TMS, multip'licity, assignment. Signaìs of carbons with long relaxation times were observed by acquiring spectra using a 4 second interval between pul ses.

Mass spectra were recorded on a Hitachi Perkin-Elmer

RMV-7D double focusing spectrometer or an AEI MS3074 Spectrometer both operating at 70eV. Qnly the molecular ion and/or signìficant fragment ions are quoted.

All solvents for chromatography, extractions or recrystal- lizations were redistilled. All solvents and reagents were purified by standard methods.tt' 0", ether and dry tetrahydrofuran were distilled from sodium/benzophenone under nitrogen immediately prior to use. Light petroleum refers to the fraction boi'ling between 63-67".

All organic extracts were dried using anhydrous sodium sulfate unless otherwise stated. 104

Analytical thin layer chromatography (t.t.c.) was performed using Merck Kieselgel 60 tZS4 uluminium foil backed plates or

Merck Atuminium oxide 150 FZS4 neutral (Type T) aluminium foil backed pìates. Preparative t.l.c. was carried out using 359 of a 1:1 mixture of Merck Kieselgel G and HFrUO coated on 200mm x

200mm glass plates. Càlumn chromatography *as cur.ied out using

Sorbsit sitica gel, Spence neutral alumina or [lJoelm neutral alumina (Ì,J 200 N, activity I). Flash chromatogruohrllu3, carried out using Merck Kieselgel 60 (230-400 mesh) undera nitrogen pressure of 5 p.s.i. 105

5.1

3.4-Dimethoxy-6-ni trobenzoic acid (15)

This compound was synthesized using a sìightly modified procedure to that used by Pschorr and Sumu'l.unu.35

3,4-D'imethoxy-6-nitrobenzaldehyde3s (2.00g, 9.48 mmo'l ) was suspended in water (50 ml) and solid potassium hydroxide (0.53g, 9.5 mmol) was added while the mixture was heated to 80o on a steam bath. Potassium permanganate (1.50S, 9.5 mmo'l) was then added in small portions until the purpìe colour persisted. The solution was then boiled for a further 10 min and filtered while hot. The colourless filtrate was acidified with dilute hydrochìoric acid and cooled in an ice bath. The yellow precipitate was collected and recrystallized from dichloromethane/ light petroleum to give the acid (15) as ye]low needles (1.50g, 7s%), m.p. 195-197' (1it.104 tgt-t92").

6-Amino-3.4-dimethoxybenzoic acid (17)

Th'is preparation u,as adapted from the method of Fetscher and Bogert36 who stated that they were unable to obtain reproducibìe yields of the amine. However, the method described belowwas found to give excellent and reproducibìe results.

3,4-Dimethoxy-6-nitrobenzoic acid (900mg, 3.96 mmol ) was di ssol ved i n ethanol ( 125 ml ) and p'l ati num oxi de (Adams ' cata'lyst) (100mg) was added to the solution. The stirred mixture was hdyrogenated undera pressure of 1 atmosphere until no more hydrogen 106

was absorbed (approx. 2h). The solvent was then removed in uaeuo and the crude compound recrysta'llized from ethyl acetate to give (17) as coìourless needìes (760 n9,97%), m.p. 184-185' (tit.35 tgO').

2-Bromo-N- ( 3 4 -di methoxvbenzvl i dene ) ani ì i ne ( 16)

3,4-Dimethoxybenza'ldehyde (10.0g, 60.2 mmol), 2-bromoaniline (10.36g, 60.2 mmol) and 4-toluenesulfonic acid (70m9) were dissolved in dry benzene (300 ml) and reluxed in a Dean-Stark water separator until the theoretical amount of water was collected (^,1]h). The solvent was then removed under reduced pressure to give an orange o'il (18.9S, 94%). Column chromatography on alumina and elution with- dichtoromethane followed by recrystallization from light petroleum gave the Schiff base (16) as paìe yeìlow needles, n.p.74.5-76" (Foundr C, 56.5; H,4.4; N,4.5. C:.sHraNO2Br requires C, 56.3; H, 4.4; N, 4.4%). vru* 1630, 1590, 1510 .r-1. N.m.r. ð 8.10, s, lI,HC=N i 7.63-6.73, m, 7H, ArH; 3.92, 3.88, 2 x s,OMe. 13C n.m.r. 6 149.8, 148.8, 145.3, 132.7, 131.7, 128.8, 119.8, 118.3, II2.0, 111.0,56.1,48.1. Mass spectrum m/e 319, 321 (M).

2-Bromo-N-(3.4-dimethoxybenzyl )ani I ine (14)

2-Bromo-N-(3,4-dimethoxybenzyl idene)ani ì ine (16) (5.009'

15.7 mmol) was dissolved in methanol (100 ml) and the solution stirred vigorously while sodium borohydride (3.55g, 94 mmol) was added slow'ly in small portions. After the addition was compìete the colourless solution was stirred for a further 15 min. r07

The bul k of the methanol was then removed under reduced pressure and the residue acidified with conc. hydrochloric acid to pH 1 in order to destroy any amine-borane complexes. The pH was then adjusted to 11 with conc. sodium hydroxide soìution and the mixture cooled in ice. The precipitated solid (3.70S) was removed by filtration and the aqueous solution extracted wìth dichloromethane

(3 x 50 ml ). The combined organic extracts were drjed and evaporated to yìeld a further amount of the crude product (1.0 g; total yieìd 93%). The crude amine was recrystallized twice from methanol to give (14) as colourless needles,m.p.84-85.5' (Found: C, 56.3; H, 5.1. CrsHreNOzBr requires C, 55.9; H, 5.0%). vru* 3400, 1600, 1510.r-1. N.m.r. ô 7.53-6.2, fr, 7H, ArH; 4.63, br, NH; 4.30, d, J 5Hz, ?H, CH2-N; 3.87, s, 6H, 2 x OMe. Mass spectrum m/e 321, 323 (M).

Attempted reaction of 2-bromo-N-(3,4-dimethoxybenzyl )ani I ine ( 14) wi th 2-dj azoni um-4,5-dimethoxybenzene carboxyl ate

6-Amino-3,4-dimethoxybenzoic acid (17) (197mg, 1.0 mmoì ) was dissolved in a mixture of methanol (2.0 ml) and conc. hydrochìoric acid (0.25 ml) and the solution cooled to approx. 0-5". To this solution was added one of sodium nitrite (70m9, 1.0 mmol) in water (0.2 mì). The resulting so'lution of the diazonium salt was then treated with crushed ice (2.0g), powdered potassium acetate (196m9, 2.0 mmol) and 2-bromo-N-(3,4-dimethoxybenzyl)aniline (14) (320 mg, 1.0 mmoì). The mixture was then stirred for th at 0-5" and 30 min at room temp. l^Jater (S ml ) was added and the brown precipitate collected by filtration. lH This compound was identified as (14) (280 mg,8O%l by its n.t.r. 108

and i.r. spectra.

The aqueous phase was extracted with dic\bromethane (3 x

10 ml) and the combined organic extracts were dried, filtered and

the solvent removed to give a black oil (100 mg). This oil which could not be purified further had the following spectral data:

1 vru, (CHCI3)3400-2400 (br), 1690, 1600' 1500' 1260 cm

N.m.r. 6 7.73-6.27, complex, 9H, ArH; 3.9, s, 6H' 2 x OMe. Mass spectrum m/e 363/365 (M ).

Attempted reac tìon of (14) with benzenediazonium carboxylate

(i) In methanol - Z-Aminobenzoic acid (137 mg, 1.0 mmol) was diazotized as described for (17) and treated with 2-bromo-N- (3,4-dimethoxybenzyl )aniline (14) (321 mS, 1.0 mmol ). The mixture was stirred for th at 0-5o and then 30 min at room temp. I^later (5.0 ml) was then added and the resultant precipitate removed by filtration. This material was found to be identical in all respects to (1a) (1SO mg,50%). Extraction of the aqueous phase at pHl w'ith dichloromethane gave a dark red oit (150 mg) which was

found to be a compìex mixture by t.ì.c.

(ii) In acetone/methanol - Z-Aminobenzoic acid (137 m9, 1.0 mmo'l) was dissolved in a mixture of methanol (1.0 ml), acetone (1.0 ml) and conc. hydrochloric acid (9.25 ml). The resulting solution was diazotized as descrjbed previously and then treated with crushed ice (2.0 g), powdered potass'ium acetate (196 m9,2.0 mmol) and 2-bromoJ,{{3,4-dimethoxybenzyl )aniline (14) (320 mg, 1.0 mmoì ). The red mixture was stirred for th at 0-5o and then 30 min at room temp. 109

The addition of water (S.O ml) resulted in the formation of a precipitate. This compound was shown to be the amine (14) (300 mg,

1 85%) by its'H n.m.r. and i.r. spectra. The aqueous phase was acidified to pHl w'ith hydrochloric acid and extracted with dichloromethane to yield a red oil (100 mg). This material was found to consist of a mjxture of several components by t.l.c. and was not investigated further.

Attempted oxidation of the Schiff base (16)

(i) Unbuffered - The Schiff base (16) (320 mg, 1.0 mmol) was dissolved in dichloromethane (0.5 ml) and the resultant pale yel'low solution cooled to approx 0" in an ice bath. A solution of m-choroperbenzoic acid (300 mg; 1.1 mmol) in dichloromethane

(2.0 mt) was added over 30 min and the colour of the solution changed to dark brown with the formation of a white precipitate. The mixture was then stirred at 0" for 30 min and allowed to warm to room temperature. The precipitate of m-chlorobenzoic acid vvas removed by fittration and the filtrate lvas concentrated to give a dark brown oil (a00 mg). Examination of the crude residue using t.l.c. (dichloromethane) showed it to be a gross mixture of products. Attempted separation by flash chromatography using dichloromethane gave a red oil (12a mg) which was shown to consist of at least two components. The higher R, material was f,ound to be 3,4-dimethoxybenza:ldehyde by t.1.c. and spectral analysis, while the second component could not be identified. Further elution with dichloromethane/ethyl acetate (9:1) gave a brown 110

crystalline solidt (50 mg) whose spectral properties wene consistent with those expected for the hydroxamic acid (25): vru* 3300 (br), 1660, 1600, 1510 cm-l. N.m.r. ô 8.46-8.08,2H,

H6' and 0H; 7.50-6.10, m, 7H, ArH; 3.73, s,6H,OMe. Mass spectrum m/e 351, 353 (M).

(ii) Buffered - A solution of the Schiff base (870 n9,2.73 mmo'l) in chloroform (10 ml) was added to a saturated solution of sodium bicarbonate (tO ml ) containing benzyìtriethyìammonium chloride (43 mg) and the resultant two phase system cooled to

0-5o. A soìution of m-chloroperbenzoic acid (610 mg, 3.00 mmo'l) in chloroform (tO ml) was then added dropwise with vigorous stirring over 30 min. The colour of the solution changed from pa'le yellow to a dark green during this time. After the addition was comp'lete the mixture was stirred at 5o for a further 15 min and then allowed to warm to room temp. The organic phase was separated and washed with water (5 mt), 10% sodium sulphite (2 x 5 mì) and saturated sodium chloride solution (Z ml). The solution was then dried, fiìtered, and the solvent removed to give a dark brown oil. Flash chromatography of the residue (ethyl acetate/dichloromethane) gave in order of elut'ion, the benzanilide (2a) (500 mg,55%) and the formamide (23) (230 mg, 25%). The identity of both products was confirmed by comparison of fl.p., i.r. and n.m.r. data wìth authentic sampìes.

The results of other attempted oxidations are summarized in Table 1. In each case the residue was examined by t.l.c. and by

1 'H n.m.r. and i.r. spectroscopy. t Th. solid oxidized in air and consequently an analytical sample could not be obtained. 111

Tabl e I

At d oxidations of the Schiff se 16 wi th m-chloroperbenzoic acjd (nCPBAL

m-CPBA Addition Reacti on Sol vent Resul t eq Time Temp Time Temp (min) ('c) (h) ( "c)

1.3 (solid) 20 2 20 compl ex m'ixture

2 30 20 2 20 compì ex mi xture

2 2 0 (i) I 0 compì ex mi xture (ii) 1 5 20 compl ex mi xture cH2cl 2 1 2 0 (i) I 0 compl ex mi xture (ii) 1 5 20 compl ex mi xture

1.1 30 0 mi xture with 20% al dehyde

1.1 60 0 compì ex mi xture

1.1 30 0 0.5 0 comp'lex (in dark) mi xture

Benzene 2.0 30 0 0.3 0 compì ex mi xture

Ethanol 1.0 (solid) 4B 20 startì ng ( sunl i sht) materi al recovered

15 0 (24) ( 16) cHct 3 1.1 30 0 25% 37% 712

2-Bromo-3',4' -dimethoxybenzani I ide (24)

A mixture of 2-bromoaniìine (410mg, 2.39 mmol),

3,4-dimethoxybenzoic acid (435m9 , 2.39 mmol ) and ethy'l poìyphosphate (1ml) was heated at 170" for th under nitrogen. The mixture was then cooled and water (-10 ml) was added in order to hydroìyse the polyp(sophate. The sol ut'ion was then neutral i zed w'i th sol i d sodìum carbonate and cooled in an ice bath. The resulting off-white precipitate was collected and recrysta'llized twice from ethanol to give the benzanilide (24) (580mg, 73%) as colourless needles, m.p. 148.5-150o (Found: C,53.5; H,4.4. CtrHtaN03Br requires C, 53.6; H, 4.2%). v*u* 3600, 3300, 1650 .*-1. N.m.r. ô 8.47,

8.33, dd, J 2, 8Hz, lH, ArH; 8.28, br s, NH; 7.60-6.73, m, 6H,

ArH; 3.92, s, 6H, 2 x OMe.

N- ( 2-Bromophen.yl ) h.ydrox.yl ami ne (26')

2-Bromonìtrobenzene (10.0g, 49.5 mmol) and ammonium chloride

(3.03g,56.7 mmol) were dissolved in a mixture of ethanol and water (1:1, 100m1). Zinc dust U.a$g, 115.0 mmol) was then added in small portions to the vigorously stirred solution. The temperature of the solution sìow'ly rose to 60o with the formation of a white precipitate of zinc oxide. After the addition was comp'lete, the solution v'Jas stirred for a further 20 min and then filtered. The zinc oxide was washed with hot water and the combined filtrate and washings saturated with solid sodium chloride. The saturated solution was then cooled in an ice bath and extracted with ethyl acetate (3 x 100m1). The combined organic extracts were dried, filtered and the solvent removed to afford the crude 113

lamine (26) (e.Z¡S, 94%) as a brown oil which was used without further purification. (Found: M+', 186.9626. coHíÑoar requires M+', 186.9633). umax (film) 3300, 1590, 1460 cm-1. N.m.r. ô 8.00-6.50,6H, NH,0H,4 x ArH. 'line 2-Bromo-N- ( ¡ .+-dimethoxvbenzvl ìdene)anf N-oxide (28)

N-(Z-Bromophenyl )hydroxylamine (8.73g, 46-4 mmoì ) and 3,4-dimethoxybenza'ldehyde (8.40g, 51.1 mmol ) were dissolved in ethanol (ZSO ml) and the solution was kept in the dark overnight.

The mixture was then concentrated, cooled to 0o, and the precipitated product collected. The crude product lvas recrystallized from ethanol to give the N:oiide (28) (L2-?3g,78%), ffi.P. 166-169" (dec') (Found! C,53.6; H,4.4; N,4.0. CrsHriruOrAr requires C,53.6;

H, 4.2; N, 4.2%). vru* 1590, 1510 , 1470, I27O.t-1. N.m.r. ô ) 6xArl-l H-C=N; 3'91 3'90,2xs" 0Me' 8.33, d, J ?Hz, ,lr.t 7.73'6.80, m, 7|ü 13C n.m.r. ô 153.0, 149.6, (2 x C-OMe); 138.7, 133.9, 130.7, 728.6, 126.0, 124.0, 123.5, 116.6, 111.5, 111.0, 56.1 (2 x OMe).

Mass spectrum m/e 335,337 (M).

Rearranqement of N-oxide ( 28)

(1.00g, (i ) In ethanol - A solution of the N'oxide (28) 3.00 mmol) in redistilled ethanol (600 ml) was irradiated at 350 nm in a Rayonet photochemical reactor for th with intermittent stirring. The react'ion progress could be conveniently followed by the decrease in absorption due to the N-oxidg, trmax 330 nm. Alternatively, a small aliquot of the solution was evaporated to dryness and 1H examined by n.t... spectroscopy. After th the aromatic hydrogen 114 signal of the N-oxide at ô 8.33 had disappeared, to be replaced ,0. by a signal at ô 4.67, Hi-Ñ, ìndicating the presence of the lH isomeric oxaziridine ring proton (75% Uy n.m.r. spectrscopy)'

The ethanolic solution !,Jas then heated at reflux for th' Removal of the solvent gave a brown oiì (950 mg) which crystallized on standing. The crude product v,,as recrystallìzed from ethanol to (23) gr ve N- ( 2-b rorhophehvl ) -N -(3.4:dimethoxvphenvl )formamide (750 mg,75%), m.p. 134-136o- (Foundr C, 53.3; H,4'2; N, 4'2' ç\ CrsHr-aN03Br requires C, 53.6; H, 4.2; N, 4.2%). uru* (CHCI3)

1680 (br), 1590, 1500, 1210 (br) cm-1. N.m.r. ô 8'53 , 8'27 , 2 x s, H-C=O; 7.76'6.57, m, 7H, ArH; 3.82, 3.78, 2 x s, 0Me'

Mass spectrum m/e 335,337 (M).

(ii) In benzene - A solution of the N-oxide (28) (1.0g, 2.98 mmol) in dry redistilled benzene (600 ml) in a quartz vessel was placed in bright sunlight for 2åh. The solution was stirred occasionaìly and a small aliquot (2Sm1) was removed periodically, the solvent evaporated to give a light brown oil. The spectral properties of this oil were consistent wìth those of the oxaziridine (22) which lH v,,as present to the extent of 75% ¡y n.m.r. T.he a'liquot was returned to the originaì solutjon which was refluxed for th' The solvent was then removed under reduced pressure to give an oil which crystallized on standing. The residue was recrystallized from ethanol to give the benzanilìde (2a) Q\r") which was identified by t.l.c. and n.m.r. comparison wjth an authentic sample. The mother liquor contained 3,4-dimethoxybenzaldehyde as the only other identifiable product' 115

(iii) In djchloromethane - A solution of the N-oxide (28) (1.00g' 2.98 mmol) in dry dichloromethane (600 ml) was irradiated by direct sunlight for 2åh. The solution was then refluxed for I hour and the solvent removed under reduced pressure to give an oil which crystal'lized on standing. Flash chromatography of the residue gave in order of elution, 3,4-dimethoxybenzaldehyde (90mg , 20%), N-oxide (28) (200mg,20%) and benzanitide (24) (400 m9, 40%). The identity of all products was confirmed by comparison of t.l.c', n.m.r. and i.r. data with authentic samples.

( 2-Bromop henvl ) (g;+-¿'imethoxyphenyl )amine (4)

N-(2-Bromophenyl )-N -(3,4-dimethoxyphenyl )formamide (1.009, jn 2.98 mmol) and solid potassium hydroxide (1.00g) were dissolved a mixture of water (+ ml) and ethanol (80 ml) and the solution was refluxed for 40 min under nitrogen. The bulk of the ethanol

was then removed and the residue treated with ice-water to precipitate the free amine. The crude product was sublimed (137-138'/0.01 mm) to g'ive the diphenvlamine (4) (800mS ' 86%) as a colourless solid,m.p. L24-I45" (Found: 9, 54.6; H' 4'4; ít N, 4.6. Cr,*Hrí¡¡O.gr requires C, 54-6; H, 4.6; N, 4'6%) ' v*u* (cHcl3) 3400, 1590, 1510 cm-l N-m.r. ô 7-48-6.50, m,7H, ArH; 5.88, br s NH; 3.83, 3.80, 2x s, OMe. Mass spectrum m/e 307,309 (M).

EthyI 2-cvano-3-hvdroxvbut-2-enoate (31)

The hydroxybutenoate (¡1) was prepared by the general method of Hori and Midorikawas9 in lo% yield after fractional 116

di sti I I ati on , b. p. 116-118'/10 mm ( I i t.59 toz-to3'/10 mm) .

Ethyl 3-chl oro-2:cyanobu!-2:e!qa,!q ( 3a)

Ethyl 2-cyano-3-hydroxybutenoate (2.00g, 12.9 mmol) and phosphorus pentachloride (2.}ag, 13.6 mmoì) were dissolved in benzene (8 ml) and the solution heated at reflux for 3h. The solvent was evaporated to yield a yelìow oil (2.22g) which r,¡as fractionalìy distilled under reduced pressure to give the title compound (1.38g, 62%) as a colourless ìiquid (mixture of

E and Z isomers),b.p. 52-53'/0.05 mm (lit.62 62"/0.1mm) umax (film) 2230, L740,1590 cm-l. N.m.r. ô 4.23, 9, J 7Hz,2H, 0CH2CH3: 2.75, 2.60, 2 x s, Me-CCl; 1.33, t, J 7Hz, 3H,

OcH2-cH3.

Et 12- ano-3- dime I ami no but-2-enoate (35)

The chlorobut-2-enoate (34) (200 mg, 1.15 mmol) and dimethyìformamide dimethyl acetal (0.18 ml, 1.2 mmol) were dissolved in dry dimethylformamide (1.0 ml) and the solution heated at 80" for 3h under nitrogen. The solvent and unreacted acetal Were removed under reduced pressure and the oìly residue purified by chromatography on alumina. Elution with dichloromethane gave ethy'l 2-cyano-3-(dimethylamino)but-2-enoate (35) (170 mg,

80%) the spectraì properties of which were identical to those reported by Daìquist.63

Ethvl -2-cyano -3 .4-bi s ( di methvl ami no ) pênta-2 ,4-di enoate (36)

A solution of ethyì 3-chloro-2-cyanobut-2-enoate (34) (200 mg, It7

1.15 mmol) and dimethylformamide dimethyl acetal (0.5m.l, 3.60 mmoì) in redistilled dimethyìformamide (1.0m1) was heated at 140o for

24h under nitrogen. The solvent and unchanged acetal were then removed under reduced pressure to give a red oil (190mg) which was chromatographe d on alumina. Ethyl 2-cyano-3,5-bis(dimethyl- ami no ) penta-2 ,4-dì enoate (36) (171 mg, 63%) was eluted with ethyl acetate/dichloromethane (1:9) and recrystallized twice to give pale yelìow needles from ethy'l acetate/ether, m.p.97.5-100o

(Found: C, 60.5; H, 7.9; N, 17.9. CrrHrrNr0, requires C , 60.7;

H, 8.1; N, 17 -7%). umax 2200, 1660, 1640, 1550 cm-1. N.m.r. 6

7.33, d,J LZHz, H5; 4.53, d, J I2Hz, H4; 4.10, q, J 7Hz, 0CH2-CH3; 13C 3.08, 3.03, 2XS, NMez; 1.27,- t, J 7Hz, 0CH2CH3. n.m.r. ô 187.8,

I72.8, 168.4, 156.3, I25.0, 88.5, 59.9, 42.5, 14.7. Mass spectrum nle 237 (M).

Ethyl 2-bromo-4- ( dimeth.yl amino)pyridine-3-carboxyl ate (37 )

Ethyl 2-cyano-3,5-bi s (dimethyl amino)penta-2,4-di enoate

(SO¡ (257 ng, 1.0 mmol) was dissolved ìn glacial acetic acid (1.4 ml) and to this solution was added dropwise a solution of hydrogen bromide in acetic acid (48ï", 10 ml), while maintaining the temperature at c. 50o. The mixture was then heated at 75o for 2h, cooled, pouréd'into water (20 ml), and neutralized with solid sodium carbonate to pH7. The mixture was extracted with dichìoromethane (3 x 50 ml), the combined organic extracts were dried and the solvent removed to afford a colourless oil (200 mg, 73%) which was recrysta'llized from ether/light petro'leum to give ethy'l 2-bromo-4-(dimethyl ami no)p.yi"idine-3-carboxyl ate (37) as 118 colourless prisms, m.p. 67.5-7I" (Found: M+ , 272.0165. CroHr3BrN202 requires M+ , 272.0161). uru* (film) 1730, 1590, 1530 .*-1. N.m.r. ô 7.80, d, J 6Hz, H6; 6.43, d, J 6Hz , H5; 4.37 , q, J 7Hz, OCHzCHg; 2.97, s, NMez; 1.4, t, J 7Hz,0CH2CH3.

Attempted reaction of 3-hvdroxvbut-2-enoate (31 ) with dimethyl - formamide dimethyl acetal .

(i) A mixture of (31) (0.50 gm 3.2 mmol) and dimethy'lformamide d'imethyl acetaì (5 mt) was allowed to stand overnight at room temperature under an atmosphere of nitrogen. The unreacted acetal and methanol were removed in üacuo to give a ye'llow oil which was induced to crystallize by the addition of ethyì acetate.

Recrystallization from the same solvent ga ve ethyl 2-cyano-3-

( di methvl ami nomethoxy ) methyl but-2-enoate (41) as colourless plates

(0.30 g, 38%), ffi.p . L32-l34of (Foundr C, 60.0; H, 9.1; N, 13.5. Cr.rHrrN2O, requires C,54.5; H,7.5; N, ll.6%). umax 2200, 1.670,1550, 1380 cm-1. N.m.r. ô 4.00, Q, J 7Hz,2H, OCH2CH:i 3.27, s, 10H, NMez,0CHs, H-C-0i 2,20, s, 3H, Me-C=C; 1.20, t, J 7Hz,

3H, 0CH2CH3. The mass spectrum showed no molecular ion at 70 or 18 eV.

(ii) A solution of (31) (155 mg, 1.0 mmol) and dimethyìformamide dimethy'l acetal (0.q ml , 3.0 mmol ) in dimethy'lformamide (2 ml ) was refìuxed at l40oovernight under an atmosphere of nitrogen-

Removal of the solvent and unreacted acetal under reduced pressure gave a black oil which crystallized on standing. Examination of

t This compound was extremely moisture sensitive and an ana'lyti cal samp'le proved di ff i cul t to obtai n . 119

lH the crude residue uy n.m.r. spectroscopy showed that the mixed acetal (qt) was once agat'n the major product. No viny'lic resonances attributable to the expected enamine (39) could be detected.

EthyI 2-cvano-3-methoxvbut-2-enoate (43)

The methoxybutenoate (43) was prepared by a procedure similar to that used by Nichoìl and BlohtT3 in 80% yield after recrystallizat.ion from benzene, ffi.p. 133" (1it.105 133-t¡4" ).

(44) Ethvl 2 -cvano-5- ( di methvl ami no ) -3 -methoxvpenta-2,4-di enoate

A mixture of ethyl 2-cyano-3-methoxybut-2-enoate (a3) (4.00 (5.00 g, 29.6 mmol ) and dimethy'lformamide dimethyl acetal m],44.4 mmol) was heated at 140o for th under nitrogen. The

unchanged acetal and dimethylformamide were removed under reduced pressure to give a viscous red oil. Column chromatography 'l on alumina and elution with dichloromethane g ave ethy 2-cyano-5-

( dì methvl ami no)-3-methoxvpenta -2,4'dienoate (44) as bright ye'l1ow

needles (5.69, 857,), ffi.p. 68.5-70o after recrystaìlization from ethyì acetate/l'ight petroleum (Found! C,58'7; H,6'9; N' 12'5'

Cr.,.Hre Nz0e requires C, 58.9; H, 7.2; N, L2.5%) ' umax 2200, 1690, 1610, 1510 cm-l. N.m.r. ô 7.30, d, J l11z, H5; 6'03, br d' J IZHz, H4; 4.72, q, J 7Hz, oCHzCHg overlapping with'3'93' s' 0Me; 3.00, br s, NMe2; I.27, t, J 7Hz, 0CH2CH3' Mass spectrum nle 224 (Ì4). 120

Ethyl 2-bromo-4-methoxypyri di ne-3-carboxyì ate ( 45 )

Ethyl 2-cyano-5- dimethylamino -3-methoxypenta-2,4- dienoate (44) (6.00 g, 26.8 mmol) was cyclized as described for the preparation of (37) to g ive the crude bromo ester (45) (6.21 g,89%) as a paìe brown oil wh'ich crystallized on standing. The ana'lytical sampìê, fi.p. 48-49', was obtained after recrystaìlizatjon from light petroleum containing 1% benzene (Found! C,4I.6; H,3.9; N,5.4. CrHroBrNO. requires C,41.8; H, 3.9; N, 5.5%). uru* (film) !740, 1590 cm-l. N.m.r. ô 8.13, d, J SHz, H6; 6.73, d, J 5Hz, H5; 4.35, q, J THz,OCHzCHg;

3.83, s, OMe; 1.37, t, J 7Hz, OCHzCHg.

2-Bromo-4-methoxypyri d i ne-3-ca rboxyl i c ac i d (+oa)

Ethyì 2-bromo-4-methoxypyridine-3-carboxyìate (1.00 g,

3.9 mmol) was suspended in a solution of sodium hydroxide (1.8 g, 44.6 mmol) in water (¡O m'l) and the mixture refluxed for 45 min. Thesolutionwas cooled and acidified to pH 2 with conc. hydrochloric acid, saturated with solid sodium chloride and extracted with tetrahydrofuran (3 x 25 ml). The combined organic extracts were dried, and the solvent removed to give a paìe brown oil which crystallized on standing. The crude product was recrystallized from methanol to g i ve 2-bromo-4-methoxypyri di ne-3- carboxyl ic acid (a6a) as colourless prisms (720 nS, 80%), n.p.

I72-I75" (dec. ) (Found ! C, 36.5; H, 2.9; N, 6 .2. CzHe ¡tOrgr requires C, 36.2; H, 2.6; N, 6.0/,). vru* 3300-2200 (br) , L720, 1620 crn-l. N.m.r. ô 10.27, br s, 0H; 8.20, d, J 6Hz, H6; 7.28, d, J 6Hz, H5; 3.92, s, OMe. Mass spectrum n/e 23I, 233 (M). t2L

2-Bromo-4-ethoxvpvridine-3-carboxvlic acid (46b)

The titìe compound was prepared in three steps from ethyì 2-cyano-3-ethoxybut-2-enoate73 as described for the preparation of (46a), but the intermediates were not fully characterized. Recrystallization from acetone/light petroleum then ethyl acetate gave the acid (+OU¡ as colourless prisms,ffi-P. 15Bo (dec.)

(Found: C, 39.3; H, 3.1. CsHsBrNO3 requires C, 39.1; H,3'3%)

v,nu* 3400 (br), 2600 (br), 1900 (br), 1720, 1580 cm-l. N.m.r. (cDcl3/cD3s0cD3) ô 8.03, d' J 5.5H2' H6; 7.73' br s, 0H; 6.77, d, J 5.5 Hz, H5; 4.!2, q, J 7Hz, OCHzCH3; 1.38, t ' J 7Hz, 0CH2CH3'

Cyc lization of Enamines to the P.vridin-2(1H)-ones

The pyridin-2(lH)-ones were prepared by the following general procedure. A solution of the enamine (1.00 mmol) in

80% aqueous acetic acid (1.5 ml) was heated at 110" and the 'ly d'i sappearance of the enami ne was fol I owed by t. I . c. General the time taken for completion was 2'2åh. The solution was then diluted with water (0.5 ml) and neutralised with solid sodium carbonate to pH7. Extraction of the solution with ethyl acetate (5 x 1 mì) gave the py¡idin-2(1H)-one. In this manner

was prepared: Ethvl 4-meth oxv-2-oxo-1 -z-dihvdropvri d i ne-3 - carboxy'late (47) (60%), ffi.P. 126-127.5o after recrystallization from ethyì acetate/l i.ght petrol eum (Found: Mt' , 197.0687. CgHr.rN0+ ) 4 requires M*' , l;í.0688). umax 3200 (br), 1720,1640, 1570 cm-l. N.m.r. ô 7.40, d, J 7Hz, H6; 6.03, d, J 7Hz, H5; 4.33, q, J 7Hz, 0CH2CH3; 3.80, s, OMe; 1.33, t, J 7Hz,0CH2CH3. t22

4-Methoxy -2-oxo-1 .z-dihvdropvrldine-3-carboxvl ic acid (48).

Ethy'l 4-methoxy-2-oxo-1,z-dihydropyridine-3-carboxyl ate (47)

(283 mg, 1.!t4 mmol) was suspended in a solution of sodium hydroxide

(SOO mg,7.5 mmol) and water (10 ml) and the mixture refluxed for 30 min. The solution was then cooled and acidified to pH2 with conc. hydroch'loric acid to give a white crystalline soljd (150 mg' 63%). Recrystallization from water gave colourless needles of the acjd (48), m.p. 215-220" (dec.) (Found: Ç, 49-7i H, 4.1. CzHzNOh requ'ires C,49.7; H,4.1%). vru* 3400-2500 ' !720, 1650.t-1. N.m.r. (CD3S0CD3) ô 10.4, br, 0H; 7.73, d, J 7Hz, H6; 6-47, d, J 7Hz, H5; 3.92, s,0Me.

Extraction of the orjginal aqueous solution with tetrahydrofuran, gave after removal of the solvent, 4-hydroxy-2-oxo-1'2-

dihydropyridine-3-carboxyìic acid (49) (40 mg , L8%), ffi.P. I7g'I82o (dec.) (tit.75 182' (dec.)). N.m.r. 6 7.76, br t, H6; 6.76, br d, H5; 5.6, br s, 2 x 0H, NH. t23

5.2 Preparation of acid chlorides from the acids (46a) and (46b)

The approprÍate acid (500 mg) was suspended in oxaìyl chloride (5 ml) and the mixture heated at refìux for 2-2+h under nitrogen. The reaction course could be convenient'ly followed by i.r. spectroscopy which showed the characteristic absorption bands expected for the acid chlorides, vmax 1790, 1760 cm-1. The unreacted oxa'lyl chloride was then removed under reduced pressure to give the acid chloride which was used without further purification. A general method of work up used for the reactions described in Table 2 was:-

The solvent was removed and the residue treated with water to hydrolyse any remaining acid chloride. The aqueous solution was neutralized by the addition of solid sodium carbonate and then extracted with dichloromethane/ethyl acetate. The extract was lH subsequently examined by n.r... and i.r. spectroscopy and a'lso by t.l.c. t24

Table 2

Attempted reactions of the acid chlorides derived from (46a) and

(46b) with (2-bromophenyl )(3,4-dimethoxyphenyì )amine (4)

Acì d Sol vent Base Temp Time Product chl ori de ("c ) (h)

Pyri di ne Benzene (2 eq) 20 3 (4)

(46b) Benzene il 80 0.5 (4)

ll cH2cl 2 20 1 (4)

+ Tol uene DMAP r20 15 (4)

Acetone K2C0 3 20 72 (4)

cH2cl 2 DMAP 20 15 (4) (2 eq) (+oa) lt cH2cl 2 40 24 (4)

THF Pyri di ne 50 2 (4) /c|,c1, (2 eq)

il DMAP 20 48 (4) (2 eq)

f DMAP is 4-dimethylaminopyridine 125

Table 3

Attempted coupling reactions of diphenylamine (a) with the carboxylic acids (a6a), (46b) and (48)

Aci d Coupl i ng Sol vent Temp Time Product Reagent ('c) (h)

DCC THF 20 15 (4)

( 46b)

DCC THF 90 2 (4)

(a6a) DCC THF 20 15 (4) (4) PPA r20 I + decomposition

PPA 110 2 (4) (48) mel t 1 (4)

DCC THF 20 24 (4) / CH3CN

DCC THF 20 24 (4) I DMAP / CHsCN t26

2-Cyano-N,N-di phenyl acetamide (50 )

(i) Cyanoacetic acid (0.50 9, 4.88 mmol) and diphenyìamine (0.99 g, 5.BB mmol) were dissolved in ether (40 ml) and the solution cooled to 0o. Dicycìohexyìcarbodiimide (1.22 g,5.92 mmol) in ether (2 ml) was then added and the mixture allowed to warm to room temp. over 3h. A further amount of solid dicyclohexy'lcarbodiimide (0.2S g, 1.2 mmol) was then added and the thick suspension stirred overnight at room temperature. The precipitate was filtered and washed several times with dichloromethane. The combined filtrate and washings were then concentrated in ud.cuo to give a pa'le brown oil which crystallized on standing. Recrystallizatìon from dichloromethane/light petro'leum gave 2-cyano-N,N-diphenylacetamideST (50) as colourless needles (1 .23 g, 8g%), rn.p. 153-154.5" (Found: M+' , 236.0957. crsHr2N20 requires M+' , 236.0950). uru, 2250, 1660, 1590, 1490 .r-1. N.m.r. ô 7 .27, s, 10H, ArH; 3.37, s, 2H, CH2-CN. Mass spectrum m/e 236 (M).

(ii) A mixture of ethyì cyanoacetate (1.13 g, 10.0 mmol) and diphenyìamine (1.699,10.0 mmol) was heated at 240o for 3h using an air condenser in order to remove any ethanol formed during the reaction. A further portion of ethyl cyanoacetate (0.57 g, 5.0 nr¡nol) was then added and the heating continued for 2åh. The mixture was then cooled and the crude product (0.80g, 34%) which precipated, rvas collected by filtration, and shown to be identical in all respects with that obtained in (i) above. L27

2-Cvano-N .N-di phenvl -3-methoxvbut-2-enami de (s1)

A mixture of 2-cyano-N,N-diphenyìacetamide (710 mg, 3.41 mmoì), trimethyl orthoacetate (691 mg, 5.76 mmoì) and two drops of acetic acid was heated to 140-150o for th. The methanol which formed was removed by fractional distillation. A further portion of acetic acid was added and the mixture refluxed for an additional th or until no more methanol was collected. The unreacted orthoacetate was removed under reduced pressure to give a viscous orange oi'1. The crude product was chromatographed on alumina with dichloromethane to g ive 2-cyano-N,N-diphenyl -3- methox.ybut-2-enami de (51) as a pale yellow solid (950 ng, 95%).

The analytical sample b,as prepared by recrystallization from ethyl acetate/l'ight petroleum to give (51) (mixture of E and Z isomers) as pale yellow crystaìs, m.p. 77.5-115" (Found: M*', 2g2.12L4. CreHr..Nz0z requires Mr' , 2g2.1212). vrur 2200, 1650, 1600, 1480.,n-1. N.m.r. ô 7.13, s, 10H, ArH; 3.80, 3.63, 2 x s, 0Me; 2.33,2.00,2 x s, Me. Mass spectrum mle 292 (tt).

2-Cvano-5-di me thvl ami no-N.N-di phenvl -3-methoxvpenta-2 ,4- dienamjde (52)

A mixture of the amide (51) (400 mg,1.37 mmol) and dimethylformamide dimethy'l acetal (0.4 ml , 3.02 mmol) was heated at 80" under a nitrogen atmosphere for 2åh after whìch time the mixture became dark red in colour. The unreacted acetal and any vol ati I es were then removed under reduced pressure to give a red oil. The crude product was chromatographed on alumina LzB

tog i ve 2-cyano-5-di methyl ami no-N,N-di phenyl -3 -methoxypenta -2, 4- di enami de (52) (411 mg, 86%) as a yellow oil which crystallized on standing.

The ana'lyti cal sampl e was prepared by recrystal I i zati on from dichloromethane/light petroleum to give (52) as bright yeìlow needles, m.p. 166.5-169'. (Found! C,72.6; H,6.1.

C2rH2rN302 requires C, 7?.6; H, 6.1%). vmax (film) 2L50, 1640, 1600,900 cm-l. N.m.r. ô 7.43-6.90, m,llH,10 x ArH overlapping with lH, d, J 13 Hz, H5; 5.63, br d, J 13 Hz, H4; 3.83, s,3H,

OMe; 2.93, s , 6H, NMe2.

2-Bromo-N N-di I -4-metho i dine-3-carboxamide (53) .

The enamine (52) (280 mg,0.81 nunol) was dissolved in a solution of hydrogen bromide in acetic acid (45%,5 ml) and the mixture stimed at 55o for 3h. Water was added and the solution neutralized to pH7 with solid sodium carbonate. Extraction with

ethyl acetate (g x ZS ml) gave, after removal of the solvent,

2-bromo-N .N-di phenyl -4-methoxypyri di ne-3-carboxami de (53) (276 ns,

89%) as a brown oil which could not be induced to crystallize. (Found: M+', 382. 0322. crgHrsNz0zBr requires M+' , 382.0317) vru* 1.660, 1650, 1560, 1490, 900 .*-1 . N.m. r. ô I .02, d, J 6Hz H6; 7.35, s, 5H, ArH; 7.18 comp'lex m, 5H, ArH; 6.60, d, J 6Hz, H5; 3.84, s,OMe.

Attemp ted reaction of (2-bromophenyl )(3,q-¿jmethoxyphenyl )amine

(4) wi th anoacetic acid.

(ì) Dicycìohexyìcarbodiimide (DCC) (163 mg, 0.79 mmol) was t29

added to a mixture of diphenylamine (4) (243 m9,0.79 mmol) and cyanoacetic acid in ether/tetrahydrofu.ran (10 ml, 1:1) at 0o. After the formation of a white ppt (c. 5 min) the mixture was stirred for 2h at 0o, a'l'lowed to warm to room temperature and then stirred for a further 2h. Examination of the solution by t.ì.c. (dich'loromethane) showed the amine (a) to be still present. A further equivalent of DCC was added (163 mg, 0.79 mmol) and mixture stirred at room temperature overnight. Water was added, the solution filtered to remove the precipitated dicyclohexyìurea and the filtrate extracted with dichloromethane. Removal of the solvent gave an off-white crystalline solid (220 ng). lH Examination of this residue by n.r.r. spectroscopy and t.l.c. showed it to be the amine (4).

(ii) The amine (a) (486 mg, 1.58 mmol) and cyanoacetic acid

(67 mg, 0.79 mmo'l) were dissolved in a mixture of dimethylformamide and dichloromethane (10 ml, 1:1) containing a cataìytic amount of 4-dimethylamÍnopyridine (SO mg). The solution was cooled in ice, and di cycl ohexyl carbodi i mi de ( 163 mg , 0.79 mmo'l ) added sl owly. The mixture was stirred at 0" for th and then at room temperature overnight by which time the solution uras red in colour. A further equivalent of dicyclohexylcarbodiimide was introduced and the mixture stirred for 4h more. After cooling 'in ice, water was added and the precipitated dicyclohexy'lurea removed by filtration and washed with dichloromethane. The filtrate was washed with

10% aqueous sodium carbonate solution, dried and the solvents

removed to give a red soljd. This compound was identified by t.l.c. 130

and lH n.m.r. spectroscopy as (2-bromophenyl)(g,+-¿imethoxyphenyl)- amine (4) (+So mg , 93%).

Attempted reaction of ( 2-bromoohenvl ) ( 3 4-dimet hoxvphenvl )amine (4) with ethvl cvanoacetate.

A mixture of amine (4) (588 mg, 1.8 mmoì ) and ethy'l cyanoacetate (820 mg,7.26 mmol) was heated at 240" for 3h using an air condenser to allow removal of any ethanol formed. The course of the react.ion v1as followed by removing aìiquots from the mixture, evaporating them to dryness and examining the residues uy 1H n.m.r. and .i .r. spectroscopy. After 3h on'ly the amine (4) could be detected. Longer reflux times led to rapid darkening of the reaction mixture and decomposition of (4).

Attempted reaction o f (4) with chloroacetyl chloride.

(i) n-Buty]lithium (1.55 ml , 0.575 mmo'l) was added to a stirred so'lution of (2-bromopheny'l )(3,4-dimethoxyphenyl )amine (177 mg, 0.575 mmol) in dry tetrahydrofuran (2 ml) at room temperature under nitrogen. The resulting brown solution was stirred for 5 min and ch'loroacetyì chloride (+B uI,0.58 mmol) was then added slowly at room temperature. The reaction mixture was stirred for a further

2H then poured into ice/water. The organic phase was separated

and the aqueous solution extracted with dichloromethane. The

combined organic extracts were dried and the solvent removed to gìve a red solid. This was shown to be principalìy the amine (4) 1IH by i.r. and n.m.r. spectroscopy and comparìson with an authentic

sample (150 mg, 85%). 131

(ii) Methyllithium (1.7 m1,0.74 mmoì) was added to a stirred solution of the amine (a) (2I7 ng,0.705 mmol) in ether (tS ml) at 0o under nitrogen. The resultant thick white suspension was stirred at 0o for 20 min. Chloroacetyì chloride (gg mg, 0.78 mmoì) in ether (3 ml) was added dropwise and the mixture stirred at 0" for a further 10 min after which time it was allowed to attajn room temperature. The'in'itial precipitate redissolved and the solution took on a red colour. Work up as in (i) led onìy to the recovery of amine (4) (200 mg , 92%).

Metal lation of (2-bromophenyl ) (3.4-dimethoxyphen.yl )amine (4) and reaction with eth.yl 3-chloro-2-cyanobut-2-enoate (34)

(i) 0.72 ¡l Methyllithium (0.64 ml , 0.53 mmol) was added to a stirred solution of freshly sublimed diphenyìamine (4) (164 mg,

0.53 mmol) in dry ether (10 ml) at 0'under nitrogen. The resultant white precipitate was stirred at 0o for 20 mÍn and

0.52 M n-buty'llithium (1.02 ml , 0.53 nr,mol) was added, to gìve a paìe lemon coloured suspension of the dilithiated species (S7). The suspension was stirred at 0o for 10 min and then a solution of ethy'l 3-chloro-2-cyanobut-2-enoate (34) (92 mg,0.53 mmol) in ether was added all at once. The solution took on a very deep red colour while some of the precipitate redissolved. The mixture was stirred at 0o for 10 min and then aìlowed to warm to room temperature and stirred overnight. After quenching the solution with saturated ammonium chloride solution, t,he organic phase was separated and the aqueous phase re-extracted with dichloromethane

(3 x 30 ml). The combined organic extracts were dried and the 132

solvent removed to give a red oil (203 mg). Preparative t.l.c. of the oil with dichloromethane gave the following: (2-bromophenyl )(9,+-¿imethoxyphenylþmine (4) (Z.S mg, 5%) lH identjfied by t.l.c. and n.t... 3,4-Dimethoxydiphenylamine (61) (49 mg, 40%), n.P. 99-100' after sublimati on (112"/0.005 mm) (Found: C, 73.3; H, 6.6; N, 5'8'

CruH,.5N02 requires C, 73.3; H, 6.6; N, 6.1/"). vru* (CHC'I:) 3400 (br), 1600, 1520 cm-l. N.m.r. 6 7.20'6.60, m, 8H, ArH; 5.50, br, NH; 3.83, 3.80, s, 6Hr2 x OMe. Mass spectrum n/e 229 (¡ú).

The remaining co'loured material of low R, was eluted with ethyl acetate to g'ive a red oil (119 mg). Analysis of the oil 1H Uy n.m.r. and t.ì.c. showed it to be a mixture of the requ'ired material (60) (30%) and more poìar components, presumably arising from polymerization of the 3-chlorobut-2-enoate (34). The oìl was further chromatographed on alumina with dichloro-

methane/ethyl acetate (0:t) to g ive ethyl 2-cyano-3-12-(3,4-

di methoxyphe nvl ami no ) phenvl I but-2-enoate (60) (so mg, 26%) as a mixture of E and Z isomers. This oil which could not be induced to crystall'ize had spectral data consistent with structure (60) (Found: M+', 366.1579. CzrHzzNz0a r€Quires M+', 366.1579) 2200, 1710, 1690, 1590, 1500.n'-1. N.m.r. ô 7.60-6.45, m, v--.max 8H, 7 x ArH, NH; 4.15, q, J 7Hz, 0 CHzCHs; 3.78, 3.73, s, 6H, 2 x OMe 2.45, 2.26, s, Me-C=C; 1.27, t, J 7Hz, OCHzCHg. 133

(ii) A solution of the diphenylamine (4) (3q0 mg, 1.1 mmol) in ether (40 ml) was lithiated as described in (i) at 0o. A solution of tetrakis[iodo(tri-n-butytphosphine)copper (t)]

(433 mg, 1 mmol) in ether was then added at 0o to give an orange coloured solution. The mixture bras stirred at 0o for 10 min and the 3-chlorobut-2-enoate (34) (287 mg, I.7 mmol) in ether (5 ml) was added sìowly. The dark red mixture was stìrred at 0o for 10 min and th at room temperature. The mixture was then quenched by the addition of saturated ammonium chloride and the organic phase separated. Examination of the crude reaction

1 mixture by ^H n.m.r. and thin layer chromatography showed no significant increase in the yie'ld of (60) compared to (i).

Table 4 summarizes the attempted reactions of the dilithiated amine (57) with various 3-substituted but-2-enoates.

All reaction mixtures were allowed to warm to room temperature (unìess otherwise stated) and then worked up as described in (i). lH The residues were then examined by t.t.c. and Uy n.m.r. spectroscopy. 134

Table 4

Attempted reacti ons of lithiated Q -bromoohenvl ) ( 3, 4-d'i methoxy- (43) phenyl ) ami ne (4) with the 3-substituted but-2-enoates (34) and (62)

Metal I ati on Sol vent Substrate E!'- Addi t'ion Resul t Condi t i ons Ternp TT)

ether/THF (34) 1 -105 (61 ) (j) 5:1

THF ( 34) 1.5 0 (61)

THF (43) 1.5 0 (61)

ether (+:¡ 1.5 0 (0t) + small in THF amount (60)

ether (62) 2 0 (6i)

(ii) ether ( 34) 4 0 same as ('i )

ether ( 43) 1.5 0 ( 61) in THF

nBuli , Zeq, hexane ( 34) 4 -78 (61) 00 /THF (0.5h) 5:1

THF (43) 5 -78 (60) major

THF ( 34) 4 -78 compìex mixture

I nBu Lì, 2eq THF ( 34) 1 5 0 (61) 00 (61) 2.t Cu I(nBu)tPln THF (43 ) 1.5 0 1 eq , 0o, 10min

1. MeLì,0o ether ( 34) 4 -78 (4) 2. nBuLi -78o, th 1. MeLj, 0" 2. TMEDA ether (34) 1.5 10 same as (i) 3. nBuL'i , 0" th 135

Ethvl 2-cyano-3-i odobut-2-enoate (62)

Ethy'l 3-chloro-2-cyanobut-2-enoate (34) (1.73 g, 10.0 mmol), potassium iodide (4.98 S, 30.0 mmol) and sodium thiosulphate pentahydrate (7.45 g,30.0 mmol) were suspended in acetone (40 ml) and the mixture heated at 60o for 1.5 h. After being stirred at room temperature overn'ight, the mixture was filtered.

The filtrate was concentrated under reduced pressure to g'ive a brown oil which crystallized on standing. Recrystallization twice from dichloromethane/ether gave (62) as colourless plates,f m.p. 125-135' (dec.) (Found: M+',264.gsg7. CzHaN0zI requ'ires

14+' , 264.9602). vru, 2200, 1700, 1540, 1300 .r-1. N.m.r. ô 4.30, q, J 7Hz, 2H,0CH2CH3; 2.57, s, 3H, Me-C=C; 1.37, t, J 7Hz, 3H,

OcH2-cH3.

Metallation of diphenylamine (4) and rea ction with ethyl 2-cyano-5- (dimethyl amino)-3-methoxypenta-2,4-dienoate (44)

(i) In Ether - The diphenylamine (4) (308 mg, 1.0 mmo'l) was dissolved in ether (1S mt) and lithiated as described previously. A solution of enamine (aa) (310 mg, 1..38 mmoì) in ether/ tetrahydrofuran (S ml,5:1) was then added dropwìse at 0o to the vigorous'ly stirred suspension. The dark red mixture was stjrred at 0o for 10 min and finally at room tempenature for 30 min. The reaction mixture was then quenched with saturated ammonjum chloride solution (fO ml) and the organic phase separated. The aqueous phase was extracted with ethy'l acetate (3 x 10 ml ) and

f This compound slow'ly decomposed on standing at room temperature. 136

the combined organic extracts dried, filtered and the solvent removed to give a dark red oil. Preparative t.l.c. of the crude residue with djchloromethane/ethyl acetate (g:t) gave (4) (109 mg,35%), the reduced amjne (61) (g1 m9,36%) and enamine

(o+¡ (72 ns, L7%).

(ii) In tetrahydrofuran - 0.87M Methyllithium (1.3 ml, 1.13 mmoì) was added to a solution of diphenylamìne (4) (233 mg,0.756 mmol) in dry tetrahydrofuran (10 ml) at 0" under nitrogen. The solution was stirred for 5 min and 1.0 M n-butyììithium (1.13 ml, 1'13 mmoì) was added. After 3 min a solution of enamine (44) (338 mg,2.3 mmol) in tetrahydrofuran (2 ml) was added all at once to the dilithiated amine. The dark red mixture was stirred at 0" for

10 mjn. and at room temperature for 30 min. The reaction was quenched with saturated ammonium chloride solution (5 m'l) and the organic phase separated. Work up of the solution gave a dark red oil which crystallized on standing. Preparative t.l.c. of the crude residue with dichloromethane/ethyl acetate (9:1) gave the

enamine (65) (100 mg, 31%) as a red oil. Recrystallization from ether/l ight petroleum gave ethyl Z-cyano-3-(3,4-dimethoxydiphenyl-

ami no ) -5 -d i methvl ami ooenta-2 .4-di enoate (6S) as red needles, m.p. 117-134. (Found: M+' , 4ZL.Igg7. CzqHzzN¡0,* requires M+', 421.2001). umax (cH2cl 2) 2200, 1690 (br)' 1610 cm-l' N.m.r. 7.60-6.40, m, 8H, 7 x ArH and H5; 5'15, d, J 12 Hz' H4; 4.03, q, J 7llz,0CH2CH3; 3.80,3'73, s,6H,2 x OMe; 3'10' 2.87,2 x br s, NMez; 1.30, t, J 7Hz, 0CH2CH3' r37

Ethvl 2- CV ano-3- l2-ß 4-di methox vohenv lamino)ohenvl l-5- di methy I ami nopenta-2 .4-di enoate (64) was prePared as described for (4a) except that 2h reflux was used. The crude product was separated by preparative t.l.c. on silica (dichloromethane/ethyl acetate, 4:1) to afford a red oil. Fur"ther purification by chromatography on alumina and eluting with dichlorotnethane gave (6a) as a yellow solid (80%),m.p. 73-90' (Found: M+', 42I.20L4. cz,tirzNs0,, requ'ires M+'r42r.2001) uru* {cH2cl2) 3400 (br) , 2200, 1740, 1750, 1700 (br) , 1600 .t-1. N.m.r. ô 7.33-6'43, m, 9H, 7 x ArH, NH, H5; 5.36, d, J !2H2, H4; 3-97, q,J7Hz, OCHzCHa: 3.83, 3.73, 2 x s , 6H, 0Me; 2.72, br s, NMez; 1'13, t, J 7Hz'

OcH2-cHa.

Ethy'l 4 -12-ß,4-di methox vphenyl ami no) Phe nyl I -2-oxo- 1,2-di hydropyri d'i ne-3-carboxyl ate (67 )

This compound was obtained i n 70% yie'ld from the correspond'ing enamine (64) by cyclization in aqueous acetic acid using the procedure descrjbed for the preparation of (a7). The ester, isolated as an oil by preparative t.l.c. (dichloromethane/ethyl- acetate, 20:1), could not be induced to crystallize. The spectral data of the oil were consistent with its structure (Found: M*',

394.153g . Czz¡zzN2g5 reQuires M+', 394.1534). umax (cHcl3) 1720, 1630, 1600, 1520 cm-l. N.m.r. 6 7.27-6.57, m, 10H, ArH, NH and H6; 5.82, d, J 7Hz, H5; 3.85, 3-77,2 x s, OMe; 3'58, q, J 7Hz,

0CH2CH3; 1.25, t, J 7Hz, OCH2CHa.

A smaìl amount of the enamine (65) (c. 10%) was also isolated by preparative t.l.c. 138

4-12-(3,4-Dimeth oxvphenvl ami no ) ohenvl f-2-oxo-1 .2-di hvdropvri di ne- 3-carboxyl ic acid (68) (60%) was obtained as an oil using the procedure described for (49) and refluxing for 2h. Thìs compound could not be induced to crystallize and was used wjthout further purification (Found:M+'-H.0, 348.1120. CzoHr..Nr0,* M+'-Hr0 requires 348.1110). umax 3500-2600 , !720, 1630 (br), 1600 cm-1'

Attempted c.ycl i zati on of (68)

(i) The acjd (68) (so mg,0.14 mmol) was added to a solution of dìcyc'lohexylcarbodiimjde (58 mg, 0.28 mmoì) in tetrahydrofuran at 0o. The mixture was stirred at 0" for 30 min and then refìuxed for th. Water was added and the precipitated dicyc'lohexy'lurea removed by filtratìon. Removal of the solvent gave unchanged (68)

- (45 mg , 90%).

(ii) To a solut'ion of the acid (68) (SO mS,'0.14 mmol) in dichloromethane (0.5 ml) was added phosphorus pentoxide (50 mg'

0.35 mmol) and the mixture heated at reflux under a nitrogen

atmosphere for th. water was then added and organic phase separated, dried and the solvent removed to return the starting

material (40 mg, 80%).

2-(3. 4-dimethoxvphenvl ami no)acetophenone (69)

To a suspension of 2-bromoacetophenone (2-8 g, 14.2 mmol) 3,4-dimethoxyaniline (4.3 g, 28.4 mmol) and potassium carbonate (3.92 g,28.4 mmol) in l-butanol (+O ml) was added copper bronze (28 mg) and cuprous iodide (28 mg). The mixture was then refluxed for 6h after which time the solution became black in colour. 139

The solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution then was washed with dilute hydrochloric acid (2 x 1 ml), dried, and the solvent removed to afford a black oil (1.5 g). The oil was purified by column chromatography on alumina (neutraì, activity 2) to give

(69) (1.0 g, 26%) as a yellow solid. Recrystallization from dichloromethane/light petroleum gave (69) as bright yel1ow needles,m.p. 105-107.5o (Foundr C, 70.9; H, 6.5; N, 5.1.

Cr.oHr.7N03 requires C, 70.8; H, 6.3; N, 5.2%). vru* 1640,

!520,1270 cm-l. N.m.r. ô 10.28, br s, NH; 7.77'6.43, m , 7H,

ArH; 3.82, 3.77 , 2 x s , 6H, 0Me; 2.6 , s, 3H, Me-C0. Mass spectrum nle 27I (la).

When the oil was chromatographed on alumina (neutraì, activjty I), elution with dichloromethane/ethyl acetate (19:1) ga ve 2,3-dimethoxy-9-methylacridine (70) (720 ng, 20%) as a pale yeìlow solid, ffi.p. 130-134o (Found: M+' , 253.1108. cr6HrsN02 requires M+',253.1103). umax (CHcl 3) 1630, 1570, 1480, 730 cm-1. N.m.r. ô 8.07', 7.97, dd, J 7Hz, ZHz, H5, H8; 7.70-7.10, complex,

2H, H6, H7 overlapping with 7.33, 7.10, 2 x s, 2H, Hl, H4; 4.00, s, 6H, 2 x OMe; 2.90, s, Me.

Attempte d reaction of 2-ß,4-dlmethox.yphenylamino)acetophenone (69) wi th ethyl cyanoacetate

To a solution of sodium ethoxide (0.44 mmol ) in ethanol (10 mg sodium metal in 1.5 ml ethanol) was added ethyl cyanoacetate (161 mg,1.43 mmol) followed by the acetophenone (09) (257 ng,0-95 mmo'l). The mixture was then refluxed overnight under a n'itrogen 140

atmosphere: The red solution v'ras filtered and the ethanoì

removed under reduced pressure to gìve a dark red oil (205 mg). lH Examination of the residue Uy n.m.r. spectroscopy and by t.l.c. showed it to be a 1:1 mixture of 2,3-dimethoxy-9-methy'l- acrjdine (70) and the starting amino-ketone (69).

The following tabìe summarizes the attempted Knoevenageì condensations of (69) with ethyl cyanoacetate. All reactions were performed with a Dean-Stark water separator using two equivalents of ethyl cyanoacetate. Alìquots were wìthdrawn periodical'ly, the lH solvent removed and th.e residue examined by n.t.r. spectroscopy.

The presence of two new resonances at ô 2.3 and 2.47 was attributed to either (60) or the fuì'ly cycìized . Less ryterial than 5% was always observed. 141

Table 5

Attempted reactions o f 2-(3.4-dimethoxvphenvl ami no)acetophenone (6e) with ethyl cyanoacetate.

Catalyst Sol vent Temp Time Product ('c) (h)

csHllNH2 Benzene 80 24 (6e) . HOAc

NH4OAc Benzene 80 24 (6e) .Ac0H

Tol uene r20 24 (6e ) 742

5.3 Attemp ted reaction of Haqemann's ester wjth dimethylformamide dimethyl acetal

A mi xture of ethy'l 2-methyl -4-oxo-2-cyc'lohexene-1- carboxylate (1.00 g, 5.50 mmo'l) and dimethyìformamide dimethy'l acetal (0.82 m'|,6.18 mmol) was heated at 115o for th under a nitrogen atmosphere. The volatile material was removed by rotary evaporation leaving a red viscous oil. The crude residue was d'istilled under reduced pressure to g i ve ethyl 3-di meth.yl - aminomethyl ene-Z-methyl -4-oxocyclohexene-1-carboxy.late (35) as an orange viscous oil (I.I2 g, 86%), b.p. 125-128"/0.07 mm (Found: M+' , 231.1361. cr3H1eN03 requires M+' , 231.1365). uru* (fjlm) 1690, 1640 (broad) 1570 (broad) .t-1. N.m.r. 6 7.48, br s, lH, H-C=C; 4.77, g,J 7Hz,2H, OCl.l2Me; 3.03, s, 6H, NMez; 2.72-2.L2, m,4H, CHz-CH2-C=Q; 2.23, s, 3H, Me-C=C; 1.28, t,

J 7Hz, 3H, 0CHz-Me.

Attempted nitration of Hagemann's ester

(i) Sodium (52 mg, 2.26 mmol) was dissolved in absolute ethanol (3.3 ml) and the solution cooled to room temperature.

Hagemann's ester (¡0q mg,2.0 mmol) was added slowly over 20 min and the orange solution stirred at 70o for 2h to allow complete formation of the anion. Ethyì nitrate (300 mg, 3.3 mmo'l) was then added dropwise over 20 min to the stirred solution at room temperature and the mixture then heated at reflux for 2h. The cooled mixture was acidified with dilute hydrochloric acid (10 mì) and the aqueous solution extracted with dichloromethane (3 x 10 ml). 143

The combined extracts were dried and the solvent removed to give a red ojl. Preparative t.l.c. of the crude resjdue wìth ethy'l acetate/dichloromethane (9:1) gave Hagemann's ester (t+O mg, 40%) and a yeì1ow oil (50 mg, LL%) whose spectral properties were consistent w'ith those expected for ethy'l 4-hydroxy-2-methyl-3- nitrobenzoate. The oil could not be induced to crystallize and was not further purified. uru* (film) 3,700-3,100, 1710, 1610' 1580, 1540, 1370 cm-l. N.m.r. ô 7.90, d, J 9Hz, H-5; 6. 97, d, J 9Hz, H-6; 4.38, q , J 7Hz, OCH2Me; 2.7, S, Me-Ar; 1' 4, t, J 7Hz,

OCHzMe. Mass spectrum n/e 225 (M), 208 (M-OH).

(i ì ) Hagemann's ester (364 ms , 2.00 mmo'l) in tetrahydrofuran (1.2 ml) was added to a solution of freshly sublimed potassium t-butoxjde (358 ffig, 3.2 mmol) jn tetrahydrofuran (1.8 ml) at -50'.

The orange coloured mixture v^,as stirred at -50" for 10 mjn and a solution of 3-methylbutyl nitrate (g0o mg,2.2 mmol) in tetrahydrofuran (0.6 ml) was then added dropwise over 20 min at -40o, after which a thick ye'l'low precipitate developed. The mixture was then quenched by the addition of acetic acid (0.6 ml) in tetrahydrofuran (2 m'l) which caused the precipitate to red'issoìve and a

second precip'itate to appear a few seconds later. The suspensÍon

was warmed to room temperature and stjrred overnìght. The precipitate, presumed to be potassium acetate, v',as removed by fi'ltration and washed free of any colour with tetrahydrofuran- The orange filtrate was then concentrated, in Ðqcuo to give an orange oiì (376 mg) which did not crystallize. Examination of the lH crude reaction mixture by t.l.c. and n.m'r. spectroscopy showed it to be a mixture of Hagemann's ester and ethyl nitrate. This t44

was confirmed by t.l.c. comparison to authentic samp'les

(iii) Acetyl nitrate was prepared according to the method of -/' Bordwell; and Gorbir.h32 utilizing acetic anhydride (5.00 ml) and

concentrated n'itric acid (0.675 g , 7 .5 mmol ). The mixture was then cooled to -20o and Hagemann's ester (546 mg,3.00 mmol) was

added, followed by anhydrous sodium acetate (500 mg,6.10 mmol).

The suspension was stirred at -20o for th and then allowed to

warm to room temperature. After stirring the mixture at room temperature for 30 min the reaction v',as quenched by the addition of ice (10 g). The aqueous solution u,as then neutralized with solid sodium bicarbonate and extracted with ethyl acetate

(3 x 5 ml). Removal of the solvent gave a colourless oil (510 mg, lH 93%) which was shown to be Hagemann's ester by comparison of n.m.r. and i.r. spectra as welì as by t.l.c.

Attempted pre ration of 3-chloro-5,s-dimethyl -Z-nitro-Z-

cycl ohexen- I -one (39b)

2-Nitrodir.don.33 (o.so g, 2.7 mmol ) was suspended in dry

chloroform (1 ml) and oxalyl chloride (0.47 m1,5.4 mmol) was

added dropwise at room temperature with vigorous stirrìng. The suspension gradually dissolved and the clear solution was stirred at room temperature overnight. The solvent and unreacted oxaìyl

chloride were removed under reduced pressure and the res'idue treated with water (1 ml). The aqueous solutìon was extracted with dichloromethane and the combined organic extracts washed with

saturated sodium bicarbonate solution. Removal of the solvent gave 145

1.7-di oxo-3 3 9 .9-tetramethvl -2 3 I 9 -tetrahydrodi benzo( c, g ) -

1 5 di oxa 2 6 dia ine dioxide (43) as a pa]e brown oil (850 ng, 94%) which crysta'll ized on standing. Recrysta'll jzation from ethyì acetate/light petroleum gave (43) as colourless needles, m.p. II2-II4" (Found: C,57.8; H,5.4; N,8.3. C,..Hr."Nz0, requires C, 57.5; H, 5.4; N, 8.4%). vru,. 1790, 1600 .t-1. N'm'r' ô 6.23, s, lH and 5.85, s, 1H, H-C=C; 2.63, s, 2H and 2-55' s, 2H,

CH2-C=0; 1.25, s, IzH, 2 x CMe2.

A sjmilar product was obtained when the oxalyl chloride was rep'laced by phosphorus trichloride.

5 ,5-Di meth.y l -3-methoxy-2-nitro-2-c.ycl ohexen-1-one (44)

To a solution of 2-nitrodimedone (39b) (0.50 9, 2-7 mmol) and freshìy distilled d'imethyì sulfate (0.374 9, 2.97 mmoì ) in acetone (10 ml) was added soljd anhydrous potassium carbonate

(0.373 g,2.7 mmol) and the mixture heated at reflux for 2h under a nitrogen atmosphere. The solvent was then removed under reduced pressure, the res'idue treated w'ith water (10 mì) and the mixture extracted with djchloromethane. The comb'ined organic extracts were dried and the solvent removed to g'ive a pa'le yeì1ow oìl which crystallized on standing. The crude product was recrystalljzed from dìchloromethane/l'ight petroleum to give 5,5-dìmethyì -3- methoxy-2-nitro-2-cyclohexen-1-one (44) (4S7 mg, B5%) as pale yeììow plates, m.p. 128-130' (lit.36 t¡o').

Attempted preparat'ion of 2 -nitrocycl ohexane-1,3-dione (39a)

Attempted nitrat'ion of cyclohexane-1,3-dione (gga) (9.009' t46

80.4 mmol) with a mixture of concentrated nitric and sulfuric acids as descrjbed by Neilands and Laizane3S led to the isolation of an orange oiì (2.0 g). This oil was triturated with ether and the ether-insoluble material was recrystallized from ethy'l acetate/light petroleum to g'ive 6-njtro-S-oxohexanojc acid (1.7 g' l2%), n.p. g2-g7" (dec.) (lit.38 96-97" (dec.)). v*u, 3500-2500, 1730, 1700, 1560, 1380 cm-1. N.m.r. (CDCl r/ co,socur¡ ô 10'5' br s (exch.), lH, 0H; 5.53, s , 2H, gH2-NOz:' 2.62, q, ?H, 9H2-C0; 2.28, q, 2H, CH2-COzH; L.97, 9' 2H, 3-CHz. Mass spectrum m/e r57 (M-HrO).

5,5-Di meth.yl -3- ( 2-di meth.y I ami noethenyl ) -Z-cy clohexen - 1-one (47)

A mixture of isophorone (10.0 g, 72.5 mmol) and dimethylformamide dimethy'l aCetal (15.0 mì,113 mmol) was heated at 160o under a nitrogen atmosphere. The methanol formed during the reaction was removed by fractionation. After 4h the dark red mjxture was cooled and the excess acetal removed by rotary evaporation. Fractional distillation of the oiìy residue gave two products. The first was 2-dimethylaminomethylene-3,5,5-trimethyl-3-

cyclohexen-1-one (48) (2.8 g, 20%),b.p. 101'/0.15 mm (ttris compound

decomposed rapidly at room temperature and could not be fu]ly characterised). N.m.r. ô 6-45, s, 1H, C=CH-N; 5'03, br s, lH, H-C=C; 2.93, s, 6H, NMez; 2.32, s, 2H, CHz; 1'8, s, 3H, Me-C=C; !.02, s, 6H, CÞIe2. The second was 5,S-dimethyl-3-(2-dimethyl-

aminoethenyl )-2-cyclohexen-1-one (47) (10.2 g, 73l,), b.p. 141'/0.15 mm, which solidified on standing. Recrysta'llization from ethyl L47 acetate/light petroleum gave (47) as orange needles, m.p. 94-95" (Found; C, 74.6; H, L0.2, N, 7.5. CrzHrgNO requires C, 74.6; H,9.9; N,7.3%). ,ru* (CH2Cl2) 1610, 1590, 1530 cm-1. N.m.r. ô 6.82, d, J 13H2, H-CNMe2; 5.58, s, H-21' 4.99, d, J 13H2,

H-C=C-NMez; 2.88, s, 6H, NMez; 2.28, 2.I5, 2 x s, CHz-C=C and CHz-C=0; 1.03, s, 6H, CMez. Mass spectrum m/e 193 (M).

Reaction of enamÍne ( 47 ) wi th.:

(i) hydroxylamine hydroch'lorjde and sodium acetate.

Sodium acetate (800 mg, 9.76 mmol) and hydroxylamine hydrochìoride (+OO mg,5.76 mmol) were added to a solution of the enamine (47) (200 m9,1.04 mmol) jn ethanol (g ml) and the mixture heated at reflux for 30 min. During the first 5 min the colour of the solution changed from orange to yeìlow and after 30 min was almost colourless. The ethanol was then removed under reduced pressure and the residue treated with water (5 ml ). Extraction of the aqueous solution with dich'loromethane gave, after removal of the sol vent, 9,9-dimethyl -1-oxa-2-azaspi ro[4,5]de c-Z-en-7-one oxime (51) as a colourless oil (200 mg,9B%) which crystallized on standìng

Recrystallization from ethyl acetate/tight petroleum gave (51) as colourless needles (sublimes, 130'), rn.p. 142-149' (Found: C, 61.5; H, 8.2; N, 14.3. CroHroNz02 requires C, 6L2; H, 8.2; N, 14.3%). v*u* 3250 (broad), 1650 (weak), 1610 .r-1. N.m.r. ô 9 .22, br s, 0H; 6.98, br s, H-C=N; 2.63, br s,2H, C-CH2-C=N; 2.40, s, 2.30, br s, 2.05, s, 1.85, s,I.75, s, 6H, 6-CHz, 8-CHz and 10-CHz (mixture of isomers); 1.10, 0.93, 2 x s, 6H, CMe2. Mass spectrum m/e 196 (M). 148

(i i ) hydroxy'l ami ne hydrochl ori de Hydroxy'lamine hydrochloride (571 mg, 8.2 mmoì ) was added to a solut'ion of enamine (47) (Z0S mg, 1.37 mmol) in ethanol (2 ml)and the mixture refluxed for th. The solvent was removed under lH reduced pressure and the dark red residue enamined. The nmr spectrum showed that the spiro-oxime (51) was present as indicated by the vinylic hydrogen resonance (6 6.97) but t.l.c. ind'icated that many other products were a'lso present. Attempted reaction of enamine (47 with sodium azide in acetic ac'id:

A mixture of enamine (47) (300 mg, 1.55 mmol) sodium azide

(300 mg,4.62 mmol) and acetic acid (5 ml) was refluxed for 30 min after which time the orange solution became dark brown. The acetic acid was removed ín uacuo and the residue treated with water (3 ml). The aqueous solution was extracted with dichloromethane (g x S m1), the combined organic extracts drjed, filtered and the solvent iemoved to give a brown solid (450 mS). Recrystallization from ether and then light petro'leum gave

3 ,3-d i meth.yl -7 - ( 5 ,5-di meth.yl -3-oxocycl ohexen- 1-yl ) -3 ,4-di hydro-

1 ( 2H ) -naphthal enone (57) as colourless prisms, m.p. 130-132o (Found: C, 80.8; H, 8.1. Czoïz+O2 reQuires C, 81.0; H, 8.2%). v-^.. 1680, 1660, 1590, N.m.r. ô 8.03, d, ZHz, lH, max 1540.r-1. J H-8; 7.60, dd, J 8Hz, ZHz, 1H,H-4; 7.17, d, J 8Hz, 1H, H-5;

6.33, m, lH, H-2'; 2.87, S, 2.50, s , 2.32, s, 6-CHr, 8-CH, and 4'-cHr: 2.67, m, zH, 6'-cHr; 1.13, 1.08, 2 x s, 12H, 2 x CMe2. Mass spectrum m/e 296 (M). 149

Reaction of enamine (qt ) wi th metho xvam'ine hvdrochl ori de (i) in ethanol with sodium bicarbonate A mixture of enamine (47) (500 mg' 2.6 mmo'l), sodium bicarbonate (655 m9, 7.8 mmol) and methoxyamine hydrochloride

(650 mg , 7 .78 mmol ) in ethanol (10 ml) was refluxed for 30 min. After the first 5 min the solution changed colour from an orange to a pale yellow. The ethanol was then removed in uacuo and dichlorome thane

(15 ml) added to the residue. The organic solutjon was washe d with water (5 ml), dried and the solvent removed to give a pa le ye]'low oi'l (570 mg,98%). Purjfication by flash chromatograp hy (ethyl acetate/dichloromethane, 1:9) g ave 2-(5.5-dimeth.vl -3- methoxyi mi no- I -cycl ohex ì )ethanal 0-methyloxime (52) asa colourless oìl (mixture of isomers) which decomposed on attempted distil'lation (Found: C, 64.2; H,9-2; N, 12-6. Ctz\zoNr0z requires c, 64.3; H, 9.0; N, 12.5%). umax (film) 2800, 1630 (weak),

1620 (weak), 1050 cm-l. N.m.r. 6 7.25 and 6 .55, 2 x t, J 6Hz, 1H, H-C=N-OMe, 6.55, overlappìng and 5 -93, 2 x s (br), 1H,

=CH-C=N-OMe; 3.82, s, (br) , 6H, 2 x OMe; 3.1 and 2'98, 2 x d (br)' J 6Hz, 2H, C!z-CH=N-0Me; 2.3 and 2-0I, 2 x s, 2H, CHz-C=N-0Me; !.97, s (br) ,2H, CHz-C=CH; 0.97, s, 6H, 2 x Me. '224 Mass spectrum m/e (14) . (ii) in acetic acid:

Enamine (47) (500 mg,2.6 mmol) was dissolved in acetic acid (10 ml) containing methoxyamine hydrochloride (650 m9, 7.78 mmol) and the mixture heated at reflux for 30 min. The acetic acid was

then removed under reduced pressure, and the dark red residue 150

subjected to column chromatography on alumina. Elution with a mixture of dichloromethane and ethyl acetate (t:t) gave a red oil (a00 mg) which was shown to be a comp'lex mixture by t-ì.c. and 1H n.m.r. spectroscopy. Attempted cyclizatjon of bismethyloxime (52)

(i) wìth so dium hvdride and HMPTA in tetrahvdrofuran

The bi smethyì oxjme ( 52 ) ( 130 mg , 0. 58 mmol ) and hexamethyìphosphoric triamjde'(HMPTA) (0.5 ml ) were dissolved in tetrahydrofuran under a nitrogen atmosphere. Sodium hydride

(14 mg,0.58 mmoì) was added and the solution refluxed for 4h after which time the mixture was brown jn colour. 2-Methylbutyl nitrate

(0.25 mì) was then added in order to quench any of the unreacted anion and the mixture refluxed once more overnight. The solution

was evaporated to dryness under reduced pressure and the residue treated with water and extracted with ethyl acetate. Removal of lH the solvent gave a brown oil. the n.m.r. spectrum of the

residue showed that the oxime (52) had been consumed but no signa'ls which could be ascribed to the aromatic ring hydrogens of a pyrroìe were present. T.l.c. showed the residue to be a complex mixture of products. (ii) in polyphosphorlc acid A mixture of the bismethyìoxime (52) (SOO mg, 2.23 mmol) and polyphosphoric acid (5 ml) was heated at 110o for th under a nitrogen

atmosphere. The mixture was then cooled to room temperature, treated with water (-50 m'l) and the solution extracted with dichloromethane (3 x 10 ml). Removal of the solvent gave a pale 151 yel'low oil (55 mg). Purification by preparative t.l.c.t (dichloromethane/ethyì acetate,l:1) gave a product, ffi'P' 81-125' whose structure could not be deduced but had the following spectral data: uru* (CDC13) 3400 (br), 2800, 1700 (br), 1600, 1050 tt-l' N.m.r. ô 8.55, br s, 2H; 7.70, br t, lH; 7.07, br t, lH; 6.53, br s, lH; 3.83, s, 6H; 2.4, s, 6H; 2-2, s, 2H; 1'07, s, llï. Mass spectrum 381 (M). The product was recovered unchanged after attempted reduction wìth sodium borohydride in methanol.

5.4 Preparat'ion of substi tuted 2 . 3-epoxvcvcl ohexanones (i) 2,3-Epoxy-3-methy'lcyc'lohexanone (58a) was prepared from 3-methyl-2-cyclohexen-l-one using the procedure described by preparatìon of 2,3-epoxy-3-methyl- Yamazaki "t oLI04 for the cycìopentanone. Distillation under reduced pressure gave (5Ba)

in 87% yieìd, b.p. 83o/14 mm (tit.105 gs'/15 mm). (ii) Ethyl 2,3-epoxy-2-methyl-4-oxocyclohexane-1-carboxy'late

(78) was prepared from Hagemann's ester in 93% yie'ld using the procedure described in (i) but using ethanol instead of methanol

and allowing the reaction to proceed at 40" for 45 min. Distillation under reduced pressure gave the epoxide (78) as a

colourless oil, b. p. 92-96"/1 mm (1it.106 gs'/O.5 mm). N.m.r. ,q ô 4.20, g, J 7Hz, OCH2Me; 3.22, s, l.H, H-C-C overlapping wjth 3.!7, br t,CH-COzEt; 2.62'2.82, m, 4H, CHz-CHz-CO; 1'48' s' ,q Me-C-C; 1.32, t, J 7Hz, OCHzMe.

* possibly a mixture of isomers. r52

4-Methoxybenzyl ami ne

4-Methoxybenzaldehyde oxime (50.0 9, 0.33 mol) was dissolved jn ethanol (500 ml) and sodium (18.0 9,0.78 mol) was added in smal'l pieces over 30 min. After the addition was compìete the solution was refluxed for approximateìy 5 min and then stirred for a further 30 min until all the metal dissolved. The bulk of the ethanol was removed, water was added and the mixture extracted with dichloromethane. Removal of the solvent gave a pale brown oil (10 g),which was distilled to give 4-methoxybenzy'l- amine (6.0 g, l3%) as a colourless oil, b.p. 122"/14 mm (1it.107 122-n4o/ 14 mm). Acidification of the originaì aqueous solution and extraction with dichloromethane gave the starting oxime

(40 g , 80%). Preparation of enamines (59d), (SgU), (79) and (59e) from the corresDondinq substituted epoxycVclohexanones.

( i ) A sol ution of i sophorone epoxide ( 1.00 g, 6.5 mmol ) and benzy'lamine (0.8 ml , 7.8 mmoì ) in 1-propanoì (t.S ml ) and water (0.5 ml) was heated at reflux under a nitrogen atmosphere. Aìiquots of the solution were withdrawn, the solvent removed lH in uacuo and the residue examined by n.t.r. spectroscopy. After 5 min reflux, quantitative conversion to the imine had occurred. An analyticaì samp'le u,as prepared by bulb to bulb distillation of a portion of the crude residue to give

N-benzvl -2.3-epoxv-3.5.5-trimethvl cyclohexanone imine (61) as a colourless oil, b.p. l2l-L22"/0.3 mm (Found: .C,78.7; H, 8.6- Cr.oHzrNo requires C, 79.0; H,8.7%). urax (film) 1660, 1600' 1490'

740 cm-l. N.m.r. ô 7.18, s, 5H, ArH; 4.50, s , 2H, N-CHz; 153

3.30, s, lH H-db, 2.20, s,2.10, s, 1.85, s, 1.68, s,4H, ,0r 2 x CHz; 1.35, s, MeC-C; 0.97, 0.85, 2 x s, CMez. Mass spectrum m/e 243 (M).

The conversion of imine (61) to the enamine (59d) was lH conveniently followed using ntr^ spectroscopy by observing the resonances of the benzylic methylene protons at o 4.50 and ô 3.94 for the jmine and enamine respectìve'ly. After 4å hours reflux no further increase in the amount of enamine vvas evident.

Removal of the solvents gave a red oil whjch was subjected to column chromatography on alumina. Elutjon wjth dichloromethane gave a fraction containing main'ly the enamine (59d) contamìnated with a small amount of the imine (61). Fractional distillation under reduced pressure g ave 2-phenyl methyl ami no-3 ,5 ,5-tri methyl -

2-cycl ohexen-1-one (59d) (0.79 g, 50%) as a pa'le yelìow viscous oil, b.p.(block temp.) 109"/0.01 mm (Found, M*', 243.7620. CtL Hr, ¡ìldbo requires M+', 243.1623). uru* (film) 3060,3030,1650,1600,1495 cm-1. N.m.r. ô 7.13, s,

5H, ArH; 3.95, s , 2H, CH2-N; 2.20, br s, 5H, Me-C=C overlapping wìth CH2'C=C; 1.92, s, 2H, CH2-C0; 0.87, s, 6H, CMez.

The following compounds were prepared in a simi'lar manner, although the intermediate imines were not isolated.

(ii) 3-Methyl -2-p henvlmethyl ami no-2-c.ycl ohexen-1-one ( 59b)

was prepared from 2,3-epoxy-3-methy'lcycìohbxanone (Sga) in methanol/water and refluxing for 4h. Chromatography as in (i) followed by fractionaì distillation gave (59b) as a pale yeììow

oil (70%), b.p. 101"/0.01 mm (Foundi C,78.3; H,7.8; N' 6.7.

Cr+HrzNO requires C, 78.1, H, 8.0; N, 6.5%). v*u^ 3350, 1760, 154

1640, 1600 cm-'.-1 N.m.r. ô 7.15, s, 5H, ArH; 3.93, s, 2H, N-CHzi

2.33, rn, CH2-f,=C overlapping with CH2-C=0; 1.92, s, 3H, Me-C=C overlapping with m, 2H, CHz-CH2-C=Q. Mass spectrum m/e 215 (M).

(iii) Eth.yl 2-methyl -4-oxo-3-phenyl methy I ami no-2-cyc I ohexene- 1-carboxyl ate (79) was prepared from ethyì 2,3-epoxy-2-methyl 4- oxocyclohexane-l-carboxylate (78) in methanol/water and refluxing

the solution for 18h. Column chromatography on alumina gave, after elution with dichloromethane/ethyl acetate, (79) as an orange oil (87%). Distillation of a small portion of this material gave

the ester (79) as a pale orange oil,t b.p. (block temp.) 130"/0.03 mm (Found: M+' , 2g7.1531. cttiz1N03 reQuires M+' , 287.i521) uru* (f ilm) 3350, 1730, L670,1635 cm-1. N.m.r. ô 7.15, s, 5H, ArH; 4.!2, g,

J 7Hz, O-CH2-Me overlapping with 3.98, s,2H, N-CH2; 3.27, brt, lH,

CH-CO2Et; 2.63-1.87, m,4H, CH2-CH2-C=0 overlapping with 1.97, br s,

Me-C=C; 1.23, t, J 7Hz, OCHzMe.

(v) 2 - ( 4-Methoxyphenyl meth y ì ) ami n o- 3 -methyl -Z-c.y cloh exen - 1 -on e

(59e) v',as prepared from 2,3-epoxy-3-methylcyc'lohexanone and

4-methoxybenzyìamine in methanol/water at 70o for 5h. Removal of the soìvent and fractional distillation of the black residue gave

(59e) as a pale yeìlow oil (65%),b.p. t32"/0.004 mm (Found: C, 73.5; H,7.9. CrsHreN02 requires C,73.4i H,7.8%). uru, (film) 3325,1660, 1630,1610, 1500.r-1. N.m.r. ô 6.93,6.98, ABq, J 8Hz,4H, ArH; 4.5, br s, NH; 3.87, s,2H, N-CHz; 3.73,

s, 3H, OMe; 2.53-2.20, m,4H, CHz-C=O and CH2-C=[; 1.93, s, 3H,

Me-C=C overlapping with 1.87, m, 2H,5-CH2.

f Some decomposition resulted on distillation. 155

2-Morphol i no-3,5,5-trimeth.yl -Z-cyc\ohexen-1,-one (62) A solution of isophorone epoxide (58b) (1.00 g, 13-0 mmol) and morpholine (1.17 g, 13.0 mmol) in methanoì (10 mì) and water

(S ml) was heated at 80" overnight. (Examination of an aììquot 1H of the solution by n.t.r. spectroscopy after 2h showed new resonances for the 3-methyl and 4-methyìene hydrogens at ô 2-20

(overlapping) indicative of the formation of the enamine in 60% yield). Removal of the solvent and distillation of the crude residue g ave 2-morpholino-3,5,S-trimethyl-2-cyclohexe¡-l-one (62) as a colourless oj1 (2.61 g,90%), b.p. (block temp.) 90"/0.09 mm

(Found: M+', 223.1577. cr3H2rN02 requires M*', 223.1572). umax (CH2CI2) 3050, 1660, 1520, !270.t-1. N.m.r. 6 3.63, br t, 4H, 2 x CH2-0; 2.83, br t, 4H, 2 x N-CH2; 2.2, s, 5H, Me-C=C and

CH2-C=[; 1.98, s, 2H, CH2-C=Q; 1.00, s, 6H, CMez.

Cyc lization of enamines to 7-oxo-4.5.6.7-tetrahydroindoles: (i) A mixture of 2-phenylmethylamino-3,5,S-trimethyì-2-

cyclohexen-1-one (SSa¡ (SOO mg , 2.06 mmol ) and dimethy'lformamide dimethyl acetal (5OO ul , 3.77 mmo'l) was heated at 150' overnìght under a nitrogen atmosphere. A further amount (500 pl ) of the acetal was added and the dark red mixture heated again overnight.

Removal of the unreacted acetal and volatile material in uaeuo gave a red oil which was chromatographed on alumina. Elution with dichloromethane gave the crude product (60b) as a vjscous orange oilt (365 mg,7O%). Bulb to bulb distillation of a small portion

g ave 5,5-dimethy I -7 -oxo- 1 -phenyl methyl -4,5,6, 7 -tetra hydroi ndol e

t This compound was air sensitive and a satisfactory microanalysis could not be obtained. 156

(60b) as a pale yellow viscous oiì, b.p. I4I-742"/0.25 mm

(Found: M+' , 253.1467. crzl'lrgNo requires M+', 253 .1467) - ,ru* (film) 3075,3025, 1640, 1500, 1595 cm-1. N.m.r. ô 7.10, s,5H, Ar H; 6.73, d, J ZHz, H-2; 5.92, d, J ZHz, H-3; 5.43, s, 2H, N-CHz; 2.58, s, 2H, 4-CHz; 2.30, s, 2H, 6-CHz; 1.05, s, 6H, CMez.

('ii) 7-Oxo- 1-phe nvlmethvl -4.5.6.7-tetrah.vdroindole (60a) was prepared from the correspond'ing enamine (59b) by the procedure described in (i) except that the m'ixture was on'ly refluxed for 3h after the second addit'ion of dimethy'lformamide dimethy'l acetal .

Removal of the unreacted acetal and volatiles in uacuo gave a dark red oil which was chromatographed on alumjna. Elution with

di chl oromethane/ethy'l acetate ga ve 7-oxo-1-phenylmethYl'4,5,6,7 -

tetrahydroindole (60a) (80%) which was distilled to give (60a) as a paìe orange viscous oil, b.p. 86-88'/0.005 mm (Found: M+',225.1149. crsHrsN0 requires M+',225.1154). rmax (film) 1650, 1600, 1550, 1500 cm-l. N.m.r. 6 7.I2, s, 5H, Ar H; 6.68, d, J 2.5H2, H'2; 5.92, d, J 2.5 Hz, H-3; 5.45, s, 2H, N-CH2:' 2-67, m, 2H, CH2-C=0; 2.35, m, 2H, 4-CHz; 1.97, m, 2H, 5-CH2.

(iii) A complex mixture resulted when ethyl 2-methyì-4-oxo-3- phenylmethylamino-2-cycl ohexene-1-carboxylate (79) and

dimethylformamjde dimethy'l acetal (2 eq.) were heated at 160" for 2h. The acetal and volatile material was removed in uacuo and the lH residue examined by n.t.r. Spectroscopy. No resonances which could be ascribed to the cyclized material (80) were present.

T.l.c. showed the residue to be a complex mixture of products.

( i v ) Attempted reacti on of 2- (4-methoxypheny'lmethy'l )ami no-3-methy'l - Z-cyclohexen-I-one (Sle) with d'imethyìformamide dimethyì acetal

(2 equiv.) at 160o for 2h led to decomposition of (Sge). t57

Prep aration of 2-amino-3,5,5-trimeth.yt -2-cyclohexen-1-one (59c) A suspension of isophorone epoxide (5.00 g, 32-5 mmol) in aqueous ammonia (110 ml, s.g. = 0.88) was subiected to ultrasound in a sonicator for 6h at 35-40o. The solution was acidified with

10% hydrochlöric acid and then extracted with dichloromethane.

Removal of the solvent gave a pale brown oil which was shown to be the starting epoxide (2.62 g, 52%). The aqueous solution was basified with sodium carbonate and extracted with dichloromethane (4 x 50 ml). Removal of the solvent gave the crude amino compound (59c) as a light brown oil (950 mg, I9%). The crude product was purifìed by column chromatography on alumina using ether as the eluting solvent. Recrysta'llization from ether/pentane gave

2 -ami no- 3 .5 .S-tri methyl -2 -cvcl ohexen - 1 -one (59c) as off-white plates, m.p. 66.5-75" (dec. ) (Found: C, 70.3; H, 9.8. CaHrsNO requi res C , 70.6; H, 9 .9%) . N.m.r. ô 3.33, br s, NHz; 2.25, s,3H, Me-C=C overlapping with 2.20, m, 2H, CH2-C=C; 1.78, s, 2H, CH2-C=Q; 1.00' s, 6H, CMe..

Mass spectrum m/e 153 (M).

A summary of some unsuccessful attempts at the preparation of (59c) ìs given in Table 2. In all cases only the starting epôxide was recovered.

2-Ami no-3-me 1-2- clohexen-1-one (Sga)

2,3-Epoxy-3-methy'lcyclohexanone (1.00 g, 7 .94 mmol ) was dissolved in aqueous ammonia (30 ml, s.g. 0.888) and the mixture stirred vigorously for th at 35o. The solution was then carefu'lìy neutralized to pH 7 with concentrated hydroch'loric acid and saturated with solid sodium chloride. Extraction with 158

dichloromethane gave after removal of the solvent, a brown oi'l (470 mg,39%) whjch could not be induced to crystallize. The oil had spectraì chracteristics consìstent with those reportedTg for 2-amino-3-methy'l -2-cycìohexen-1-one (59a) : (Found: M*' ,

125.0838. CzHrlN0 requires M+',125.0840). umax (film) 3400-3550

(br),1650,1580 cm-1.

Tabl e 2. Attempted parations of 2-amino-3,5,5-

trimethyl -2-cycl ohexen- 1-one (5ec) from i sophorone epoxide (58b)

Reactant Sol vent Condi t'ions

Di oxane sealed tube 110o, 2h

NH3/H 2 0 1-Propanol sealed tube 75", 4h. (d = 0 88)

Methanol sealed tube 90", låh

NH3/H20 (d = 0.88) Ether RT 2 days alumina

NHg Ethanol -79" . RT; (neat I jquid) RT, 4 days. 159

Reaction of 2-am'ino-3-methvl-2-cvclohexen-1-one (59a) with dimethylformam'ide dimethyl acetal A mixture of 2-amino-3-methyl-2-cycìohexen-1-one (59a) (500 mg,4.00 mmol) and dimethyìformamide dimethyl acetal (530 ul,

4.00 mmol) was heated at 150o for 2h. A small aliquot was withdrawn, the volatile material removed and the residue

1 examined by 'H n.m.r. spectroscopy. No resonances attributable to the cycìized material could be detected. The remainder of the mixture was further heated overnight under a nitrogen atmosphere. The solution was again evaporated to dryness 'Ln uacuo and the

residue chromatographed on alumina. Elution with ethyl acetate/

dichloromethane (1:1) gave Nl N1-dimet I -N2- 6-met I -2-oxo-6-

cyclohexenyl )formamidine (63) (325 mg, 45%) as a pale brown oil Thìs oil, which could not be jnduced to crystallize had spectra'l data consistent with structure (63) (Found! M*' , 180.1256. croH,.5N20 requires M+', 180.1263). umax (film) 1650, 1640, 1630 cr-l. N.m.r. ô 7.2, br s, H-C=N; 2.93, s, 6H, NMez; 2.67'1.60,

m, 6H, (CHr)rC=0 overlapping with 1.93, s, 3H, Me-C=C. Further elution with ethy'l acetate gave a paìe yellow oil

(-100 mg) which appeared to be a complex mixture by t.'l .c. but conta'ined a small amount of the required cyclized product, 7-oxo-4,5,6,7-tetrahydroindole (11). (Found: M*', 135.0688. lH C8HsNO requìres M+',135.0684). The n.r.r. spectrum showed the presence of the aromatic pyrrole hydrogensrô 7.07, n, lH, H-2 and ô 6.15, m, lH, H-3, which was in agreement with the pub'l'ished lH n.r.r. data for 7-oxo-4,5,6',7-tetrrahydroindole (11).103 160

'i j Attempted cycl zat on of ami di ne (63 ) (i) The amidine (63) (100 mg, 0.56 mmol) was dissolved jn poìyphosphoric acid (10 ml) and the mixture heated at 1250 for 3h under a nitrogen atmosphere. Water (10 ml) was added, the mixture neutralized with solid sodium carbonate and the aqueous solution extracted wjth ethyl acetate. Removal of the solvent gave a brown oil (30 mg) ìdentica] to the starting materiaì by n.m.r. and t.l.c. analysis. (ii) The amidine (63) was dissolved in deuteriotrifluoroacet'ic acid and the solution heated at 100" for th then allowed to stand at 35o for 5 days. Work up as in (i) gave a brown oil which was a complex mixture by t.l.c.

(iii) The amidine was recovered unchanged after refluxing a solution of (63) in dimethylformamide overnight. (iv) The amidine (63) (100 mS, 0.56 mmol) was dissolved in tetrahydrofuran (25 mì) containing sodium hydride (30 mg, 1.25 mmoì).

The mixture was heated at reflux for 6h, the solvent removed and the resjdue treated with water. Extraction with ethyì acetate gave amidine (63) (90 mg) unchanged.

Attemp ted heteroannelation of enamines (SSal and (59c).

(i) The enamjne (59a) (100 m9, 0.8 mmol) was dissolved in trìmethyì orthoformate (2 ml) containing 1 drop of acetic acid and the solution was heated at reflux overnight under a n'itrogen atmosphere. Removal of the unreacted orthoformate by rotary lH evaporation gave a brown oil. n.t.r. spectroscopy showed it to be ìarge'ly unchanged starting material. 161

(ii) A mixture of 2-amino-3,5,S-trimethyl-2-cyclohexen-1-one

(59c) (50 mg, 0.33 mmot ), bis(dimethylamino)t-butoxymethane63 (100 mg,0.57 mmol), potassium t-butoxide (50 m9,0.45 mmo'l) and deuteriochloroform (1 m'l) was heated in a n.m.r. tube at 35o and lH the reaction followed Uy n.m.r. spectroscopy. After 2 weeks the starting materjal was still present.

(iii) 2-Amino-3-methyl-2-cyclohexen-1-one (59a) (100 mg, 0.8 mmoì) was dissolved in chloroform(2 ml) and ethy'l chloroformate (100 mg,

0.92 mmol) added (slowly) dropwise. The mixture was stirred at room temperature for 10 min and then washed with saturated sodium bicarbonate solution (t ml). The organic phase was separated, dried, filtered and the solvent removed to g ive ethyl N-(6-methyl- 2-oxo-6-cycl ohexenyl ) carbamate (74) as a pale brown oil (116 mg, 90%). Although the oil could not be induced to crystallize it had spectra'l däta consistent with structure (74) (Found: M*',

rg7.Lo52. C10H1sN03 requires M+' , !g7.1052). umax (cDcl 3) 1710, 1665, 1640 cm-l. N.m.r. ô 4.13, Q, J 7Hz, 2H, 09[r; 2.90, br s, N-H; 2.5, br t,2H, CHz-C=C; 2.27-I.7,fr,4H, CH2-CH2-C=0 overìapping with 1.97, s, 3H, Me-C=C; 1.27, t, J 7Hz, OCHzMe.

The carbamate (74) (100 mg, 0.51 mmol) was heated with dimethy'lformamide dimethy'l acetal (ZOO uì , 0.91 mmol ) at 160" for 'left 6h. Removal of the volatile material under reduced pressure lH a brown oil. Examination of the oil Uy n.m.r. spectroscopy showed it to be a mixture of methyl and ethyì carbamates but no resonances which could be attributed to the cycìized material were present (the doublet resonances of the pyrro'le aromatic protons being diagnostic). t62

Attempted preparation of Z-azido-3-methyl -2-cyclohexen-1-one (67 ) from epoxide (58a) The results of this reactìon are summarized in Table 3.

In each case the organìc ìayer u,as separated, the aqueous solution saturated with solid sodium chloride and then extracted with dichloromethane. After removal of the solvent the residue was lH examined by t.l.c. and by infrared and n.t... spectroscopy.

Table 3. Attempted reactions of 2,3-epoxy-3-methylcyclohexanone (58a) with azide ion.

Reactant Sol vent Condi ti ons Resul t Ref.

NaNe/ cH2cl z/Hz} RT, 15h A - Me(n-oct)rN+cl l:1

NaN3 Di oxane/ 900 , 4h B 59 Hz0 1:1

NaNg/ RT, 15h A Ms(Cì0+)z il r02 g0o, 15h c

NaNg / tfi!trt,o 50o, 15h B 60 NH '*Cl 7:I

( nBu ) uN+Ni cHcl 3 35o, 3 days A

KEY A Starting materiaì recovered.

B Product isoìated but no azide absorbance ìn i.r. spectrum.

c Compìex mixture of products by t.l.c. 163

3-Methvl -Z-nitro-2-cycl ohexen- 1 -one (6e)

METH0D 1. A two phase mixture of 2,3-epoxy-3-methylcycìohexanone (Sga) (500 mg,3.97 mmoì) in dioxane (10 mt) and saturated aqueous potassium nitrite (¡ ml ) containing methyìtri -n-octylammonìum chloride (50 mg) was stirred vigorously at ref'lux overnight. The organic phase was then separated and the solvent removed to give a yeìlow oil (200 mg). Distil'lation g ave 3-methyl -2-ni tro-Z' cycÏohexen:l-one (69) as a yellow oil, b.p. (block temp.) 70-80"/ 0.1 mm (Found: M+', 155.0580. czHsN03 reÇuires M+', 155.0582). uru* (film) !670,1640, 1550, 1430 cm-l. N.m.r. 6 2.33, m, 4H,

CH2-C=C and CH2-C=0; 2.00, n,2\1, CH2-CH2-C=0 over'lapping with

I .93 , s, 3H , Me-C=C. The nitroketone (69) was always contaminated with a small amount (cf . 5%) of the aromatic by-product 3inì9th.y]:?:nilrophenol .

This compound was also formed if (69) was allowed to stand at room temperature for a few days. ,*u* (film) 3300 (broad), 1600, 1590,

1530, 1340 cm-'.-1 Mass spectrum m/e 153 (M).

METHOD 2. Nitronium tetrafluoroborate (2.00 g, 15.1 mmol) was added s'lowly over 15 min to a solution of 3-methyl-2-cycìohexen- l-one (1.00 9,9.1 mmoì) in dioxane (15 ml) keeping the temperature of the mixture below 30o with external cooling. The mixture was stirred at room temperature overnight then poured into water (-SO ml). The aqueous solution was extracted with dichloromethane (3 x 15 mì) and the combined organic extracts dried, and the solvent removed to give 3-methyl-2-nitro-2-cyclohexen-l-one (69) as an orange oil (549 mS,39%),identicaì ìn all respects to that obtai ned previous'ly. 764

Attemp ted reaction of (Og) with dimethvlformamide dìmetly'l-sçe'!ql A mixture of 3-methyl-2-nitro-2-cyclohexen-1-one (100 mg,

0.65 mmol ) and dimethyìformamide dimethy'l aceta'l (0.2 ml , 1.51 mmol ) was heated at 160' for 20 min under a nitrogen atmosphere. The unreacted acetal and volatile material was removed under reduced pressure to give a dark red oil (120 mg). Attempted purification by column chromatography on alumina gave'after elution with ethyl acetate,a red oil (80 mg) which crystallized on standing. The spectraì data of this oil indicated that hydrolysis of the nitro group had occurred on work up to give 4-dimethylaminomethylene- 2-hydroxy- 3-methylcyclohexen-1-one (Found: M+', 181.1100. CroHrsN0z requi res M+' , 181.1103) . umax (CH2CI 2) 3350 (broad) , 1630 (broad) , 1530 (broad) .t-1. N.m.r. 7.28, br s, C=CHNMez (possibly E and Z isomers); 5.63, br, 0H; 3.03, s, 6H, NMe2; 2.25, m, 4H, 5-CH2

and 6-CHz; 1.83, s,3H, Me-C=C. 165

Attempted deben zvlation of 7-oxo-l-phen.vlmethvl -4,5,6,7 - tetrahydroi ndol e (6oa)

( i ) 7-0xo-1-phenyl methyl '4 ,5 ,6,7-tetrahydroi ndol e ( 6Oa ) (100 mg,0.44 mmol) was dissolved in methanol (ZS ml) contaìning

10% paìladjum on charcoal catalyst (10 mg) and the solution hydrogenated at I atmosphere at room temperature for 24 h. The solut.ion was then filtered and the solvent removed to give unchanged starting material (98 Ing). (iì ) The above reaction v,,as repeated but with the additjon of 1 drop of concentrated hydrochloric acid. The solutjon was hydrogenated at 1 atmosphere for 4h then filtered. The solvent

WaS removed under reduced pressure and the residue dissolved in dichloromethane (10 ml). The organic solutjon was then washed with saturated sodium bicarbonate, dried, filtered and the solvent removed to g'ive a dark oil (92 mg). ll.m.r. analysis showed it to be largely starting material. (iii ) 7-Oxo-1-phenylmethy'l-4,5,6,7-tetrahydroindole (60a) (100 mg, 0.44 mmol)'in ether (2 ml) was added to a solution of sodium (61 mg,2.65 mmol) in liquid ammonia (7 ml). The mixture was stirred for 5 min and then quenched with saturated ammonium chloride solution. The organic phase was separated, the aqueous solution extracted with dichloromethane and the combined organic extracts concentrated in'r)a.cuo to give a brown oil (ZO mg). The residue was 'ltH exam'ined by n.m.r. spectroscopy which showed that only a small

amount of the benzyl compound remained (ô 5.42). 166

Chromatography on alumina gave, after elution with dichloromethane, the starting material (OOa) (23 mg). Further elution with ethyl acetate gave a brown solid (30 mg) which darkened extremely rapidìy and decomposed upon attempted recrystallìzation'from dichloromethane/light petroìeum. T.l.c. and n.m.r. analysìs of the sol'id showed it to consìst of 2 maior components, one of which was identified as the startìng material

(60a). The other component contained no benzy'l substituent and lN exhibited two resonances in the n.t.r. spectrum (both multiplets) cort'esponding to the aromatjc pyrrole protons of 7-oxo-4,5,6,7-tetrahydro'indole (11)103 (o 2.05 and 6.10).

Attempted Schmidt reaction on the ketones (60a) and (!9Ð. (i) A mìxture of 5,5-dimethy'l-7-oxo-1-phenylmethyl -4,5,6,7' tetrahydroindole (60b) (400 mg, 1.58 mmoì) and sodium azide

(113 mS , I.74 mmol ) in polyphosphoric ac'id (40 ml ) was heated at 80o for 2h under a nitrogen atmosphere. The mixture was then cooled, ice (50 g) added and the aqueous solution neutral'ized with solid sodium carbonate. Extraction with dichloromethane (4 x 20 mì) gave the starting material (¡qO mg, 85%).

(ìi) When the Schmidt reaction !ì,as carried out as in (i) but at 100o for 4h, only the startìng'material could be isolated (63%). Extraction with tetrahydrofuran gave no further material.

(iìi) The ketone (6OU) (SOO mg, 1.98 mmol) and sodium azide (257 ng, 3.45 mmol) were dissolved in poìyphosphoric acid (10 mì) and the mixture heated at 120o for 3åh. Work up as in (i) gave after extraction with tetrahydrofuran, a brown oil (300 mg). A mass spectrum of the crude reactjon mixture before chromatography L67

showed that rearrangement products vuere possibìy present (m/e 268).

Column chromatography on alumina gave after elution with ethyì acetate/dichloromethane (1:5) the starting ketone (50 mg, I0%)-

Further elution with ethyì acetate/dichloromethane (2:3) gave a brown oil (100 mg) whìch was identified as 5,5-dimethyl-7-oxo- 4,5,6,7-tetrahydroindole (42) (3L%). This oil, which could not be induced to crystallize, had spectra'l data consistent with its structure (Found: M+', 163 .O74L C10Hr3N0 requires M+',

163.0746 ). N.m.r. (Or0 exch.) o 7.00, d, J 2.5H2, H-2:' 6.02, d, J 2.5H2,

H-3; 2.62, s, 2H, 6-CH2; 2.33, s , 2H, 4-CH2; 1.08, s, 6H, CMer. Further elution wìth ethyl acetate gave a dark brown oil

(100 mg) which was a comp'lex mixture by t;'l .c. and n.m.r. analysis.

(iv) The Schmidt reaction on 7-oxo-1-phenylmethyl-4,5,6,7- tetrahydroindole (60a) us'ing sodium azide (3 equivalents) in concentrated hydrochloric aci¿79 led to a complex mixture of products, as ana'lysed by t.l.c. N.m.r. anaìysis showed that extensive debenzyìation had occurred under the conditions. (v) The Schmidt reaction on 5,5-dimethyl-7-oxo-1-phenylmethy'l- 4,5,6,7-tetrahydroindole (60b) using a two phase ether/concentrated su'lphurìc ac'id mixtureS0 ut 0" and allowing the mixture to warm to room temperature returned the start'ing material, confìrmed by t.l.c., n.m.r. and mass spectral analysìs.

Attempted pre paration of7-oxo{-p henvl methvl -4 . 5.6,7-tetrahvdroi ndol e ox'ime (81a). A mixture of 7-oxo-1-phenyìmethy'l -4,5,6,7-tetrahydroindole

(60a) (500 mg,2.22 mmol) and hydroxylamine hydrochloride (500 mg, 168

7.19 mmol) in methanol (25 m'l) was heated at 80o fo.r 2 days. The mixture was then evaporated to dryness under reduced pressure and treated with water (10 ml). Extraction of the solution wjth ethyl acetate (3 x 5 mì) and removal of the solvent gave a brown oil (100 mg). Column chromatography on alumina, eìuting with lH ethyì acetate, gave a paìe brown oil (a5 mg). The n.,n... spectrum of this oil showed a neÌ^, set of resonances for the aromatic pyrrole protons (o 6.47, d, J 3Hz, H-2; 5.87, d, J 3Hz, H-3) and the benzy'lic hydrogens (o S.35, s). vru* 3300, 1710, 1610,

1590 cm-l. Mass spectrum mle ?40 (14),223 (M-OH). Examìnation of the product by t.l.c. showed that a small amount of the ketone (60a) was also present. The oxime could not be further purifìed.

Preparati on of 2 ,3-epox.yc.ycl ohexanone oxi mes

(i) 2,3-Epoxy-3,5,5-trimethyìcyclohexanone oxime (84b) was prepared in 95% yield as a mixture of E and Z isomers according to the method of CoreyS3 et aL The o'iìy product was of sufficient purity to be used directìy in the subsequent reactions (Found:

M+', 169.1099. cgH,.5N02 requires M+', 169.1102). N.m.r. ô 8.58, ,q br s,0H; 4.08, s and 3.32, s,lH,.H-C-C; 2.80-1.62, complex,4H,

3-CH2 and 5-CHz; 1.38, s, 3H, ¡le-C'-b; 0.95, 0.87, 2 x s, CMez. (ii) 2,3-Epoxy-3-methylcyclohexanone oxime (84a) was prepared by adding 2,3-epoxy-3-methylcyclohexanone (58a) (1.00 g, 7.94 mmol) to a solution of hydroxy'lamine hydrochloride (552 mg,

7.94 mmol) and sodium bicarbonate (667 m9,7.94 mmol) in water (50 ml) and stirring the mixture vìgorousìy for 20 min. Extraction with ether (3 x 25 ml) and removal of the solvent gave (84a) in 169

90% yield as a colourless viscous oil (mixture of E and Z isomers) (Found: M+', 141.0785. CzHr1N02 reQuires M+',

141 .0790 ). ,max (fitm) 3300 (broad), 1640 (weak) .t-1.

3-Hydroxy-2-p henvl methyl ami no:3 ,5 ,5-tri methyl cyc'l ohexanone oxime (86b).

Isophorone epoxide oxime (3.70 g, 21.9 mmol) and benzy'lamjne

(2.34 g,2!.9 mmol) were dissolved in methanol (25 mì) and the s'olution heated at reflux for 6h. The methanol was removed in uacuo to give a pa'le yellow oil. Ether was then added and the precip'itate which formed was removed by filtration. Spectral data of the crystalline soljd suggested that it was a mixture of

E and Z i somers of 2 -hydroxy-3 -ohenvl methvl ami no-3 ,5 ,5-tri methyl - cycìohexanone oxime (87b) (1.00 g, l7%), n-p- 155-159o (Found:

M+' + l, 277.1905. Cr5H25N202 requires M+' + t, 277.1916) . vru* 3450, 3360, 3310, 1650 (weak) .t-1. N .m. r. (CDCI r/ (CDr ) rS0) ô 9.94, br s,0-H; 7.18, s, 5H, ArH; 3-70, ABq, J l?Hz, 2H, N-CH2; 3.33, s, and 3.00, s,1H, H-C-OH; 2.35, q, J 13Hz , 2H, 6-CH2; 1.6, s, 2H,4-CHz; 1.17, s'Me-C-N ; 1.05, 0.97, 2 x s, CMe2. The mother ìiquor gave upon distillati on, 3-hydroxy-2- phenyl meth vl ami no-3 .5 .5-tri methvl cvcl ohexanone oxime (86b) (4.50 g,74%) as a colourless oil (mjxture of E and Z isomers), b.p.158'/0.01 mm which crystallized on standjf,9, ffi.P. 148-158' (Found: M+'-0H, 259.1805. CreHz¿Nz0z reQuires M+'-0H, 259.1810). v--.. 3350, 3000-2500 (broad), 1650 (weak), 1600, 1500 cm-1. N'm'r' max ô 7.15, s, 5H, Ar H; 3.75, br s, 2H, N-CH2; 2.92, s, lH, HC-NCH2; 2.72, s,1.85, s,1.63, S,1.48, s,4H,4-CH2 and6-CHz; !.22, s, 3H, Me-C-0H', I.0?, 0.93, 2 x s, 6H, CMe2. 170

13C n.m.r. ô 157.3, C-l; 139.9, 128.4, I27.2, ArC; 74.2, S, C-3; 65.7, d, C-2; 53.6, t, CH2-Ar; 49.3, t, 6-C; 36.3, 33.4, 31.5,

29.4, 28.I, 3 x Me, C-4 and C-5.

3-Hydroxy-3-methyl -2-phenyl methyl amÍ noc.ycl ohexanone oxi me (86a )

The tit'le compound (86a) was prepared in 90% yieìd as described for (86b) prevìous1y. Dist'illation of a portion of the crude reaction mixture yielded a colourless ìiqu'id, b.p. (bìock temperature) I70"/0.06 mm which crystallized on standing. Recrysta'llization from ethy'l acetate/light petroleum gave

3-hydrox.y-3-methyl -2-phenyl methyl ami nocycl ohexanone oxi me ( 864 ) as colourless needles, m.p. 140-170". vru, 3300, 1645 (weak), 1600, 1490 (weak) .r-1. N.m.r. ô 7.15, s, 5H, ArH; 3.68, br s, 2H, N-CHz; 2.96, br s, lH, HC-OH ; 2.70-2.07, m, 2H, 6-CH2; 1.62, m, 4H, 4-CH2 and S-CHz; 1.18, s, 3H, Me-C-OH. Mass spectrum nle 249 (M+1) , 231 (M-HrO).

2-Phenylmethvl ami no -? 5 .5-trimethvl -2-cvclohexen-1-one oxime (85b)

An intimate mixture of fine'ly powdered lithium hydroxide (100 mg,4.18 mmol) and the oxime (86b) (200 mg,0.72 mmol) was heated s'lowly under vacuum in a bulb to bulb apparatus until the product began to distilì. The enamino-oxime (85b) (125 mg, 67%) was thus obta'ined as a v'iscous yel'low oiì, b.p. (block temp.) 145"/0.03 mm.

(Found: M+'+1 , 25g.1813. CraHzsNz0 requ'ires M*'+!, 259.1810) - u*u* (film) 3500-2500, 1650, 1615, 1590 cm-l. N.m.r. 6 7.73, br s, NH; 7.32, s, 5H, ArH; 3.85, s, 2H, N-CH2 ' 2.97, S, 2.63, s, 2H, 6-CH2 (E and Z isomers); 2.12, m, 5H, Me-C=C and 4-CHr; 0.97' br s, 6H, CMe2. 17L

3-Methyl -2 -ohenvl methvl ami no-2 -cvcl ohexen-1-one oxime (85a)

The title compound was prepared by dehydration of the corresponding oxjme (86a) as previous'ly described for (86b).

The enamino-oxime (Bsa) was obtained in 83% yieìd as a viscous ye] ì ow oi I , b. p. 142" /0.015 mm ( Found: M*i ! , 23I. 1489. cr,,HrsNz0 requ'ires M*ï I , 231 .r4g7) . uru* (cHzcl z) 3500-2500,

2900, 1665 (broad), 1590, 1560, 1490 .t-1. N.m.r. ô 7.70, br s, NH,OH ; 7.3,s,5H,ArH; 3.85, s, 3.80, s, 2H, N-CH2 (E and Z 'isomers); 3.02-1.53, m,6H,4-,5- and 6-CHz; 2.10, s,3H, Me-C=C.

Attempted reactìon of enam'ino-oxime (85a) with dimethvlformamide dime I acetal A mixture of the enamino-oxime (85a) (500 mg, ?.I7 mmoì) and dimethyìformamide dimethy'l acetal (SZO mg, 4.37 mmol) was heated at 150" for 3h under a nìtrogen atmosphere. A small portion of the reaction mixture was withdrawn, the volatile material removed lH and the residue examined by n.t.r. spectroscopy. After 3h, the starting material appeared to be present, as well as a new resonance at ô 3.30 which was presumed to be due to the O-methyloxime: no resonances attributable to the pyrro'le ring hydrogens of the cyclized materiaì could be detected.

l,rjhen the reaction was repeated with bi s(dimethylamìno)-t-

butoxymethun.63, a complex mixture of products was formed. A 1H n.r.r. spectrum of the crude reaction mixture revealed that none of the desjred product was present (two doublets, ô6-7, J-ZHz expected for pyrrole ring hydrogens). t72

Table 4

Summary of unsuccessful attempts to dehydrate oxit" (aOO)

Reagent Solvent Conditions Ref

I2 neat rooo/o.ot-,''

KH SO4 neat rsaof o.o:tmm 92

DMSO raoo/ sn r08

MeOH I rcn HrO toof

pTsO H Benzene eoysn

to9 I 2 Benzene aoo/t

vacuum pyrolysis ssoo/o.s^^ through quartz tube ssoo / o.3mm

I cF3co2D cDct3 sso¡ t t73

-Methyl -2 .5 .6 .7-te trahvdro- lH-azePi n-2-one ( 13 ) The tit'le compound was prepared according to the method of

Mitsuhashi and No*u.u79 in 85% yield. Recrystallizatjon from hexane gave (13) as colourless p1ates,m.p. 80-81" (l it.79 8t-AZ'¡.

3 -Bromo -4- hvdroxv-4-meth vl -2.3.4.5.6.7 -hexa hvdro- lH-azePi n-2-one

(8e) 'in The caprolactam (13) (1.00 g, 8.00 mmol) was djssolved water (SO ml) and N-bromosuccinimide (1.42 g, 8.00 mmol) was added to the vigorousìy stirred solution. The N-bromosuccinjmide dissolved and the solutjon was stirred at room temperature for

30 mjn. The aqueous solution WaS concentrated 'Ln uacuo to a volume of approximately 5-10 ml and the product allowed to crystalljze' affording the tyane bromo?rydr¿n (89) (1.0 g, 56%) as colourless needles. An anaìyticaì sample was prepared by recrystallization twice from acetone/light petroleum and had m.p. 181.5-184" (dec.) (sublìmes 155o) (Found: C,37.8; H,5.3. C7H1;N02ùr requires -1 C, 37.8; H, 5.5%). vru* 3275, 3225, 1650 cm '. N.m.r. ô 10'77' br s, 0-H; 7.43 br s, N-H', 4.15, s, H-CBr; 3.18, m, 2H, N-CHz; 2.?6-1.48, m, 4H, 5-CH2 and 6-CH2; 1.3, s, 3H, Me-C. Mass spectrum nle 22I/223 (M). (88) 3 ,4-Epox.y-4-met hvl -2,3,4,5, 6.7-hexahydro-1H-azepi n-2:qne

METHOD 1. jn The bromohydrin (89) (1.0 g, 4.50 mmol) was dissolved a solut'ion of sodium hydroxide (200 mg, 5.00 mmo'l) in water (50 ml) and the mixture stirred at room temperature for 30 min. The

solution was extracted with ether (3 x 20 ml) and the combined extracts dried, filtered and the solvent removed to gìVe the crude 174 epoxide (88). Distil'lation under reduced pressure yielded (88) as a colourless oil (SlZ mg, g0%),b.p. 97"/0.001 mm (Foundi M*',

141.0784. CzHrrNOz requires M+', 141.0790). uru* (film) 3250 (broad), 1660, 1180 .r-1. N.m.r. ô 7.17, br s, N-H; 3.28, m, 2H, 0 N-CHz overlapping with 3 .22, s, H-Ct 2.32'1.53, m. 4H, 5-CH2 0 and 6-CHz; 1 .40, s , 3H, Ne-C-'C .

METHOD 2

The bromohydrin (89) was prepared from the capro'lactam (13)

(3.17 g,25.4 mmol as described previously and after 30 min solid sodium hydroxide (1.00 g, 25.4 mmol) was added. The mixture was stirred for a further 30 min and then extracted with ether.

Removal of the solvent gave the crude epoxide (88) (2.03g), Distillation under reduced pressure gave 3,4-epoxy-4-methyl -2,3,

4,5,6,7-hexahydro- lH -azepin-2-one (88) (1.5 g which was contaminated with a colourless crystalline solid (0.50 g) whose spectral properties were consistent with it being the cis bxomohydri.n (89). Purification by column chromatography on alumina with dichloromethane followed by recrystaìlization from carbon tetrachloride gave coìourless prismsr ffi.P. 77-100". v--.. 3450, 3200, 3075, 1640 (broad) .t-1. N.m.r. (CCl ,r/Dz0) max ô 4.07, s, lH, H-CBr; 3.13, m, 2H, N-9Hr; 2.60-1.68, m, 4H,

5-CH2 and 6-CHz; 1.50, s, 3H, Me-C-OH. Mass spectrum m/e I47 (M-Br).

4-Hydroxy -4-methyl -3-phenyl methyl ami no- 2,3 ,4,5 ,6 ,7-hexahydro-1H- azepi n-2-one (eOa).

(i) The bromohydrin (89) (2.4 g, 10.8 mmol) and benzylamine

(1.169, 10.8 mmoì) were dissolved in water (25 ml) containing L75

sodium bicarbonate (900 mg, 10.7 mmol) and the solution refluxed for 2h. The mixture was then cooled and extracted with chloroform (3 x 15 ml). Removal of the solvent gave the cis amino- hydroxyoxime (90a) as a colourless sol id (2-20g, 82%). An ana'lyti cal samp'le, prepared by bul b to bul b di sti I I at j on (bl ock temperature 135o/0.001 mm) yielded (90a) as colourless needles, m.p. 141-53o (Found: C, 67 .3; H, 8.4. Ct uHroNz0z requires c, 67.7; H, 8.1%). 'ru* (cH2cl 2) 3300 (broad), 1660, 1610 (weak), 1 1500 (weak) cm-'. N.m.r. ð 7.25, s, 5H, ArH; 6.53, br s, lH, NH; 3.73, ABq, J lZïz,

2H, N-CHz-Ar 3.28, s, 1H, H-C-C=O overlapping with 3 -23, m, 2H,

CH2-N-C=O; 2.28-I.47, m, 6H, 5-, 6- and 7-CHz; 0.97 s, 3H,

Me-C-OH.

4-Methyl - 3 -phenyl methyl ami no-2,5,6,7-tetrah.ydro- lH azepi n-2-one (e1)

A mixture of the hydroxyamine (90a)(500 mg, 2.00 mmol) and anhydrous lithium hydroxide (50 m9,2.08 mmol) was heated under reduced pressure in a bulb to bulb apparatus. The enamine (91) was obtained as an orange oiì (80%), b.p. I25o/0.001' mm (Found:

M+', 230 .1425. cr,*HreNz0 requires M+', 230.1419). ura" (film)

3300 (broad), 1650, 1630, 1490 .t-1. N.m.r. (80MHz) o 2.44, s, 5H, ArH; 6.25, br s, N-H; 3.83, br t,2H, Ar-CHz-N; 3.28, m, 3H, CHz-N-C0 and N-H; 2.45, m, 2H, CHz-C=C; 2.16, !, 3H, Me-C=C; I.78, m, 2H, 6-CHz. 176

3-Aminopropi oni tri I e ( 96) 3-Aminopropionitrile was prepared in 70% y'ield by heating a 2:I (moie rat'io) mixture of calcium oxide and 3-aminopropionitriIe (0.5) fumarate under reduced pressure and collecting the fraction, 110 b. p . 7g-8r" /27 mm ('l i t. 79-81"/ 16 mm) .

2-Ami no- 1 5-di hydro-4H-imì dazol e-4-one (7) Glycocyamidine (7) was prepared as the hydrochloride from the cyc'ljzation of guan'idine acetjc acid in dilute hydrochloric acid.111 Recrystallization from ethanol gave the hydrochloride (g5%) (7) as colourless crystals, m-p. 208-211" (dec.) (tit'111 208-210' dec. ).

Ethvl 3-N - ( 2-pvrrolvlca rbonvl ) ami nopropanoate ( e8) 'in D'icycl ohexy'lcarbodi imi de (927 ng, 4.50 mmol ) dry aceton'itrile (S ml) was added to a mixture of pyrrole-2-carboxylic acid (500 mg, 4.51 mmol) and ethyl 3-aminopropanoate (527 ng, 4.50 mmol) in dry acetonitrile (zo ml). The mixture was then stirred vigôrously at room temperature overnight. The precipitate of N,N ' dì cycl ohexyl urea v,,as removed by f i I trati on and the solution concentrated ín uacuo to give a paìe yellow oil which soliCified on standing. Column chromatography on alumina, wìth chloroform as the eluting solvent, gave the am'iio-esler (98) (889 mg,

94%) which was of suffic'ient purity to be used in the subsequent steps . An ana'l ty'icaì sampl e u,as prepared by recrystal I i zati on

from benzene which yielded (98) as colourless prisms' m'p' 175-179' (sublimes -155") (Found: M+', 2r0.1007. CrqH1aN203 requires

M+" 210.1004). umax 3250 (br), !720, 1620,1560, 1510 cm-1. L77

H N.m.r. 6 10.36, br s, N-C=O; 6.80, m, H-5'; 6.55, 5, H-3'; 6.07, t, H-4'; 4.10, q, J 7Hz, OCHz-Me; 3.62, q, 2\, N-CHz; 2.55, t,2H, CHz-C=O; 1.23, t', J 7Hz, OCHz-Me.

N- ( 2-cy anoethvl ) -2-pvrrol ecarboxami de (e7 )

The titìe compound was prepared as described for (98) from 3-aminopropionitrile and pyrrole-2-carboxylic acid jn a mjxture of acetonitrile and tetrahydrofuran. The crude product was purified

by column chromatography on alumina using dichloromethane as the eluting solvent to give N-(2-cyanoethyl )-2-pyrrolecarboxam'ide (97) as a pale yellow oil (90%) which crystallized on standing. An analtyica'l sample was prepared by recrystalf ization f irst from ethy'l acetate/light petroleum then ethyl acetate as pale yel'low plates, m.p. 146-147" (Foundi C,58.8; H,5.5. CBHsN30 requires C,58'9; H, 5.6%). v,nu* 3375, 3210 (broad),2250, 1640, 1630, 1560, 1535.t-1"

N.m.r. (CDCI s/CDsS0CD3) o g.98, br s, NH pyrroìe; 6'90, m, lH, H-5'; overlapping with 6.80, m, 1H, H-3'; 6-20, m, lH, H-4'; 3'62, q, 2H, NH-CHz; 2.65, t , 2H, CH2-CN. Mass spectrum m/e 163 (M) '

3-N- ( 2- rrol vl carbonvl )aminooropanoic acid (17) The ester (98) (6.00 9,28.57 mmol) was added to a solution of sodium hydroxide (2.29 g, 57.14 mmol) in water (10 ml) and the mixture warmed in a water bath until it became

homogeneous (10-15 min). The solution was stirred for a further 5 min, cooled and acidified wjth concentrated hydrochloric acid to pH 2. The aqueous solution was saturated with solid sodium chloride and extracted with a mixture of tetrahydrofu.ran and ethyì acetate

(1:1). Removal of the solvent gave a crude acid (17) (2.80 9,54%) 178 as a pale yellow oit which crystalljzed on standing. Recrystallization from ethyl acetate/light petroleum gave 3-N-(2-pyrrolylcarbonyl )- aminopropanoic acid (17) as colourless needles,m.p. 148-150o

(Found: M+' , r82.0690. caHroNr0g requires M+' , !82.0691) ' uru* (film) 3420,3350, 3500-2500 (broad), 1710, 1590 (broad), 1540 cm-l. N.m.r. (CDCI r/CD3SOCO.)o r+.00, br s, CgzH; 10'68, br s, N-H pyrro'le; 7.32, br t, NH-C0; 6.78, m, H-5'; 6' 62, m, H-3'; 6.05, m, H-4'; 3.58, q, 2H, N-CHz 2'55, t, 2H, CH2-C02H'

Pyrrol o 4.5lazenin-6,10-dione (3)

A mixture of the acid (17) (585 mg' 3.21 mmol) and polyphosphoric acid (75 g) was heated while being stirred vigorously at 95o for 30 min under an atmosphere of nitrogen. The mixture was cooled, ice (- 30 g) added and the resuìting soìution neutralized with solid sodium carbonate. Extraction of the mixture with tetrahydrofuran and removal of the solvent gave (3) as a brown solid (300 mg, 57%1. Column chromatography on alumina with methanol gave (3) as a pale ye'llow solid which was of sufficient purity to be used in the subsequent steps. A small sampìe was recrystallized from ethanol to give (3) as plates which subl'imed at

zs¡./760 mm and had m.p. and mixed m.p.98 294-296" (lit.r 275-277o, l'it.7 269") (Foundr M{', 164.0589. cBHsNz02 requ'ires M+',

164.0586). umax (CDCI3) 3425, 3275, 3075 (weak), 1650, 1640, 1560 cm-l. N.m'r' (cDClr/CD3SoCD.)o B'13' br s' NH; 6'83' d' J 3Hz, H-2; 6.53, d, J3Hz, H-3i 4.2, br s, NH-CO; 3'33, m,2H,

N-CH2; 2.66, m , 2H, CH2-C=0. 179

Attemp ted reaction of pvrroloazepinedione (3) wi th ql ycoc.yami di ne hydrochloride (7). A mixture of the pyrroìoazepinedione (3) (tOO mS, 0.61 mmol), g'lycocyamidìne hydrochloride (83 mg, 0.61 mmol) and sodium acetate

(100 mS, I.?2 mmol) in acetic acid (5 ml) was heated at reflux for 3h. The acetic acid was removed under reduced pressure and the res'idue d j ssol ved 'in methanol and chromatographed on al umi na . This gaverafter removaì of the soìvent,a colourless oil which 'large solidified on standing (-140 mg) (tfiis solid contained a amount of sodiunr acetate). A smalì sampìe h,as sublimed at

190-200"10.05 mm to give a compound consistent w'ith the structure

4- 2- ce I ami no-4-oxo-2-i mi dazoI i n-5- I -4- -4 5 6 7- tetrahydropyrro'l o[2,3, -C] azepi n-8-one

(100), ffi.p . 220-245o(oec.) (Found: C, 52.0; H, 5.2; N, 21.9.

Cr.sHrsNs0+ requ'ires C, 5!.2; H, 5.0i N, 22.9%). umax 3200, 3400-2500, I700 (broad), 1660, 1650, 1600 .t-1. N.m.r. (CD3SOCD3,

300 MHz) ô 8.30, br s, lH, NH; 6.96, t, J 3Hz, lH, H-2; 6-55, t, J 3Hz, lH, H-3; 3.79, s, lH,CH-C=O; 3.34, m,2H, CHz-CONH; 2.69, m, 2H, 5 -CXz; 2.2L, s, 3H, NH-COMe. Mass spectrum (180"/18eV) , mle (re]ative intensity) 220 (32), 206(16), 205(100), 164(46), 136(17), 107(25) , 60(72). Attempted react ion of 1-acetvlovrrolo[4.5lazepine-6.10-dione (101) with ql.ycocyamidjne (7)

A mjxture of the pyrroloazepinedione (3) (100 mg, 0.61 mmol ) acetic anhydrìde (10 ml) and sodium acetate (50 mg) was refluxed

t An accurate analysis could not be obtained due to lack of sampl e. 180 for I hour. Examination of the reaction mixture by t.ì.c. (a'lumina using methanoì as the developing solvent) showed that the startìng material had disappeared to be rep'laced by a new spot of h.igher Rr. Sodium acetate (100 mg, I.22 mmol) followed by gìycocyam'idine hydrochloride (83 m9, 0.61 mmol ) was added and the mixture heated at 130" for 6h. The acetic anhydrìde was evaporated under reduced pressure, rep'laced with acetjc ac'id (10 ml) and the solution heated at 130o for a further 2h. The solvent was removed once more and the mixture neutralized wìth dilute potassium carbonate solutjon then adiusted to pH9 with dilute sodium hydroxide. The solution was saturated with solid sodium chloride and extracted with tetrahydrofuran (g x tO ml).

Removal of the solvent gave a dark brouln oil which was subjected to column chromatography on alumina. Elution with methanol gave a pale brown oil which crystallized on standing (110 m9,88%)' A small sample was purifìed by sublimation (190-200'/760 mm) to give 1-ac I pyrrol o[4 ,5 lazepi n-6 .10-di one ( 101 ) as col ourl ess needles, m.p. ?27-23L (subljmes L90o) (Found: M+' , 206.0690' CroHroNr0, requ'ires M+' , 206.0691). vru* 3230, 1690, 1680, 1640 lH .r-1. the n.m.r. spectrum (CDCIr/(CDr)rS0) showed a downfield sh'ift of the doublet (J 3Hz) at ô 6.83 to ô 7.18 corresponding to H-2 of the acetylated material. REFERENCES 181

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PUBL ICATIONS

Part of the work described in this thesis has been reported in the following publicatjon:

"A 'Classical' Approach to the Synthesis of Perloline", Kasum, B. and Prager, R.H., Aust.J.Chen., 1983 , 36, 1455. Kasum, B. & Prager, R. H. (1983). A 'classical' approach to the synthesis of perloline. Australian Journal of Chemistry, 36(7), 1455-1467.

NOTE:

This publication is included in the print copy

of the thesis held in the University of Adelaide Library.

It is also available online to authorised users at:

http://dx.doi.org/10.1071/CH9831455